[House Hearing, 108 Congress]
[From the U.S. Government Printing Office]
FDA'S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA'S REVIEW OF
SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN
=======================================================================
HEARING
before the
SUBCOMMITTEE ON
OVERSIGHT AND INVESTIGATIONS
of the
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED EIGHTH CONGRESS
SECOND SESSION
__________
SEPTEMBER 23, 2004
__________
Serial No. 108-125
__________
Printed for the use of the Committee on Energy and Commerce
Available via the World Wide Web: http://www.access.gpo.gov/congress/
house
__________
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COMMITTEE ON ENERGY AND COMMERCE
JOE BARTON, Texas, Chairman
W.J. ``BILLY'' TAUZIN, Louisiana JOHN D. DINGELL, Michigan
RALPH M. HALL, Texas Ranking Member
MICHAEL BILIRAKIS, Florida HENRY A. WAXMAN, California
FRED UPTON, Michigan EDWARD J. MARKEY, Massachusetts
CLIFF STEARNS, Florida RICK BOUCHER, Virginia
PAUL E. GILLMOR, Ohio EDOLPHUS TOWNS, New York
JAMES C. GREENWOOD, Pennsylvania FRANK PALLONE, Jr., New Jersey
CHRISTOPHER COX, California SHERROD BROWN, Ohio
NATHAN DEAL, Georgia BART GORDON, Tennessee
RICHARD BURR, North Carolina PETER DEUTSCH, Florida
ED WHITFIELD, Kentucky BOBBY L. RUSH, Illinois
CHARLIE NORWOOD, Georgia ANNA G. ESHOO, California
BARBARA CUBIN, Wyoming BART STUPAK, Michigan
JOHN SHIMKUS, Illinois ELIOT L. ENGEL, New York
HEATHER WILSON, New Mexico ALBERT R. WYNN, Maryland
JOHN B. SHADEGG, Arizona GENE GREEN, Texas
CHARLES W. ``CHIP'' PICKERING, KAREN McCARTHY, Missouri
Mississippi, Vice Chairman TED STRICKLAND, Ohio
VITO FOSSELLA, New York DIANA DeGETTE, Colorado
STEVE BUYER, Indiana LOIS CAPPS, California
GEORGE RADANOVICH, California MICHAEL F. DOYLE, Pennsylvania
CHARLES F. BASS, New Hampshire CHRISTOPHER JOHN, Louisiana
JOSEPH R. PITTS, Pennsylvania TOM ALLEN, Maine
MARY BONO, California JIM DAVIS, Florida
GREG WALDEN, Oregon JANICE D. SCHAKOWSKY, Illinois
LEE TERRY, Nebraska HILDA L. SOLIS, California
MIKE FERGUSON, New Jersey CHARLES A. GONZALEZ, Texas
MIKE ROGERS, Michigan
DARRELL E. ISSA, California
C.L. ``BUTCH'' OTTER, Idaho
JOHN SULLIVAN, Oklahoma
Bud Albright, Staff Director
James D. Barnette, General Counsel
Reid P.F. Stuntz, Minority Staff Director and Chief Counsel
______
Subcommittee on Oversight and Investigations
JAMES C. GREENWOOD, Pennsylvania, Chairman
MICHAEL BILIRAKIS, Florida PETER DEUTSCH, Florida
CLIFF STEARNS, Florida Ranking Member
RICHARD BURR, North Carolina DIANA DeGETTE, Colorado
CHARLES F. BASS, New Hampshire TOM ALLEN, Maine
GREG WALDEN, Oregon JANICE D. SCHAKOWSKY, Illinois
Vice Chairman HENRY A. WAXMAN, California
MIKE FERGUSON, New Jersey EDWARD J. MARKEY, Massachusetts
MIKE ROGERS, Michigan JOHN D. DINGELL, Michigan,
JOE BARTON, Texas, (Ex Officio)
(Ex Officio)
(ii)
C O N T E N T S
__________
Page
Testimony of:
Knudsen, James, Food and Drug Administration; accompanied by
Robert Temple, Food and Drug Administration; Paul Seligman,
Food and Drug Administration; Thomas Laughren, Food and
Drug Administration; and Tarek Hammad, Food and Drug
Administration............................................. 64
Mosholder, Andrew D., Food and Drug Administration........... 21
(iii)
FDA'S ROLE IN PROTECTING THE PUBLIC HEALTH: EXAMINING FDA'S REVIEW OF
SAFETY AND EFFICACY CONCERNS IN ANTI-DEPRESSANT USE BY CHILDREN
----------
THURSDAY, SEPTEMBER 23, 2004
House of Representatives,
Subcommittee on Oversight and Investigations,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to notice, at 11:05 a.m., in
room 2123, Rayburn House Office Building, Hon. Joe Barton
(chairman) presiding.
Members present: Representatives Bilirakis, Stearns, Bass,
Walden, Ferguson, Rogers, Barton (ex officio), Deutsch,
DeGette, Allen, Schakowsky, and Waxman
Also present: Representative Stupak.
Staff present: Mark Paoletta, majority counsel; Alan
Slobodin, majority counsel; Kelli Andrews, majority counsel;
Joby Fortson, majority counsel; Billy Harvard, majority staff
assistant; David Nelson, minority investigator; and Jessica
McNiece, minority research assistant.
Chairman Barton. Today we are continuing a series of
hearings on FDA's role in protecting the public health,
examining the FDA's review of safety and efficacy concerns in
anti-depressant use in children.
As part of this committee's jurisdiction over public
health, the subcommittee today will examine the FDA's process
in determining the safety and public health concerns of anti-
depressants in children.
The controversy over the use of anti-depressants in
children is of great public interest. Over 10 million children
a year are prescribed anti-depressants in the United States.
The committee's interest in this issue began in January of this
year in response to media reports about the concerns over the
safety and efficacy of anti-depressants used by children.
One month earlier, in December 2003, British regulators
contra-indicted all anti-depressants for children except Prozac
due to the risk-benefit analysis of safety concerns related to
suicidal behavior coupled with a weak showing of efficacy.
Despite the action taken by British regulators in December
2003, at that time in the United States there appeared to still
be substantial support in the medical community for the use of
anti-depressants in children and for the belief that these
drugs saved children's lives.
The U.S. psychiatric establishment had repeatedly assured
the public that the drugs are very safe. At around the same
time that the British regulators announced their decision, an
internal FDA analysis of the pediatric clinical trials of these
drugs did show an increased risk of suicide related events, and
seemed to be at odds with these assurances of safety.
This analysis was prepared by a medical review officer
specializing in pediatric anti-depressants named Dr. Andrew
Mosholder. Dr. Mosholder was first requested in June 2003 by
the Neuropharm Division of FDA to perform this consult after
GlaxoSmithKline provided the FDA and other regulatory agencies
with an internal analysis showing an increase in suicidality
during their pediatric clinical trials of the anti-depressant
Paxil.
The Neuropharm Division requested that Dr. Mosholder review
the Paxil data as well as the data from other pediatric
clinical trials to determine whether the signal was limited to
Paxil or whether other anti-depressants showed a similar
association.
In September of this year--excuse me, in September 2003 Dr.
Mosholder informed the agency at an internal briefing of his
preliminary conclusions. He concluded that the pediatric
clinical data showed an association between children taking the
drug and suicide related behavior.
Dr. Mosholder completed a second consult in December 2003
which confirmed his preliminary findings reported in September.
Although initially scheduled to present his findings at a
February 2004 Advisory Committee meeting, the purpose of which
was to publicly discuss how the agency should handle the safety
issues raised in pediatric anti-depressant trials, Dr.
Mosholder was informed in early January of this year he would
not be presenting at the Advisory Committee.
It is my understanding that the individuals within the
Neuropharm Division, who incidentally were in charge of this
February meeting, told Dr. Mosholder that they had, ``reached a
different conclusion'' about the data. As a result of this
disagreement, he was prevented from presenting his analysis
before the FDA Advisory Committee.
The first question that this raises is quite simple: Why?
Isn't an Advisory Committee a panel of experts? Aren't those
people capable of hearing different points of view and making
decisions? What was the harm in allowing Dr. Mosholder an
opportunity to present his data, his analysis, and his opinion
to a group of experts?
I am looking forward to hearing from Dr. Mosholder and some
of the other FDA witnesses about these issues to get to the
very heart of this matter.
On September 13, 2004, which was just several weeks ago,
the FDA convened another meeting of the Advisory Committee to
consider the question again, whether there was an increased
risk of suicide related behavior in children taking anti-
depressants. This time at this meeting, Dr. Mosholder did
present his data.
As I understand it, the FDA also presented another analysis
recently completed by Dr. Hammad. Both Dr. Hammad's analysis
and Dr. Mosholder's December 2003 analysis essentially reached
the same conclusions. There is an increase in suicide related
behavior with children taking anti-depressants.
Let me repeat that. Their two analyses essentially reached
the same conclusions. There is an increase in suicide related
behavior with children taking anti-depressants. The agency now
acknowledges this association.
Where do we go from here? The FDA has now looked at the
issue in depth and has indicated that they are just about ready
to announce a final course of action. What that course of
action is and when it will be implemented are two questions
this committee is very interested in knowing.
Will we have a black box on these drugs? Will we have a new
and stronger warning label? Will we have a pamphlet, known as a
Med Guide, attached to the drug? Will we contra-indict the drug
like they did in Britain when they banned it from pediatric
populations? Will we have an informed consent form signed by
the patient, parent and physician? These are all questions that
need to be addressed at today's hearing.
We look forward to getting answers to these questions and a
better sense of direction about where the FDA is going.
One final issue that I want an answer today from the FDA:
When the FDA first become aware of the potential link between
anti-depressants and suicidality in children, and what did they
do to get to the bottom of it?
Throughout our investigation, we have learned that as far
back as 1996, 8 years ago, a medical review at FDA, Dr. James
Knudsen, raised the question of an increase in suicidality in
pediatric clinical trials of a drug called Zoloft. There was
also an analysis in 1997 of Luvox, another anti-depressant,
where the review, the same Dr. Mosholder, noted that there was
an increase in hostility in children versus adults. The issue
is noted in the Luvox labeling as a result.
The fact that children taking anti-depressants were
experiencing psychiatric adverse events at greater rates than
adults was known at the agency as far back as 1996 and 1997.
This committee wants to know what did the agency do to respond
to these concerns? Did they require that pediatric clinical
trials conducted pursuant to the Best Pharmaceuticals for
Children Act be designed to capture these types of safety
issues? If not, why not? Did the agency alert their medical
reviewers to this potential issue, tell them to look closely at
that type of data that the companies were submitting in their
pediatric trials? If not, why not?
I hope that today we will be able to view the whole picture
concerning anti-depressants and their effect on children as
well as the FDA approval process as a whole. The FDA's task is
quite commendable. It is not easy. They are entrusted with
being the guardians of our safety. That is a very difficult
trust to maintain.
As Members of Congress, it is our duty to ensure through
the oversight process that the FDA undertake this task in an
earnest and diligent and, I might also say, an open and
transparent fashion. We must ensure that the FDA fulfills its
public health role and its public trust.
The FDA serves the American people. We are the client. The
mission of the FDA is not to protect the FDA's internal
workings, but to promote and protect the public health by
helping safe and effective products reach the market by
monitoring for safety, by disclosing the accurate, science
based information, and for providing this in a clear and
concise and timely fashion to the American people.
Is the FDA accomplishing its mission with anti-depressants
used by children? I would have to say the record is open on
that, and I would say that, unless we get some very straight
answers at today's hearing, it is probably going to be answered
that the FDA is not fulfilling its mission in this particular
issue.
At the September 9 hearing concerning the publication of
anti-depressant clinical trial data, I was upset with the FDA's
lack of full cooperation with the documentation production
process pursuant to this committee's request. Since that
hearing, I have met with the Acting FDA Commissioner, Dr.
Lester Crawford, about the issue of FDA's cooperation in this
matter.
I would like to take note that, since that meeting, there
has been improvement in the FDA's cooperation in document
production, and for that I want to thank Dr. Crawford publicly.
I also want to thank Dr. Crawford for his assistance with
securing the appearances of some of the witnesses that will be
speaking today.
Finally, I would like to thank the FDA in their diligence
to responding to several member questions that were raised at
the September 9 hearing.
Having said that, I must say that we continue to be
somewhat surprised when we questioning them about their policy
of document retention at the FDA. The answer we got back was,
in writing, that they had none--that they have no policy for
document retention, which is something that we still need to
address with them.
I must say, though, that since the last hearing the FDA is
cooperating much more cooperatively with this committee, and
again for that I want to thank all of our FDA representatives.
[The prepared statement of Hon. Joe Barton follows:]
Prepared Statement of Hon. Joe Barton, Chairman, Committee on Energy
and Commerce
As part of the Committee's jurisdiction over public health, the
Subcommittee today will examine the Food and Drug Administration's
(FDA's) process in determining the safety and public health concerns of
anti-depressants in children.
The controversy over the use of anti-depressants in children is of
great public interest. Over 10 million children a year are prescribed
anti-depressants in the United States. The Committee's interest in this
issue began in January of this year in response to media reports about
the concerns over the safety and efficacy of anti-depressants used by
children. One month earlier, in December 2003, British regulators
contraindicated all anti-depressants for children, except Prozac, due
to the risk-benefit analysis of safety concerns related to suicidal
behavior coupled with a weak showing of efficacy.
Despite the action taken by British regulators in December of 2003,
at that time, in the United States there appeared to still be
substantial support in the medical community for the use of
antidepressants in children, and for the belief that these drugs save
children's lives. The U.S. psychiatric establishment had repeatedly
assured the public that the drugs are very safe. At around the same
time that the British regulators announced their decision, an internal
FDA analysis of the pediatric clinical trials of these drugs showed an
increased risk of suicide-related events and seemed to be at odds with
these assurances of safety. This analysis was prepared by a medical
review officer specializing in pediatric anti-depressants named Dr.
Andrew Mosholder. Dr. Mosholder was first requested in June 2003, by
the Neuropharm division of FDA to perform this consult, after
GlaxoSmithKline provided the FDA and other regulatory agencies, with an
internal analysis showing an increase in suicidality during their
pediatric clinical trials of the anti-depressant Paxil. The Neuropharm
division requested that Dr. Mosholder review the Paxil data, as well as
the data from the other pediatric clinical trials, to determine whether
the signal was limited to Paxil or whether other anti-depressants
showed a similar association. In September 2003, Dr. Mosholder informed
the agency at an internal briefing of his preliminary conclusions: the
pediatric clinical data showed an association between children taking
the drug and suicide-related behavior. Dr. Mosholder completed a second
consult in December 2003, which confirmed his preliminary findings
reported in September. Although initially scheduled to present his
findings at a February 2004 Advisory Committee meeting-the purpose of
which was to publicly discuss how the agency should handle the safety
issues raised in pediatric anti-depressant trials-Dr. Mosholder was
informed in early January 2004, he would not be presenting at the
Advisory Committee meeting. It is my understanding that individuals
within the Neuropharm Division, who incidentally were in charge of this
February meeting, told Dr. Mosholder-they had ``reached a different
conclusion'' about the data. As a result of this disagreement, he was
prevented from presenting his analysis before the FDA Advisory
Committee.
The first question this raises is simply: why? Isn't an Advisory
Committee a panel of experts? Aren't those people capable of hearing
differing points of view and making decisions? What was the harm in
allowing Dr. Mosholder an opportunity to present his data, his analysis
and his opinion to this group of experts? I am looking forward to
hearing from Dr. Mosholder and some of the other FDA witnesses about
these issues, to get to heart of this matter.
On September 13, 2004, the FDA convened another meeting of the
Advisory Committee to consider the question again: whether there was an
increased risk of suicide-related behavior in children taking anti-
depressants. This time, at this September meeting, Dr. Mosholder did
present his data. As I understand it, the FDA also presented another
analysis, recently completed by Dr. Hammad. Both Dr. Hammad's analysis
and Dr. Mosholder's December 2003 analysis essentially reached the same
conclusions-there is an increase in suicide-related behavior with
children taking anti-depressants. The agency now acknowledges this
association.
Where do we go from here? The FDA has now looked at the issue in
depth and has indicated that they are just about ready to announce a
final course of action. What that course of action is, and when will it
be implemented-are two questions I am very interested to know. Will we
have a ``black-box'' on the drugs? Will we have a new and stronger
warning label? Will we have a pamphlet, known as a ``Med Guide,''
attached to the drug? Will we contraindicate the drug like they did in
Britain when they banned it from the pediatric population? Will we have
an informed consent form signed by patient, parent and physician? I
look forward to getting feedback on these questions and a better sense
of that direction today.
One final issue that I want an answer from FDA today: When did the
FDA first become aware of a potential link between anti-depressants and
suicidality in children and what did they do to get to the bottom of
it? Through our investigation, we have learned that as far back as
1996, a medical reviewer at FDA-a Dr. James Knudsen--raised the
question of an increase in suicidality in pediatric clinical trials of
Zoloft. There was also an analysis in 1997 of Luvox-another anti-
depressant-where the reviewer, the same Dr. Mosholder, noted that there
was an increase in hostility in children versus adults. This issue was
noted in the Luvox labeling as a result.
The fact that children taking anti-depressants were experiencing
psychiatric adverse events-at greater rates than adults-was known at
the agency as far back as 1996 and 1997. I want to know: What did the
agency do to respond to these concerns? Did they require that pediatric
clinical trials conducted pursuant to the Best Pharmaceuticals for
Children Act be designed to capture these types of safety issues? If
not-why not? Did the agency alert their medical reviewers to this
potential issue and tell them to look closely at that type of data the
companies submitted in pediatric trials? If not-why not?
I hope that after today we will be able to view the whole picture
concerning antidepressants and their effect on children, as well as the
FDA approval process as a whole.
The FDA's task is quite commendable and not easy. They are
entrusted with being guardians of our safety. As Members of Congress,
it is our duty is to ensure through the oversight process that this
vital agency undertake this task in an earnest and diligent manner. We
must ensure that FDA fulfills its public health role. The FDA serves
the American people. We are the client. The mission of the FDA is not
to protect the FDA, but to promote and protect the public health by
helping safe and effective products reach the market, by monitoring for
safety, and by disclosing accurate, science-based information. Is FDA
accomplishing its mission with anti-depressants used by children?
At the September 9th hearing concerning the publication of anti-
depressant clinical trial data, I was upset with the FDA's lack of full
cooperation with the document production process pursuant to the
Committee's request. Since that hearing, I have met with Acting FDA
Commissioner Dr. Lester Crawford about the issue of FDA's cooperation
in this matter, and I would like to note that since that meeting, there
has been some improvement, in FDA's cooperation and document
production. I also want to thank Dr. Crawford for his assistance with
securing the appearances of some of witnesses that will be speaking
today. Finally, I would like to thank the FDA in their diligence in
responding to several member questions that were raised at the
September 9th hearing.
However, if FDA does not continue this cooperation, I will be
forced to address this issue again just as I did at the September 9th
hearing. Nevertheless, I am hopeful that we can continue to move
forward on improved document production from the agency.
Once again, I would like to thank the witnesses for appearing today
and the other members present today, and I look forward to this
hearing.
Chairman Barton. I would now like to turn to our ranking
member, Mr. Deutsch for any opening statement that he wishes to
make.
Mr. Deutsch. Thank you, Mr. Chairman, for holding this
hearing and its counterpart earlier this month.
The September 9 hearing dealt with the fact that the FDA
and drug companies withheld from the public the important
information that all but one of the pediatric trials of anti-
depressants failed to show efficacy in adolescents. Sadly, we
got no good answers from the FDA witness at that time, Dr.
Woodcock.
Today we deal with the critical question of the safety of
these potent medications in children. Specifically, we need to
understand if the risk of suicidal behavior of teens taking
SSRIs is greater than the suicide risk associated with a
failure to take these anti-depressants.
That is exactly the kind of straightforward, scientific
question that the Congress expects FDA to answer for the
American people. Unfortunately, the FDA has handled the
decisions involving both the safety and efficacy of these drugs
in adolescents in such an unscrupulous manner that it is very
hard for anyone to accept that objective science is the basis
of the agency's conclusions.
Consider that the FDA extended the monopoly status of these
drugs for 6 months, costing American taxpayers and consumers
over $4 billion, and then decided that the public didn't even
need to know that all but one of these drugs could not
demonstrate efficacy.
The only labeling change was for Prozac, the only SSRI
shown to work at all in kids. Shockingly, the FDA made a
deliberate decision to withhold information on the clinical
failures from parents as well as pediatricians and other
prescribers. But it gets even worse.
When Wyeth found evidence of elevated risk of suicidal
ideation and hostility among adolescents taking its drug and
tried to change its label to warn parents and providers about
this increased danger, the FDA said no label change to reflect
those warnings is permissible.
It is incredible that this agency charged with protecting
the public health would stop a company from warning the public
about risks associated with the use of its products by
children. But the FDA was far from finished with its cover-up
at that point.
As information flooded in from the industry and the British
authorities who had banned the use of these drugs in kids, the
FDA began a review of the 15 studies that had been done on
pediatric use of SSRIs. They turned the project over to a
scientist, Dr. Andrew Mosholder, a medical doctor, psychiatrist
and epidemiologist in the Office of Drug Safety.
Dr. Mosholder's analysis of multiple studies concluded that
there was indeed an elevated risk of suicidal behavior
discernible from the pediatric studies. Dr. Mosholder was
scheduled to present his findings before the Advisory Committee
charged with recommending action to the FDA on anti-depressant
drugs in February.
Someone within the FDA did not want those conclusions to be
public and ripped his presentation from the program. Perhaps it
was the same people who thought Wyeth shouldn't warn the public
either. The FDA excuse was that the underlying data needed to
be examined more critically before such a sensational
conclusion could be broached publicly.
When the San Francisco Chronicle got wind of the story that
the FDA had squelched its own investigator's report, the real
cover-up began. Both this subcommittee and the Senate Finance
Committee chaired by Senator Grassley began inquiries, but even
as Congress was gearing up, senior officials within the FDA
decided to conduct a witch hunt.
They sent criminal investigators to probe the source of the
leak. It is readily apparent that the probe was not about
information but, rather, about intimidation. It was a warning
to Dr. Mosholder and other dedicated epidemiologists at the
Office of Drug Safety, and the ostensible initiating officer
was the Director of the Office of Drug Safety.
When we authorized the Prescription Drug User Fee Act in
the last Congress, the clear tradeoff for the continuing rapid
review and approval of new drug applications was that the FDA
would place a renewed emphasis on post-marketing surveillance
to detect safety problems with drugs just as soon as they
emerged.
The Mosholder investigation is a substantive demonstration
that drug safety remains a stepchild in the FDA-drug company
partnership at the Center for Drug Evaluation and Research. But
it gets even worse.
To be clear, the events I am about to describe involve
response to requests from Senator Grassley, although I have no
doubt that, had this ploy succeeded, false documents would have
been supplied to this committee as well.
Andy Mosholder was forced to supply a statement to the
Office of Internal Affairs regarding the events surrounding the
decision to remove his analysis from the Advisory Committee's
agenda and the leaking of that story to the Chronicle. This
document was apparently in response to a request from Senator
Grassley.
Apparently, officials in the FDA Office of Legislative
Affairs and the Office of Chief Counsel met to decide how to
respond. They decided that not only should the Mosholder
affidavit be redacted, but that a new document needed to be
created to hide the fact that an investigation had even taken
place.
Ultimately, Dr. Mosholder on advice of his personal counsel
declined to sign the phony document suggested and drafted by an
FDA lawyer. Had Dr. Mosholder not acted to thwart the
submission of an altered document to a bona fide Congressional
investigation, a criminal act of obstruction of justice would
have occurred. As it was, the FDA and its lawyers are only
guilty of attempting to obstruct justice.
As you are well aware, Mr. Chairman, the FDA has
stonewalled lawful requests from this committee regarding
documents in the past. It has also slow-rolled and stonewalled
our requests for interviews.
I applaud the determination that you have shown to get to
the bottom of this, despite the obstruction that has been
employed by FDA and its attorneys. As a result of this
committee's efforts, the Advisory Committee did receive the
Mosholder analysis last week, as well as subsequent analysis
done by Dr. Tarek Hammad. That reached the same conclusion.
As we are all well aware, the Advisory Committee
recommended that a black box warning of increased suicide risk
in children be attached to the labels of these drugs, and that
patients be informed of the increased risk when each
prescription is dispensed. They also recommended that each drug
that has failed its efficacy test be so labeled.
I expect that the FDA will tell us at this hearing that it
will adopt the recommendations of its Advisory Committee. if
so, this may be an appropriate result. But for the
investigations by Congress, specifically this committee, and
the media, I doubt that we would have reached the level of
public knowledge and concern that has prompted this result.
Mr. Chairman, I congratulate you on the witness panel you
have assembled before us today. I hope that the Secretary will
provide us with an accurate account of events that were exposed
today.
There is something terribly rotten at the FDA. No agency
charged with protecting the public health should behave with
such indifference to the public safety as is evidenced in this
case, and no agency should ever treat Congress with the
disrespect shown by the FDA during the course of this
investigation.
Again, Mr. Chairman, you are to be applauded for your
determination and commitment to the public interest in pursuing
this difficult inquiry.
Chairman Barton. Thank you, Mr. Deutsch, and let me say
before I recognize our vice chairman: This has been a
bipartisan effort. Mr. Deutsch has been applauding me, but it
is actually the entire subcommittee and the staffs on both
sides. We have worked together on this, and we are finally
beginning to get the truth out to the American people.
With that, I would like to recognize the distinguished vice
chairman of the committee, Mr. Walden, Mr. Greg Walden, for an
opening statement.
Mr. Walden. Thank you, Mr. Chairman. I thank you for
holding this second hearing on the safety and efficacy concerns
of anti-depressants in children.
Giving parents and doctors as much information about the
benefits or lack thereof and the risks associated with drugs
that are being prescribed for millions, tens of millions, of
our Nation's children should be at the forefront of FDA's
mission. I am troubled by issues raised at the last hearing
about what information is on the label of these drugs and what
information was publicly presented to doctors and parents about
these pediatric anti-depressant trials.
Testimony from certain pharmaceutical companies at the last
hearing raised two issues that I would like the agency to fully
discuss today. The first question is about stronger warnings.
As I understand it, in August 2003, Wyeth Pharmaceuticals
issued a ``Dear Health Care Provider'' letter to more than
450,000 health care practitioners warning them of increased
hostility in children taking Efexir and recommending that it
not be prescribed to anyone under 18 years of age. Wyeth also
added a stronger warning to their label reflecting this safety
issue.
Approximately 8 months later when the FDA finally decided
to change the warnings on all the labels of all anti-
depressants, they required Wyeth to remove--to remove this
stronger labeling. What this tells me is the regulatory agency
charged with protecting the public health is preventing a
company from disseminating important safety information to
parents, the public and physicians.
I want answers from the folks at the Neuropharm Division at
FDA that made this decision to explain their rationale for it.
The second question concerns efficacy. In testimony from
various pharmaceutical companies at the last hearing, it became
clear that many companies--in fact, most except Eli Lilly--
conducted anti-depressant clinical trials in kids that showed
no efficacy. That is why none of the anti-depressants except
Prozac is approved by the FDA for use in treating depressed
kids.
Yet the FDA also decided not to allow the companies'
product labeling to state that clinical trials conducted in
kids did not demonstrate efficacy. The question is why? Why
wouldn't you put that on the label? Why shouldn't the label
reflect that information?
I note that the Advisory Committee just recommended that
this labeling change take place, but the point is that the FDA
knew about the lack of efficacy in these trials several years
ago, and nothing has been done to change the label to inform
doctors, patients and parents of this finding.
I am also interested to learn more about the FDA Advisory
Committee process and the recommendations that the Advisory
Committee made last week concerning how to notify the public
that clinical trial data indicate that there is an increased
risk of suicide related behavior in children that take anti-
depressants.
I was struck by the press release that the FDA sent out on
September 16, just a few days after their Advisory Committee
meeting. Now in that release, the FDA states, ``that it
generally supports''--generally supports--``the recommendations
of the Advisory Committee.'' Generally supports? To me, that
sounds like the FDA has some doubts about the Advisory
Committee's recommendations.
So I would like to know if the FDA has reservations about
these recommendations; if so, what they are, and why. I would
also like to know more about FDA's characterization of the
Advisory Committee's 15 to 8 vote as, ``a split decision'' on
whether a black box warning label should be on the labels of
SSRIs.
Now it is my understanding that a black box warning will
alert doctors, patients and parents about the risks of taking
these drugs without preventing these drugs from being
prescribed to depressed children. Now here in the House, if you
get a 15 to 8 vote, a 2 to 1 margin, that is a pretty
significant vote, not generally described as a split decision.
So it is my question as to how that is being described and
why in the FDA's press release. Is the FDA going to follow the
clear majority recommendation and implement this labeling
change and, if not, why? It is my understanding that Dr. Temple
and Dr. Laughren will be able to address these questions.
Finally, I hope to get some answers from the agency about
the timeline of events in terms of what they told the public
about safety concerns raised within the agency about children
taking these drugs, and then when they told the public.
As we know, the British drug regulatory agency seemed to
act much swifter on this than the FDA with the same data. So I
think it is a fair question to ask this agency: Was the public
health served by a longer deliberative process in this case?
I also would like to know why the agency made the decision,
as you have heard from my colleagues, to prevent Dr. Mosholder
from presenting the findings from his extensive 6-month
analysis of data on SSRI clinical trials at the February 2004
Advisory Committee meeting.
So I will be interested in hearing Dr. Mosholder's
perspective on his consult, why he believed the safety signals
were robust even in December 2003, and how he believes his
consult would have contributed to the February Advisory
Committee's deliberative process.
We have many witnesses from the FDA today, and I am hopeful
they will provide a more complete picture of this process and
answer these questions that are on our minds and those of the
people we represent. I thank them for being here, and I thank
you, Mr. Chairman.
Chairman Barton. We thank you, Congressman.
Now I will recognize the distinguished member from
Colorado, Congresswoman DeGette, for an opening statement.
Ms. DeGette. Thank you, Mr. Chairman. I would ask unanimous
consent to put my full statement in the record.
Chairman Barton. Without objection, so ordered.
Ms. DeGette. Thank you. I would just like to make a couple
of observations.
When I walked into our last hearing on September 9, I
didn't know anything about this rampant off-label prescription
of anti-depressants for kids, and I didn't know about the risks
about it, and I don't think most Americans did know about it.
Sometimes when I go out in my district, as I have the last
few weeks, my constituents say how can you stand doing the job
that you do; how can you stand it back there? What I have been
saying the last couple of weeks is, well, let me tell you a
little story about this hearing we had in Congress where we
found out that anti-depressants, which have been approved by
the FDA for adults, are being prescribed for kids in rampant
off-label use and, furthermore, there was data that showed
that, at best, those drugs did not work, at worse and quite
possibly, some of those drugs increase the risk of suicide for
kids.
So after we had that hearing, and with all the press
associated with that hearing and the witnesses, well, lo and
behold, the FDA's Advisory Committee decided there was an
increased risk of suicidality, and they recommended a black box
label.
So, Mr. Chairman, I guess every so often we do do some good
in Washington, but I think it is a damn shame that we have to
have Congressional hearings to make that happen.
Frankly, the public is desperate. Teen depression, in
particular, is on the rise. We only have one drug that has been
approved by the FDA for use in kids, and parents are desperate
to find some way to treat their kids. But they were unaware how
the off-label use of anti-depressants could really not only not
help their kids but could actually kill their kids.
Now I think that the FDA has to answer a lot of questions.
They need to answer questions about, for example, why there
were delays of presentation of data between the links of
suicide and anti-depressants. The FDA needs to answer what
steps will be taken to ensure that scientists at FDA are able
to present their findings to advisory committees. They have to
answer as to what future actions the FDA is taking for
pediatric and adult use of anti-depressants.
The American public and the U.S. Congress rely on the FDA
to ensure that all approved pharmaceuticals are safe. This is
the responsibility that is at the very core of the FDA's
mission, and to fulfill that mission the FDA must conduct
objective studies with rigorous scientific inquiry, and then
they must present the results to the public. They can't simply
just sweep this under the carpet or put it in the back room
because they are concerned about the rise of teen depression
and the lack of medications to deal with this.
So I think--I am really glad we are having this series of
hearings, but I think the FDA has a lot to answer for. I would
also like to add that at the last hearing, Mr. Chairman, you
chastised the FDA for its lack of cooperation with this
committee, and rightly so. But we are still having difficulty
getting information from the FDA.
Some of the documents that we requested were not produced
until 36 hours before this hearing. The questions posed by the
Democrats at and after the last hearing, including myself, have
still not been answered, and the FDA did finally, I heard,
respond to some questions that Mr. Walden had last night.
We didn't get Doctors Temple and Mosholder's testimony
until after 7 o'clock last night, and I don't know if Dr.
Temple testimony required OMB review, which is why the FDA
usually says the testimony is tardy, but the delay is certainly
a burden on the committee and our hard working staff. Some of
us on this subcommittee were here until after 6 o'clock in a
different hearing last night, and it makes it very difficult to
prepare for these hearings.
So in sum, Mr. Chairman--and I have an extension of remarks
I will put in the record--we have got to have cooperation in
this hearing by the FDA and by all the other Federal agencies.
We are elected as representatives of the American people to
find the truth, and I know. one of the things I love about this
subcommittee, we work on a bipartisan basis, as the chairman
said.
We intend to get to the bottom of this, and I really want
to thank the chairman for not relenting, and I would hope these
agencies would realize they have got to cooperate.
I yield back the balance of my time.
Chairman Barton. I thank the distinguished Congresswoman
from Colorado. You statement is the first I had heard that we
hadn't had those questions answered. I wish I had known that
yesterday, because I had a phone conversation with Dr.
Crawford. But what we might do is do another--maybe another
meeting and get you and Mr. Dingell and Mr. Deutsch involved,
and we will get your answers.
Ms. DeGette. Thank you, Mr. Chairman.
[The prepared statement of Hon. Diana Degette follows:]
Prepared Statement of Hon. Diana DeGette, a Representative in Congress
from the State of Colorado
Today's hearing is the second of this series on antidepressant use
in pediatric populations. Parents, children and physicians seeking
improved mental health carefully weigh the risks and benefits of taking
antidepressants. The Committee's investigation has uncovered that the
risks of taking antidepressants had not been fully shared.
This hearing is more broadly about the Food and Drug Agency's
ability and efforts to ensure that all approved pharmaceuticals are
safe. This responsibility is at the very core of the FDA's mission. To
fulfill that mission, FDA must conduct objective studies with rigorous
scientific inquiry. When risks are identified, it is essential that
they be communicated to the public.
The FDA staff here with us today must answer to this Committee and
to the American public. Why were there delays in the presentation of
data on the link between suicides and antidepressants? What steps will
be taken to ensure that scientists at FDA are able to present their
findings to Advisory Committees? What future actions is FDA taking for
pediatric and adult use of antidepressants?
This investigation on antidepressant use in pediatric populations
has revealed that transparency and availability of information may have
been compromised. I would once again like to remind the FDA of the
importance of their role. It greatly concerns me that the United
Kingdom's equivalent to FDA (the MHRA), contraindicated all anti-
depressants for individuals less than 18 years of age in December 2003.
That was almost one year ago. Why has the FDA not taken similar steps?
The FDA's recent Advisory Committee meeting has determined that
there is an increased risk of suicidality in pediatric patients taking
antidepressants. They have recommended warning labels, but not
contraindication. But the data has shown that a risk of suicide does
exist for two antidepressants (Effexor and Paxil). How can we not
provide that information to physicians and parents?
I, like many of my colleagues believe that we must balance safety
concerns with access to medication. I do not believe that this balance
can exist when the risks are hidden.
In addition to considerations about analysis of the data, this
investigation has revealed that post-market surveillance of
pharmaceuticals has not perhaps been as strict as this Committee would
like. I hope that the witnesses from the FDA will provide some insight
on how this monitoring process may be limited and what Congress can do
to improve it.
I continue to be concerned about the inadequacy of our mental
health research and treatment system. While antidepressants have
greatly improved treatment options, much more must be done. In addition
to examining the FDA's actions, this hearing highlights the areas of
improvement needed. While safety of medications is of immediate
importance, this Committee should not turn a blind eye to the more
significant shortcomings in our health system.
Chairman Barton. The Chair would recognize Mr. Rogers for
an opening statement.
Mr. Rogers. I will yield.
Chairman Barton. Would Mr. Bilirakis like to make an
opening statement, distinguished subcommittee chairman?
Mr. Bilirakis. Well, thank you, Mr. Chairman, just very
briefly. Obviously, the recent reports of anti-depressant drugs
possibly increasing the risk of suicidal thoughts and actions
in children taking these drugs are certainly extremely
disturbing. While there are, as I understand it, no actual
suicides, it is important to recognize any possible adverse
effects that these drugs may have on adolescents and children.
Mr. Chairman, I don't disagree with any of the comments
made by you or any of the other members of the committee up
here and the fault on the part of the FDA and that sort of
thing, but I guess, as I understand it also, there have been
some positive things that have taken place.
I think we all can agree that the new FDA labeling
requirements are a step in the right direction. The FDA has
been closely reviewing the results of anti-depressant studies
in children since June 2003, and asked that the matter be
investigated by the Psychopharmacologic Drugs Advisory
Committee, PDAC, and the Pediatric Subcommittee of the Anti-
Infective Drugs Advisory.
The Advisory Committee did recommend to the FDA that the
labeling of these drugs be revised to advise the need to
monitor patients closely when the anti-depressive therapy
started and, based on this recommendation, FDA did require
changes to the labels for anti-depressant drugs used for
adolescents to include stronger cautions and warnings about the
need to monitor patients for worsening of depression and the
emergence of suicidality.
I don't know that this will solve the problem, Mr.
Chairman, and certainly things like delays and not being
apparently cooperative and all that are concerns, but I suppose
that this is a step in the right direction. And thanks to you
and Mr. Walden, the ranking members in the committee,
hopefully, this brings it out to the fore, and these matters
will be solved on an adequate basis, and I look forward to
hearing from all the witnesses.
Thank you, Mr. Chairman.
Chairman Barton. Thank the distinguished subcommittee
chairman. We now recognize Mr. Allen for an opening statement--
Congressman Allen, I mean.
Mr. Allen. Thank you, Mr. Chairman, and thank you for
calling this second hearing to examine concerns surrounding the
safety and efficacy of anti-depressant use by children.
This committee must closely examine the FDA's role in
reviewing clinical trial data indicating serious side effects
associated with certain prescription drugs. The FDA's mission
is to protect public health and, therefore, it has the
responsibility to alert physicians and the public to safety and
efficacy concerns associated with various medical treatments.
I do find it very troubling that FDA officials appear to
have attempted to suppress information indicating that SSRI
anti-depressants may increase the risk of certain suicide
related thoughts and/or behaviors in children. I am disturbed
that Dr. Mosholder's full report on this issue conducted at the
behest of the FDA was not allowed to be presented at FDA's
February Advisory Committee meeting on this issue.
I look forward to hearing from Dr. Mosholder about the
directive under which he conducted his review on clinical trial
data of SSRIs and the conclusions of his report.
Clearly, there is debate among the scientific community
about whether episodes of attempted suicide while taking SSRIs
are attributed to the underlying depression of an individual
patient or to the taking of SSRIs. However, disagreement about
clinical trial data does not mean that the studies and
conclusions of specific researchers should be dismissed or
suppressed. Rather, vigorous debate in the scientific community
should be encouraged and conclusions challenged in order to
arrive at the best determination of what information should be
disseminated to physicians and their patients.
The increasing rate of clinical depression in children is a
serious public health issue. Children diagnosed with depression
are clearly at an increased risk for suicidal thoughts and
behaviors. Each year, more than 500,000 children and
adolescents attempt suicide, and approximately 2,000 young
people die as a result of suicide.
I had the opportunity to discuss the link between SSRI use
and the possible increase in suicidal thoughts and behavior
with a pediatric physiatrist in Maine. He said that there is a
solid agreement among physicians that they need better clinical
data on the side effects of anti-depressants and not just
studies financed by the drug manufacturers.
He also stressed that physicians need to have a variety of
drugs available to them in order to make the best choice for
their patients. Research indicates that between 30 and 40
percent of children and adolescents with depression will not
respond to the first medication. The debate surrounding this
issue clearly indicates a need for greater post-marketing
studies on prescription drugs.
I am interested in learning from Dr. Temple about the
recent recommendations of the Psychopharmacologic Drugs and
Pediatric Advisory Committee, including the suggestion of
requiring the black box warning on all anti-depressant drugs,
indicating an increased risk for suicidality in pediatric
patients.
Certain drugs prescribed to children can be ineffective or
dangerous. It is FDA's responsibility to investigate the risks
associated with prescription drug use in order to protect the
safety of our Nation's children. FDA has a critical role in
ensuring that doctors and consumers receive balanced
information.
I look forward to hearing the testimony of all of you on
this very important topic. Mr. Chairman, I yield back the
balance of my time.
Chairman Barton. Thank the distinguished member for that
statement.
Does the gentleman from New Hampshire wish to--Okay. Does
the gentleman from California, Congressman Waxman, wish to make
an opening statement? Mr. Stupak is not a member of the
subcommittee.
Mr. Waxman. Thank you very much, Mr. Chairman. I want to
commend you for holding this hearing. I am pleased with the
bipartisan way the committee has operated, and this is an
important issue, the question of anti-depressant use in
children.
The issue has a lot of different implications. Certainly,
we ought to learn how FDA oversees the safety and effectiveness
of drugs, both in the approval process and after the approval
process when drugs are used for an off-label use, and
especially when we are talking about children.
The issue also has implications for how the pharmaceutical
industry shares data on its products with the public, and
especially the medical community.
The subcommittee's investigations have revealed that all
too often the drug industry has concealed data from physicians
and patients. In the case of anti-depressants, the data that
was concealed would have shown that the drugs failed to work in
children.
Concealing these negative results had very serious
consequences. It now appears that many children taking these
potentially ineffective drugs were put at an unnecessary risk,
because the drugs they were given may have actually increased
the likelihood that they might commit suicide.
Today the FDA is going to respond to allegations that the
agency failed to act quickly enough when the risk of suicide as
first brought to light. I am very interested in hearing what
they have to say, and hearing their responses.
In the weeks and months to come, I hope that the
subcommittee will continue to examine the broader issue of how
information about pharmaceuticals is made in general, so that
we can better protect patients from serious drug risks in the
future. I think FDA has a lot to answer to today, and I am
pleased that we have them here and under oath, so that the
questions may be asked of them and that we can pursue the
matter fully.
I am disturbed to hear that perhaps they had not given the
committee all the information that has been requested. I have
very little patience, and I know the chairman feels this way as
well, that when we request information from any government
agency in order to do our job of oversight--and it is an
important constitutional function to do that job--we need to
given all the information that is requested so that we can make
a better evaluation of the matter before us.
So I commend you, Mr. Chairman, again for holding these
hearings, and I look forward to the testimony today and working
with the members of this committee to figure out what actions
we need to take thereafter.
[The prepared statement of Hon. Henry Waxman follows:]
Prepared Statement of Hon. Henry A. Waxman, a Representative in
Congress from the State of California
I'd like to thank the Subcommittee for holding this series of
hearings on anti-depressant use in children. This is an extremely
important issue, which has implications for how the FDA oversees the
safety and effectiveness of drugs. The issue also has implications for
how the pharmaceutical industry shares data on its products with the
public.
The Subcommittee's investigations have revealed that all too often
the drug industry has concealed data from physicians and patients. In
the case of anti-depressants, the data that was concealed would have
shown that the drugs failed to work in children. Concealing these
negative results had very serious consequences. It now appears that
many children taking these potentially ineffective drugs were put at
unnecessary risk, because the drugs that they were given may have
actually increased the likelihood that they might commit suicide.
Today, the FDA will respond to allegations that the agency failed
to act quickly enough when the risk of suicide was first brought to
light.
I am very interested in learning the response of the FDA to these
allegations.
In the weeks and months to come, I hope that the Subcommittee will
continue to examine the broader issue of how information about
pharmaceuticals is made public in general, so that we can better
protect patients from serious drug risks in the future.
Chairman Barton. We thank the gentleman from California.
The gentleman from New Jersey, Congressman Ferguson, is
recognized for an opening statement.
Mr. Ferguson. Thank you, Mr. Chairman. I thank you for
holding this important hearing, continuing the committee's
investigation of adverse effects of anti-depressants in
children.
Two weeks ago, we discussed how vital it is that doctors
receive all the latest relevant study data and results so they
can make the most informed decisions possible on the safety of
the drugs that they are prescribing. The drug makers discussed
steps that they are taking to make their trials available to
doctors so they can have all the information they need to
confidently prescribe medicines to patients.
I commend the work of the committee and, most importantly,
the parents of children who have suffered unspeakable pain
because of the adverse reactions to some of these anti-
depressants.
In the last hearing 2 weeks ago, I spoke about a
constituent and friend of mine, Lisa Van Sickel. Lisa is here
with us again today. I spoke about Lisa and her daughter,
Michelle, as well as other constituents of mine who have
suffered in this way. Lisa, as I say, is with us again here
today.
I am told that Michelle, who is away at college, will be
watching via the committee's webcast today. If that is the
case, hello, Michelle.
Since our last hearing, there have been developments from
the FDA regarding their recommendations for doctors prescribing
anti-depressants to children. Last week the FDA's Psycho-
pharmacological Drugs and Pediatric Advisory Committees met and
made their recommendations on the prescribing of anti-
depressants to children.
I am interested to hear today what the panel has to say
about the recommendations and whether or not the FDA plans on
fully implementing the Advisory Committee's recommendations,
but also of particular interest is the path that the FDA took
to come to the conclusions that they have decided upon.
I look forward to hearing the testimony of Dr. Mosholder
today, and then the testimony of the second panel about how we
have arrived at the point that we are at now.
Question: Why was Dr. Mosholder's work not presented to the
FDA's February 2004 advisory committee, and when did the
Neuropharm Division first become aware of an increase in
psychiatric adverse events occurring in pediatric randomized
controlled trials of anti-depressants as compared with the
adult population?
My constituents and I and members of this panel are looking
forward to hearing the answers to these and a number of other
questions from today's panels of witnesses.
Thank you again, Mr. Chairman, for holding this hearing,
and I yield back.
Chairman Barton. Thank the gentleman from New Jersey. The
gentlelady from Illinois, Ms. Schakowsky, is recognized for an
opening statement.
Ms. Schakowsky. Thank you, Chairman Barton, for recognizing
me for the purpose of making an opening statement and for
agreeing to hear the opening statement of a Member of Congress
not on this subcommittee, Mr. Stupak. I hope that the tradition
of opening statements will continue going forward.
I look forward to hearing the testimony of the members of
the panel who took part in reviewing the safety of anti-
depressants in children over the past 1\1/2\ years. We need to
get some straightforward answers as to why specific concerns
regarding the safety of those medications were kept not just
from the public and from the medical community, but from the
Advisory Committee whose job it is to advise the FDA on these
issues.
The process of reviewing the safety and efficacy of
medications is complex. What is not complex is that the
findings of someone who is charged at taxpayers' expense with
the review should not be hidden from sight. This is a
particular concern when we talk about the health and safety of
our children.
I would like to hear an explanation today as to why, after
spending months examining the connection between anti-
depressant use in children and increased suicidal ideation at
the request of his superiors, an FDA medical examiner would be
prevented by those same superiors from presenting his
conclusions to the FDA's Advisory Committee.
I find this apparent suppression of information appalling,
particularly when it serves to hide information that could have
a significant impact on how medications are used by children.
In order for an advisory committee to come up with well-
informed and accurate recommendations, it is absolutely crucial
that they are provided with the most comprehensive, up-to-date
and accurate information available. When this does not happen
and the committee is prevented from hearing the conclusions of
those who actually conducted the reviews, the recommendations
of the committee inevitably will fail to reflect the best
interests of children and their families. This not only leads
to continued misuse of medications by misinformed parents and
physicians, it results in a serious breach of trust of the FDA
in its role of protecting the public from unsafe foods and
medications.
There already exists a great deal of misunderstanding and
mistrust within our society regarding the diagnosis and
treatment of mental health disorders. Incidents such as these
only serve to add fuel to the fire and increase the anger and
frustration on all sides.
Over the past weeks, we have heard from many mental health
professionals and parents who are convinced that these
medications can be effective in the treatment of major
depression in their children if they are used in an appropriate
manner and under the right circumstances. Many parents are also
very concerned about the possible negative impact of these
drugs on their children. All of them, however, deserve to know
that the decisions about these drugs are based on a full, fair
and independent analysis, and that critical information has not
been denied them. Thank you.
Chairman Barton. The Chair would now recognize the
distinguished member of the full committee, Congressman Stupak
of Michigan, for an opening statement.
Mr. Stupak. Thank you, Mr. Chairman, and thank you once
again for allowing me to take part in this series of hearings
concerning the safety and effectiveness of anti-depressants
used by children.
Two weeks ago, this committee heard the FDA repeatedly
claim the jury was still out about the safety of anti-
depressants. Just 4 days later before an advisory committee in
Bethesda, the FDA finally admitted what they had known for a
year: There is an increased risk of suicidal thoughts and
behavior in children who take anti-depressants.
I am appalled but, frankly, not surprised by the systematic
efforts of the FDA to suppress information that could have
prevented the senseless deaths of too many children.
I believe these anti-depressants should be banned until the
jury comes back with proof that they are safe and that they
work. They are not effective to treat depression. Increased
risk, no matter how large or small, is still an increased risk
for suicidal behavior.
The American people have a right to demand the FDA to look
out for their interests and not the interests of the drug
companies. When safety is questioned, FDA should err on the
side of caution.
The tragedies experienced by the families in the audience
today may have been prevented. The jury is no longer out.
Congress at a minimum should demand that the FDA to immediately
and completely implement all the Advisory Committee
recommendations made last week. Those recommendations included
warnings on all anti-depressants, black box labeling, and easy
to understand warnings on the packaging where parents and
patients can see it.
What many here may not realize is the FDA is under no
obligation to implement those recommendations. There are many
instances when the FDA has ignored or scaled back Advisory
Committee recommendations, caving to drug company pressure.
I know from my own experience that the FDA has repeatedly
ignored for the past 4 years advisory committee recommendations
concerning the acne drug, Accutane. I am particularly concerned
the FDA might back away from the recommendation of package
labeling that parents and patients can see and understand. The
FDA should require that information about the safety and
efficacy of these drugs be dispensed with every prescription
and on the package labeling.
The FDA should also require parents to sign an informed
consent before treatment can begin. The FDA cannot ignore these
recommendations like they ignored Dr. Mosholder's analysis.
They can't drag their feet on implementing the recommendations
as they dragged their feet on posting these studies on their
website.
Congress and the American people have had enough of the
stonewalling and excuse making. It is time to take action.
Let's be clear. Package labeling is the least the drug
companies can do.
In 1997 Congress passed a law beginning a system where the
drug companies get patent extensions worth billions of dollars
to study these drugs in children. Children, the most vulnerable
members of our society, are the only group that we grant patent
extensions to drug companies in exchange for studies.
We don't grant patent extensions to drug companies to study
the effect of drugs in women. We just demand it, and the drug
companies do it. We don't grant patent extensions worth
billions of dollars to drug companies to study drugs in
minorities. We just demand it, and drug companies do it.
Patents are extended once pediatric studies are turned in
to the FDA. There is no requirement that the studies were
actually well done or actually show whether the drug worked or
was safe, and there is no requirement that the packaging label
on these drugs are actually changed before the patent extension
is granted.
At the very least, parents should get the facts in exchange
for these billions in profits. It is clear today that they are
not.
Mr. Chairman, thank you again for calling these hearings
and for your leadership on this issue. This hearing illustrates
a larger problem at the FDA where too often drug companies
trump parents where medical evidence is suppressed and where
expert opinion is silenced, and it illustrates that our system
to study the effects of drugs on children is broken.
It is a system that gives billions of dollars to drug
companies and asks little in return. The FDA is failing to live
up to its responsibility to the American people.
I yield back the balance of my time.
Chairman Barton. We thank the distinguished gentleman from
Michigan.
The Chair would now recognize the gentleman from Florida
for an opening statement, Mr. Stearns.
Mr. Stearns. And good morning and thank you, Mr. Chairman,
for holding this hearing.
I think, as Mr. Stupak and others who are parents of
children are very much interested in this, 2 weeks ago we
explored the measures to make the results of clinical drug
trials more accessible to doctors and parents, and I think that
goes without saying.
You know, in our society today there seems to be a pill for
everything that ails you and, of course, this is especially
true for depression where millions of American children are
being prescribed anti-depressants. It is probably
unquestionable that anti-depressants have improved the quality
of life for many children and their families, and may have even
saved some lives. But for years now, we have heard anecdotal
evidence that some of these same anti-depressants increase
suicidal behavior in some children.
Lately, the evidence has become less anecdotal and more and
more compelling. In March 2004 the FDA issued a warning that 10
popular anti-depressants can cause deeper depression,
agitation, and other forms of violent behavior, including
suicide.
A month later, it was reported that the number of American
children being treated with anti-depressants has soared over
the past decades--it has been in all the press--even though the
vast majority of clinical trials have failed to prove that the
medicines even help--even help children at all.
Now we have also heard that the agency's own drug safety
analyst found a link between some anti-depressants and suicidal
behavior in children. Yet, my colleagues, these findings were
suppressed, and his analysis deemed unreliable.
Finally, a recent FDA commission study by Columbia
University researchers have confirmed the adverse results, and
we are forced to admit finally the truth that there is indeed
an increase in suicide and suicidal thoughts and behavior for
some children who are prescribed certain anti-depressants.
Mr. Chairman, the FDA is responsible for protecting the
public health by assuring the safety and efficacy of these
prescription drugs. We all know that. The widespread use of
these anti-depressants should provide even more incentive for
this FDA to fulfill its stated mission. At the very least, the
drugs in question should contain strong warning labels to help
physicians and parents evaluate the risks.
So truly, all of us here hope that this hearing will help
us get to the bottom of these disturbing findings and that we
will have a chance to fully explore the findings with the
panel.
So I look forward to this hearing and to learning more
about the FDA's role in making sure anti-depressants used by
children are safe and do what they are supposed to do.
Thank you, Mr. Chairman.
Chairman Barton. We thank the distinguished gentleman from
Florida for his opening statement. Seeing no other members of
the subcommittee on either side of the aisle present, the Chair
would ask unanimous consent that all members of the
subcommittee not present have the requisite number of days to
put their formal opening statement in the record. hearing no
objection, so ordered.
[Additional statement submitted for the record follows:]
Prepared Statement of Hon. Edward J. Markey, a Representative in
Congress from the State of Massachusetts
Thank you Mr. Chairman for calling this important hearing.
As we continue the Subcommittee's examination of how the FDA and
the pharmaceutical industry evaluated, reported, and responded to data
linking certain anti-depressants to an increased risk of suicide in
children and adolescents, I think it is important to recognize that
these drugs have played a very positive role in expanding the treatment
options for so many people around the country who have been struggling
with depression. For them and their families, anti-depressant
medications have been a real life line.
However, we have learned that until very recently we did not have
the whole truth about the impact of these drugs on our children.
Today's hearing will help the Subcommittee understand how this could
have occurred.
Based on what I have heard and read so far, it seems to me that our
current system for informing the public about potential risks
associated may be broken. It failed to inform the public about
potential risks of anti-depressants at two points. The first failure
was when the pharmaceutical companies did not disclose the negative
results of their clinical trials. Congressman Waxman and I will soon
introduce legislation to address this issue. We are proposing the
creation of a federal registry of clinical trials. This will ensure
that companies cannot pick and choose what information they want to
share with the public.
The second failure was when the pharmaceutical companies told the
FDA about negative trials, the FDA did not move quickly and
aggressively to fulfill its role as the watchdog for public health.
After conducting their own study and confirming the risk, the Agency
hesitated, suppressed their own data and left the public in the dark
for months. Meanwhile, regulators in Great Britain were already taking
action to protect their citizens from the same risks revealed by the
data.
The public absolutely needs to know about the risks associated with
the drugs that they are taking. Even if Dr. Mosholder's conclusions
were wrong (which does not appear to be the case) it was completely
inappropriate for the FDA to suppress his findings. Instead, the he
should have been allowed presented his findings and conclusions to the
FDA's Advisory Committee and allowed the experts to evaluate the data,
question the study and have a complete discussion of the available
information. Instead the FDA hid the data, got embarrassed when the
public found out about their actions from the press, and initiated an
internal criminal investigation that appears aimed at scaring its own
employees into silence.
Today we are going to examine the nature of the FDA's failure. The
FDA plays a critical role in protecting the public health so I am very
concerned about the maintaining the integrity of the FDA process. It is
my hope that in the future the FDA will provide a fair, thorough
evaluation of the risks associated with drugs and promptly inform the
public of those conclusions in a timely fashion. I am looking forward
to hearing what steps the FDA is taking to restore the public's trust.
I look forward to hearing the testimony of today's witnesses.
Chairman Barton. The Chair would now call forward our first
witness, the distinguished representative from the Food and
Drug Administration, Dr. Andrew Mosholder. Would you please
come forward and be seated.
Welcome, Dr. Mosholder. You are aware that the committee
has the tradition of taking all testimony under oath. Do you
object to testifying under oath?
Mr. Mosholder. Thank you. As a member of the Religious
Society of Friends or Quakers, I would prefer to affirm rather
than swear.
Chairman Barton. We have the oath so that you can affirm
rather than swear. But you don't oppose to affirming under
oath?
Mr. Mosholder. That is correct.
Chairman Barton. Thank you. You also have the right as a
citizen of the United States of America under the Constitution
of our great Nation to be advised by counsel during your
testimony. Do you wish to be so advised during your testimony?
Mr. Mosholder. No, I do not.
Chairman Barton. Would you please stand and raise your
right hand.
[Witness sworn.]
Chairman Barton. Be seated. Dr. Mosholder, we welcome you
to the subcommittee. Your testimony in its entirety is in the
record. We would recognize you for 7 minutes to elaborate on
that formal testimony.
TESTIMONY OF ANDREW D. MOSHOLDER, FOOD AND DRUG ADMINISTRATION
Mr. Mosholder. Thank you. I have a brief oral statement
which I can read now.
Mr. Chairman and members of the subcommittee, I am Dr.
Andrew Mosholder, a medical officer in the Office of Drug
Safety at FDA's Center for Drug Evaluation and Research. My
statement will briefly summarize my role in FDA's review of
suicidality in pediatric anti-depressant drug trials.
Before joining the Office of Drug Safety, or ODS, I was
medical officer in the Division of Neuropharmacological Drug
Products, DNDP, where I reviewed a number of submissions of
pediatric data for anti-depressant drugs, including Paxil. In
my review of the Paxil pediatric data, I noted that some of the
clinical trial adverse events classified as emotional ability
involved suicidal behavior or ideation.
So DNDP requested clarification from the manufacturer,
GlaxoSmithKline. In May 2003, GlaxoSmithKline provided new
analyses showing an increase in suicidal thoughts and behaviors
with paroxetine compared to placebo. Dr. Russell Katz, the
Director of DNDP, requested my assistance in the evaluation of
these data, and my managers in ODS agreed.
In July, DNDP asked the sponsors of other anti-depressant
drugs to reproduce GlaxoSmithKline's analysis of suicidal
events for Paxil by applying the same method to their own
pediatric trial data bases.
By September 2003, I had completed an analysis of the
paroxetine data and a preliminary analysis of pediatric data on
seven other anti-depressant drugs. I presented these analyses
at a briefing for CDER management September 16, 2003.
DNDP forward responses from the other manufacturers to me
for review. I completed the first written draft of my report in
December 2003. DNDP apparently was reaching a conclusion that
these data were not adequate for definitive analysis. DNDP
requested additional data from each sponsor, and also arranged
for the possible suicidal events in these trials to be
reclassified by outside experts.
On December 18, 2003, at a planning session for the
February 2 Advisory Committee meeting on this issue, I shared a
proposed outline of my Advisory Committee presentation. I noted
that suicidal events designated as serious in pediatric
clinical trials for major depressive disorder were 1.9 times
more frequent with anti-depressant drug treatment than with
placebo, and that this was statistically significant. There was
some discussion of the pros and cons of my analysis.
On January 6, Dr. Katz informed me by telephone that
someone else would present the clinical trial data at the
February 2 meeting, since I had a different view of the data
from that of DNDP.
News of my analysis and the fact that it would not be
presented at the February 2 AC meeting reached Mr. Rob Waters,
a reporter for the San Francisco Chronicle. The Chronicle ran
the story on February 1, 1 day prior to the AC meeting.
On February 18, I completed my written report. In it I
recommended discouraging off-label pediatric use of the anti-
depressant drugs. When my report received supervisory signoff
March 19, Dr. Mary Willy concurred, and Doctors Anne Trontell
and Mark Avigan attached cover memoranda indicating their areas
of disagreement.
On March 3, 2004, two special agents from the FDA Office of
Internal Affairs interviewed me regarding the disclosure of my
findings in the February 1 San Francisco Chronicle article. I
later provided the Office of Internal Affairs with a written
statement about the matter. I indicated that I was not the
source of the disclosure.
On March 22, FDA issued a public health advisory stating in
part, ``health care providers should carefully monitor patients
receiving anti-depressants for possible worsening of depression
or suicidality.''
In mid-July Dr. Tarek Hammad of DNDP shared the results of
his analysis of the clinical trial events as reclassified by a
panel of suicide experts convened by Columbia University. The
new analysis confirmed the previous finding: Definitive
suicidal behaviors and ideation in short term pediatric trials
were 1.8 times more frequent with anti-depressant drug
treatment compared to placebo, and this was statistically
significant.
Shortly thereafter, data from a new study of paroxetine,
the treatment of adolescent depression study or TADS, became
available. The TADS data indicated a therapeutic effect of
fluoxetine, but also showed an excess of suicidal events among
those receiving fluoxetine compared to patients who received
placebo, which was a new finding for fluoxetine.
On September 13 and 14, FDA held an AC meeting to consider
this issue. I was among the presenters, and I provided a
comparison of my analysis to the current analysis. The Advisory
Committee members voted 15 to 8 in favor of a boxed warning to
the labeling of anti-depressant drugs.
Thank you.
[The prepared statement of Andrew D. Mosholder follows:]
Prepared Statement of Andrew D. Mosholder, Medical Officer, Office of
Drug Safety, U.S. Food and Drug Administration
Mr. Chairman and Members of the Subcommittee: I, Andrew D.
Mosholder, am a licensed physician and board certified in child and
adolescent psychiatry. I obtained my medical degree from the University
of Virginia. I also have a Master of Public Health degree from Johns
Hopkins University.
I am currently employed by the U.S. Food and Drug Administration
and have been so employed since 1992. During my employment, I have been
a medical officer with the Center for Drug Evaluation and Research
(CDER) for twelve years. For about the past 20 months, I have worked as
an epidemiologist in the Division of Drug Risk Evaluation, Office of
Drug Safety (ODS). Prior to that, I was a medical officer in CDER's
Division of Neuropharmacological Drug Products (DNDP) for over 10
years.
In this statement, I will briefly summarize my role in FDA's review
of pediatric use of antidepressant drugs, with particular attention to
recent concerns about the effects of these drugs on suicidal thoughts
and behaviors in children and adolescents.
As a medical officer in DNDP, I reviewed a number of submissions of
pediatric data for antidepressant drugs, including pediatric data
submitted for Paxil (paroxetine), manufactured by GlaxoSmithKline. In
my review of the Paxil pediatric supplement, I noted that a number of
clinical trial adverse events designated as ``emotional lability''
involved suicidal behavior or ideation. Accordingly, DNDP requested
clarification regarding such behavioral adverse events from
GlaxoSmithKline. In May of 2003, after I had transferred to ODS, DNDP
received new data analyses from the manufacturer, indicating an
increase in suicidal thoughts and behaviors with paroxetine compared to
placebo in pediatric clinical trials. A consultation request from DNDP
to ODS signed June 6, 2003 by Dr. Russell Katz stated: ``Since the
original review of the Paxil supplement, as well as the reviews of most
other pediatric supplements for SSRIs, was done by Andrew Mosholder,
M.D, . . . we ask that this consult be assigned to him. We seek his
advice on further analysis and interpretation of the Paxil results, as
well as more general advice on what might be done to re-evaluate the
risk of suicidality in the pediatric databases for other SSRIs . . .''
My managers in ODS agreed to Dr. Katz's request and assigned me to
this consultation on June 9, 2003. To determine whether the apparent
increase in suicidal events applies to pediatric use of other
antidepressant drugs as well, I started to review FDA's pediatric data
for other antidepressant drugs. DNDP ultimately decided that the best
way to proceed would be to ask the sponsors of other antidepressant
drugs to reproduce GlaxoSmithKline's analysis of suicidal events for
Paxil, with each sponsor applying the same method to their own
pediatric trial databases. In July of 2003, DNDP sent requests for such
analyses to other antidepressant drug sponsors.
By September of 2003, I had completed an analysis of the paroxetine
data and a preliminary analysis of pediatric data on seven other
antidepressant drugs. At the request of management, I presented these
analyses at a CDER Regulatory Briefing for upper level management on
September 16, 2003. During the briefing, I presented the paroxetine
pediatric data, along with preliminary findings for other
antidepressant drugs. As noted in the briefing minutes, there was
discussion about the clinical significance of some of the events in the
analysis: ``We need to get a better sense of what the events from these
studies really are, i.e., are they legitimate, suicide-associated
thoughts/actions or self-mutilation acts that are becoming increasingly
common in the adolescent population today and are not generally
associated with a sincere intent to die.''
The Federal Register on October 31, 2003 contained this
announcement to the public regarding an Advisory Committee meeting
scheduled for February 2, 2004: ``The Psychopharmacologic Drugs
Advisory Committee and the Pediatric Subcommittee of the Anti-Infective
Drugs Advisory Committee will discuss reports of the occurrence of
suicidality (both suicidal ideation and suicide attempts) in clinical
trials for various antidepressant drugs in pediatric patients with
major depressive disorder (MDD). The committee will consider optimal
approaches to the analysis of data from these trials, and the results
of analyses conducted to date, with regard to the question of what
regulatory action may be needed pertinent to the clinical use of these
products in pediatric patients. The committee will also consider
further research needs to address questions on this topic.''
As DNDP received responses from the other manufacturers to the July
information requests, those responses were forwarded to me for review.
I then worked on my analysis of these responses over the next couple of
months and completed the first written draft of my results in December
of 2003.
DNDP apparently was reaching a conclusion that the responses from
the sponsors to the July requests were not going to be adequate for a
definitive analysis. In October of 2003, DNDP sent requests to the
manufacturers asking for patient level data sets, to permit a more
sophisticated statistical analysis than what I could accomplish using
only the responses to the July requests. DNDP also decided that all of
the possible suicidal events in these trials should be reclassified by
outside experts in suicidology.
On December 10, 2003, the U.K.'s Medicines and Healthcare products
Regulatory Agency issued their statement, ``Use of Selective Serotonin
Reuptake Inhibitors (SSRIs) in children and adolescents with major
depressive disorder (MDD)--only fluoxetine (Prozac) shown to have a
favourable balance of risks and benefits for the treatment of MDD in
the under 18s.''
On December 18, 2003, we held one of our planning meetings for the
February 2 Advisory Committee (AC) meeting. A draft agenda distributed
for the December 18 planning meeting included a 45-minute presentation
by me entitled, ``Limited Overview of Paxil Controlled Trials and
Controlled Trials of Other Antidepressants.'' At that meeting, I shared
a proposed outline of my presentation, which included my finding that
suicidal events designated as ``serious'' in pediatric clinical trials
for major depressive disorder were 1.9 times more frequent with
antidepressant drug treatment than with placebo, and that this was
statistically significant. I recall some discussion of the pros and
cons of my analysis.
On January 6, 2004, Dr. Katz sent me an email asking to speak with
me by phone regarding my presentation at the February 2 AC meeting. In
our subsequent telephone conversation on that date, he told me that
someone else would present the clinical trial data at the February 2 AC
meeting since I had reached a different view of the clinical trial data
from that of DNDP. On January 7, 2004, I sent an email to the team
members planning the February 2 meeting, confirming that I would not be
giving the presentation as originally planned and attaching a draft of
my slides for their use and interest.
On January 12, 2004, the Agency issued a Federal Register notice
with a revised agenda for the February 2 meeting. The notice stated,
``The committee will not be considering options for definitive
regulatory action at this meeting because definitive analyses of the
data have not been completed. This topic will be covered in a second
meeting to be scheduled by summer 2004.''
News of my analysis, and the fact that the findings would not be
presented at the February 2 AC meeting, reached Mr. Rob Waters, a
reporter for the San Francisco Chronicle. I was not the source of this
information, however, and in the course of a number of contacts from
Mr. Waters I did not disclose to him any confidential information.
Nonetheless, his story about this matter ran on February 1, 2004 in the
San Francisco Chronicle, one day prior to the AC meeting.
At the February 2, 2004 AC meeting, I delivered a presentation
entitled, ``Office of Drug Safety Data Resources for the Study of
Suicidal Events Associated with Pediatric Use of Antidepressants.''
This presentation emphasized postmarketing surveillance (MedWatch) data
regarding suicidal events with pediatric use of antidepressants, but it
did not include findings from my analysis of the pediatric clinical
trial data. Dr. Anne Trontell, the Deputy Director of ODS, instructed
me to prepare brief remarks regarding my analysis of the pediatric
clinical trial data, to be used if any members of the Advisory
Committee inquired about it. No AC members asked any questions about
this, however, and so I did not deliver the brief remarks that I had
prepared.
Subsequent to the February 2 AC meeting, I completed my written
consultation memorandum regarding suicidality in pediatric clinical
trials of antidepressants, dated February 18, 2004. In it, I
recommended discouraging off-label pediatric use of antidepressant
drugs, chiefly because the one drug that appeared to have the least
risk of suicidal adverse events from the data available at that time
was also the only drug to have won approval for pediatric depression,
i.e., fluoxetine. I had extensive discussions with my management in ODS
regarding my findings and their interpretation, and when my report
received final supervisory sign-off on March 19, Dr. Mary Willy
concurred, while Drs. Anne Trontell and Mark Avigan wrote separate
cover memoranda indicating their areas of disagreement. That
essentially ended my involvement with this project until mid-July when
the results of the Columbia University reclassification analysis became
available.
On March 3, 2004, two Special Agents from the FDA Office of
Internal Affairs interviewed me regarding the disclosure of my findings
in the February 1 San Francisco Chronicle article. I was also asked to
produce a written statement regarding this matter for the Office of
Internal Affairs, and in that statement I indicated that I was not the
source of the disclosure.
On March 22, 2004, FDA issued a public health advisory which
included the following statement: ``Health care providers should
carefully monitor patients receiving antidepressants for possible
worsening of depression or suicidality, especially at the beginning of
therapy or when the dose either increases or decreases. Although FDA
has not concluded that these drugs cause worsening depression or
suicidality, health care providers should be aware that worsening of
symptoms could be due to the underlying disease or might be a result of
drug therapy.''
During the spring and summer of this year, I had several meetings
with investigative staff of this Committee and of the Senate Finance
Committee, as part of each committee's examination of this issue. FDA's
written response to this Committee, dated April 14, 2004, summarized
the rationale for withholding the results of my analysis at the
February 2 AC meeting as follows: ``. . . given the Agency's concerns
regarding the limitations of the data and the plans to pursue case
reclassification and more in-depth analyses, CDER decided that having
Dr. Mosholder present his conclusion to the Advisory Committee, with
the appearance that it was an Agency determination, would be
potentially harmful to the public health as it might lead patients who
were actually benefiting from the use of these drugs to inappropriately
discontinue therapy.''
My next involvement with the analysis of the clinical trial data
came in mid-July, when Dr. Tarek Hammad was completing the DNDP
analyses of suicidal adverse events as reclassified by a panel of
suicide experts convened by Columbia University. The reclassification
of potential suicidal events by the panel of experts had apparently
confirmed the finding; definitive suicidal behaviors and ideation in
short-term pediatric trials were 1.8 times more frequent with
antidepressant drug treatment compared to placebo, and this was
statistically significant. I was asked by my management to work with
Dr. Hammad to prepare a comparison of his analysis to my previous
analysis. We both participated in an August 9 briefing for CDER
management on this issue, during which I presented such a comparison.
Subsequently I prepared a memorandum summarizing this comparison,
along with some additional supplemental topics, and this memorandum
received supervisory sign-off August 16.
Shortly after this, Dr. Hammad obtained data from a new study of
fluoxetine (Prozac), called the Treatment of Adolescent Depression
Study (TADS). The TADS data indicated a therapeutic effect of
fluoxetine, as seen in the previous fluoxetine pediatric depression
trials, but TADS also showed an excess of suicidal events among those
receiving fluoxetine compared to patients who received placebo. The
latter was a new finding, since there did not appear to be such an
excess in previous fluoxetine trials.
On September 13 and 14, FDA held an AC meeting to consider this
issue. The consult document signed March 19 and the follow-up
memorandum dated August 16 were both included in the briefing materials
for the AC meeting, and in fact FDA posted these documents on its web
site several weeks in advance of the meeting. At the first day of the
AC meeting, I was among the presenters and provided a comparison of my
previous analysis to the current analysis, this time including the new
findings from the TADS data, which were not included in the August 16
memorandum. The following day, the AC members voted 15-8 in favor of a
boxed warning for the labeling of antidepressant drugs, to note the
observed increase in suicidal behavior and ideation among pediatric
patients treated with antidepressant drugs in clinical trials.
Chairman Barton. Thank you, Dr. Mosholder.
The Chair would recognize himself for the first series of
questions, and we will set the clock at 10 minutes.
Before I ask questions, I want to commend you for your work
on behalf of the American people. I want to thank you for your
perseverance. I want to applaud you for insisting on honesty
and integrity in the review process. My guess is it has not
been easy. So on behalf of at least this subcommittee and the
full committee, and I would think I can say on behalf of the
American people, just let me say thank you. We appreciate you
being here today.
Mr. Mosholder. Thank you very much.
Chairman Barton. My first question to you is: Do you feel
that you have been pressured in any way at the FDA to suppress
or change your conclusions regarding your consult or consults--
I think there were two of them--with regard to the efficacy of
anti-depressant drugs being prescribed off-label for children
in this country?
Mr. Mosholder. With regard to efficacy, not per se, but as
far as the suicidality issue, at the time of finalizing the
March consult document I had considerable discussion with my
managers in the Office of Drug Safety about my interpretation
of the data and the recommendation, and at one point
alternative conclusions were offered to me which I declined to
incorporate into my written document. Accordingly, we had the
document finalized with cover memoranda which in our system
indicated disagreement between the manager signing the document
and the original author of the document.
Chairman Barton. Okay. What are your thoughts on why you
were refused to participate in the February 2004 Advisory
meeting?
Mr. Mosholder. Well, I would describe that as lack of
confidence in the data and the meaning of the data on the part
of those who made the decision to remove my presentation from
the agenda. My understanding is that that lack of confidence
centered around concern about whether the cases that I had
counted in my analysis were really bona fide suicidal events or
were perhaps events that were more clinically trivial or not
meaningful.
Chairman Barton. My understanding is that you are a medical
doctor, an M.D. Is that correct?
Mr. Mosholder. Yes, that is correct.
Chairman Barton. And it is pediatric psychiatry. Is that
correct?
Mr. Mosholder. Child and adolescent psychiatry. Yes.
Chairman Barton. Okay. So you feel that you are qualified--
because of your medical training and your background, you are
professionally qualified in the medical field to make some of
the judgments and decisions that you had to make in the
analysis of this data. Nobody has questioned your credentials.
Is that correct?
Mr. Mosholder. Not as far as my clinical background, no.
Chairman Barton. So there was no--It is not one of the
reasons you were not allowed to participate in the February
Advisory, because somebody questioned your credentials or
anything like that?
Mr. Mosholder. Not to my knowledge.
Chairman Barton. Okay. Do you agree with the British
decision to prohibit the use of these anti-depressant drugs in
children?
Mr. Mosholder. Well, my comment there is--well, of course,
in the sequence of events, that came shortly before I was
completing my own report, and I am sure it had some influence
on my thinking.
A close reading of the British contraindication actually
would suggest that, under certain circumstances, physicians
might choose to use the drugs for children. So that the term
contraindication means something a bit different on either side
of the Atlantic perhaps.
In the U.S. a contraindication basically means never, that
the risk is never justified. So that I did support the British
action with the understanding that their term contraindication
is not an absolute and recognizing the fact that there might be
selected circumstances where a clinician and patient might
choose to use the drug.
Chairman Barton. This is a personal question. You don't
have to answer it if you don't want to. Do you have children?
Mr. Mosholder. I have one step-son who is married, grown
and married.
Chairman Barton. If you did have young children, would you
prescribe these anti-depressant drugs for them if they
exhibited some of the symptoms of depression and suicidality?
Mr. Mosholder. Well, my own opinion would be that, based on
the evidence we have, the so called evidence based approach to
clinical practice would be that fluoxetine appears to have the
best data for depression as far as its efficacy.
We now have data that indicate, even with fluoxetine, there
could be an increase in the suicidal events. So that that would
have to be weighed, the risk and the benefit. So I would think
that fluoxetine would sort of emerge as the default choice
among the drugs for depression. But even there, it would have
to be with careful attention to the potential risks.
Chairman Barton. So I take that, if you personally had a
child, what I heard you say is the best of a bad choice is this
fluoxetine, but you really didn't say whether you would
recommend that it be prescribed or not.
Mr. Mosholder. Well, in certain circumstances--I think my
view of the data that we have now is that we should think more
carefully about the place of medication in the broader
treatment of juvenile depression. And just again on a personal
note, I trained long enough ago in psychiatry where we did not
have Prozac or any of the other SSRIs, and in those days using
medication was something that was not necessarily the first
choice.
So I would say I would not never use it if it was my child
or my patient, for that matter, but I would do it with careful
attention to all the risks and benefits.
Chairman Barton. Why do you think that the FDA, in spite of
all these studies and all the evidence and all of the analysis
that you have done, has been so reluctant to withdraw or more
firmly encourage the medical community to stop prescribing
these drugs off-label? Why wouldn't our FDA, which is viewed as
the gold standard of the world, given the studies that have
been done and your work--why do you think they haven't followed
the lead of the British? Why have they continued to, even after
last week--you know, this 51 to 8 decision which has just put a
black box warning--It just seems to me that the cautious,
prudent, conservative approach would be to strongly indicate to
the medical prescribing community that these drugs shouldn't be
used in children.
What has caused this reluctance at the FDA which, in my
view, is quite contrary to their normal procedure, which is to
be totally cautious?
Mr. Mosholder. Well, I'm not sure I can give a complete
explanation, but I think, on the other hand, there is some
concern with abandoning the utility of these drugs perhaps to
quickly--there's concerns about whether the studies which
failed to show efficacy, whether that is due to the drug not
being effective or whether the trial was not done properly, and
it is often difficult to tell.
Another limitation is that we don't have good data on long
term effects of these drugs. All of the studies that I looked
at and that Dr. Hammad looked at were just a matter of several
weeks. So there is also the possibility there could be long
term benefits but short term risks. We just don't know.
So I think those are the caveats that perhaps the other
people in the agency are looking at.
Chairman Barton. Well, my time has expired. The Chair
recognize the distinguished gentlelady from Colorado, Ms.
DeGette, for 10 minutes.
Ms. DeGette. Thank you, Mr. Chairman. Dr. Mosholder, you
told the chairman that after you presented your initial
findings, alternative conclusions were offered to you. I wonder
if you could tell us what those alternative conclusions were.
Mr. Mosholder. Well, this was, as I recall, an e-mail from
Dr. Trontell, one of my supervisors who wrote a cover
memorandum to the report. As I recall, the difference was
whether to take the step of channeling patients toward
fluoxetine, as I said, as sort of a default choice or----
Ms. DeGette. That is Prozac, which has been approved for
pediatric use.
Mr. Mosholder. Yes, for both depression and obsessive
compulsive disorder--whether to sort of actively advise people
that that looks like the best choice or to be more cautious and
just say sort of to use the drugs with caution.
Ms. DeGette. And they were recommending that you change it
to say just use the drugs with caution?
Mr. Mosholder. That is my recollection, yes.
Ms. DeGette. And you said you rejected that. Right?
Mr. Mosholder. Yes, and the reason was I thought we had
some good reasons to sort of point toward fluoxetine as
perhaps----
Ms. DeGette. To take the stronger position, saying this is
the drug that's been approved for pediatric use, this is what
you should be prescribing. Right?
Mr. Mosholder. Yes.
Ms. DeGette. Okay. I want to ask you, Doctor, in layman's
terms what did you consult reveal about the link between
suicidality and anti-depressants?
Mr. Mosholder. Well, to put it simply, in the short term
studies events which involved suicidal thoughts or behaviors
were almost twice as frequent among the children and
adolescents who received drug compared to the placebo or sugar
pill control.
Ms. DeGette. So, basically, what your research showed: Kids
are twice as likely to commit suicide on anti-depressants, at
least in the short term, than on placebo?
Mr. Mosholder. Well, I don't think I would say suicide,
because, of course, there were no actual suicides. So suicidal
thoughts and behavior.
Ms. DeGette. Okay. Thanks. Now did these conclusions apply
to all anti-depressant drugs?
Mr. Mosholder. That is a very good question. That is the
conclusion from putting all of the studies together. When you
break that apart by individual drug, the numbers become much
smaller, and it is harder to have the same level of confidence
that you have when you combined all the studies, as I did to
get that figure.
So--But it is certainly true that in almost all of the
drugs that have been looked at individually, there is at least
an excess of such events with the drug versus the placebo.
Ms. DeGette. It would probably be helpful to have
additional research, wouldn't it? More data?
Mr. Mosholder. There is no question about that. Yes.
Ms. DeGette. That is what I think, too. Were any of your
conclusions or findings about increased risk of suicidality
ever disproved by the FDA, by the Columbia data review, or by
Dr. Hammad's reanalysis?
Mr. Mosholder. In general, I think Dr. Hammad's analysis
and mine were consistent.
Ms. DeGette. Did anybody else disprove your findings?
Mr. Mosholder. Not that I am aware of.
Ms. DeGette. Okay. Now I am curious about the February 2
Advisory Committee meeting that you testified about. I am
wondering, if you know, why they decided not to let you present
your findings at that meeting?
Mr. Mosholder. Well, it was explained to me by Dr. Katz
that I had reached a different point of view about the data
from the Neuropharm Division, and by that I understood that I
felt the data were of sufficient quality to perform an
analysis, which I did, while the Neuropharm Division felt that
any analysis should await the Columbia University
reclassification project.
Ms. DeGette. So they felt like your data was not as
conclusive as you thought it was? Would that be a fair
characterization?
Mr. Mosholder. Yes, you could characterize it that way.
Ms. DeGette. Okay. Let me ask you this. The chairman was
asking you about some of your background, and you have been at
the FDA quite sometime. Is that right?
Mr. Mosholder. Twelve years.
Ms. DeGette. And how long have you been in your current
position?
Mr. Mosholder. Just over 1\1/2\ years.
Ms. DeGette. And before that, what did you do at the FDA?
Mr. Mosholder. I was a medical officer in the Neuropharm
Division.
Ms. DeGette. And part of your job, as I understand, is you
were a reviewer of adult anti-depressants in that job. Correct?
Mr. Mosholder. Yes, that was part of my assignments. Yes.
Ms. DeGette. In your 12 years at the FDA, I am wondering if
you have ever been in a situation like this before where you
were asked to do a medical consult, where you completed the
consult, where you presented the findings to your supervisors
and got approval, and then where ultimately the FDA said, well,
don't worry about it, just keep your conclusions to yourself?
Mr. Mosholder. Well, certainly, disagreements are not an
uncommon event. Personally, I had never had the experience of
having my presentation removed from an Advisory Committee
meeting agenda.
Ms. DeGette. Have you ever known that to happen at the FDA?
Mr. Mosholder. Not by direct knowledge, but I have heard
reports of other types of events like that.
Ms. DeGette. Is it your impression that it is a rare or a
common occurrence at the FDA?
Mr. Mosholder. Well, it is hard to give an exact frequency,
I guess, but I would say I have heard of several such
circumstances, just incidentally.
Ms. DeGette. And how often is it that people are asked to
do consults like this and make presentations as to their
finding? I mean, you said you have heard of people being told
they can't do their presentations a couple of times. I am
wondering how often that happens, how often we have these types
of presentations at the FDA.
Mr. Mosholder. Advisory Committee meetings, I think, are
fairly frequent, probably on a monthly basis. There's probably
other people who can give you real figures.
Ms. DeGette. So the Advisory Committee meetings happen
fairly often. How many cases do they review at the meetings?
Mr. Mosholder. Typically, one issue or one drug per
meeting.
Ms. DeGette. Okay. So your view would be it has been
infrequent that people have been told that they can't--and
again it is anecdotal, I know, because this only happened to
you this one time.
Mr. Mosholder. That is correct.
Ms. DeGette. Okay. Now is it--I think that you--now you did
present at the February 2 meeting, but you didn't present on
your findings from the analysis of the pediatric clinical trial
data. Is that right?
Mr. Mosholder. That is correct.
Ms. DeGette. What did you testify about?
Mr. Mosholder. I did a presentation which looked at the
Office of Drug Safety's resources to evaluate this issue, the
chief resource being, of course, the post-marketing reports, as
we call them, or reports obtained through the MedWatch program
from patients and doctors about adverse experiences with
drugs--that is outside of clinical studies--along with
examining some other potential sources of information, the
conclusion being that the best source of information was the
actual clinical studies.
Ms. DeGette. But you didn't testify about your latest
consult?
Mr. Mosholder. No, that is correct.
Ms. DeGette. Mr. Chairman, I have more questions. I will
ask them during the next round. Thank you.
Mr. Walden [presiding]. I assume we will have one. Dr.
Mosholder, thank you for being here. Thank you for your good
work on all these issues.
I would like you to turn to Tab 1 in that giant notebook in
front of you there, and I would ask unanimous consent to be
able to put the binder with all the data in our official
record. Without objection, so ordered.
This is an e-mail, and I will read it or parts of it at
least, to you and then your response to Dr. Katz. It is an e-
mail from Rusty Katz to you, and then your response. Can you
tell us--Well, let me read part of it, and then maybe you can
respond to it, sir. This is dated June 2, 2003, and Dr. Katz
says:
``We have recently become aware of a presumed association
between Paxil and suicidality in pediatric patients. We
received a call from the EMEA a little over a week ago. Dr.
Raines told us the company, GSK, had submitted data that
demonstrated that use of Paxil in kids was associated with
increased suicidality compared to placebo and that the company
proposed labeling changes. I believe she also said that it was
in the news, and it was a big issue. Tom and I told her that
the company had not informed us of any of this, and we agreed
to look into it.''
Then it goes on to talk about some things, and it says:
``The sponsor has not proposed labeling changes and makes a
feeble attempt to dismiss the finding. We are also awaiting the
submission of what the sponsor submitted to UK. We want to move
quickly to evaluate this signal. We are planning to look at the
NDAs for other SSRIs to see whether or not similar events are
being hidden by various inappropriate coating maneuvers.''
Then they want to compare other things. Then they go on to
say to you: ``Given your history with this application and this
general issue, we think you would be the right person to help
us think about the best approach to the data in the other NDAs
and their sponsors, as well as to provide ideas for further
sources of potential relevant data and possible approaches to
better evaluate this signal study.''
They go on to say, you know, we want to know if you want to
do this, basically, and want to move soon.
Can you tell us, basically, what you were tasked to do as a
result of this?
Mr. Mosholder. Well, I approached my own management, and
they agreed to assign me to this issue, and it involved,
initially last summer, a review of the Paxil submission that
was referred to, and then a preliminary search of submissions
for the other drugs, looking for any kind of similar pattern
with these events.
Mr. Walden. So you looked at all the drugs, similar drugs
being prescribed to kids for anti-depression?
Mr. Mosholder. All the ones that we had the pediatric
supplement NDA applications for.
Mr. Walden. And you were specifically looking at
suicidality among adolescents? Wasn't that----
Mr. Mosholder. That is correct. Children and adolescents,
yes.
Mr. Walden. When did you first report the results of your
consult to your superiors?
Mr. Mosholder. As I recall, I completed a written consult
in early September 2003, and then there was a briefing for CDER
management also in September.
Mr. Walden. I believe it was September 16, our records
would indicate, of 2003, that the regulatory briefing took
place.
Did you attend an internal regulatory briefing then in
September 2003, and at that briefing did you present the
results of your first consult to FDA's Neuropharm Division?
Mr. Mosholder. Yes, I did.
Mr. Walden. And was Robert Temple and Tom Laughren and
Russell Katz among those who attended the briefing?
Mr. Mosholder. As I recall, they were.
Mr. Walden. What were your general conclusions about the
pediatric suicidality data you reviewed and your September 2003
consult in Tab 3, if you need to refer to it--or excuse me, Tab
8, if you need to look at that? What were your general
conclusions about suicidality?
Mr. Mosholder. Well, I need to refer to my summary here.
Mr. Walden. Sure. Absolutely.
Mr. Mosholder. Well, basically this had two components. One
was a thorough look at the Paxil data, and then a preliminary
look at the data for the other drugs. Basically, I was saying
that there did seem to be a risk with Paxil based on the data
the company had submitted and that a first look at the other
drugs showed that it was not limited necessarily to Paxil. That
was the question at the time, and it might be what we call a
class effect, which means that it applies to all of the drugs
in a particular type of drug.
Mr. Walden. So am I correct then in understanding that what
you were saying in that document is that Paxil definitely
showed potential suicidality increase in adolescents, and that
the others may also show that in a whole class?
Mr. Mosholder. Yes, and I recommended looking further at
the other drugs, which was already underway at that time.
Mr. Walden. And that was September 16, 2003?
Mr. Mosholder. Yes. The briefing presentation basically
mirrored the written document.
Mr. Walden. When this consult was first given to you and
you had experience previously in looking at some of these
pediatric anti-depressant trials, did you have any sense of
what the conclusion would likely be?
Mr. Mosholder. No, I did not.
Mr. Walden. What type of data did you review from the other
SSRIs to come to the conclusion you did come to?
Mr. Mosholder. For this work, it involved a manual review
of the reports from those pediatric trials.
Mr. Walden. That would be the adverse event reports?
Mr. Mosholder. Right, as written up in the clinical trial
reports for those drugs.
Mr. Walden. And at that time, were you waiting to receive
more data from the pharmaceutical companies. So, therefore,
this was a preliminary consult?
Mr. Mosholder. Yes, and I think, as I mentioned earlier,
what GlaxoSmithKline did was they had an electronic search of
their clinical trial data base, looking for certain key words
that had been used to describe adverse events, and that is how
they produced the data which yielded the signal for Paxil.
So what DNDP had done in July was ask all the other
sponsors to reproduce that, using the same methods that GSK had
used for Paxil, so that we had, you know, a reasonable
comparison between the drugs. Then that was still being awaited
at the time--I think those data were just arriving at the time
I was finishing this September report.
Mr. Walden. And were you the one who was going to review
those data?
Mr. Mosholder. Yes.
Mr. Walden. Okay. And did anyone at that meeting express to
you that your work was done and not to continue with it?
Mr. Mosholder. No, although there was considerable
discussion about how to pursue it and how to classify the
events, but nobody thought it was finished, although there
wasn't--there was a lot of discussion about what the next steps
should be.
Mr. Walden. Incidentally, who signed off on this consult,
because I see that the last page of it only has signature
blocks for you and Dr. Willy. Did you need to get anyone else's
approval to finalize the September consult?
Mr. Mosholder. Let's see. In my copy, if you turn to
another couple of pages, you will see that Dr. Avigan, who is
my Division Director, signed it electronically, which is our
system for sign-off.
Mr. Walden. All right. But not Anne Trontell?
Mr. Mosholder. No. Dr. Trontell did not.
Mr. Walden. Okay. So it was finalized shortly after you
completed it, and there was not a significant lag time between
you completing it and getting it signed off?
Mr. Mosholder. Well, let's see. The date I have is
September 4, and then it looks like it was signed off September
5.
Mr. Walden. Okay. If you would turn to Tab 10 then, this is
an e-mail from Russell Katz to you dated September 17, 2003 in
which he stated you had done a superb job. Is this in reference
to the presentation you made about the signal of suicidality in
children taking anti-depressants?
Mr. Mosholder. This was in reference to that September
briefing.
Mr. Walden. Okay. But on that issue. Right?
Mr. Mosholder. On this issue. Correct.
Mr. Walden. Did he or any other person in an advisory role
express any concerns with your conclusion at this time? That
is, did anyone take the position that your analysis was wrong?
Mr. Mosholder. Not wrong per se, but there was a lot of
discussion about whether the events could be more appropriately
classified and whether--which--that is the concern that led
ultimately to the Columbia reclassification project.
Mr. Walden. But one more question. Then I will yield to my
colleagues. Were there any concerns expressed by anyone within
Neuropharm or the agency at that time that the method in which
you approached the data and your analysis was incorrect or
problematic?
Mr. Mosholder. As I recall, there was--I had some
suggestions from the statisticians about how to improve the
methodology from that standpoint.
Mr. Walden. But did you ever think that--I mean, yes, how
confident were you in that consult in your methodology? Was it
any different than what Columbia ended up when they
reclassified the data?
Mr. Mosholder. Well, I mean, I would say I was reasonably
confident. People may have different opinions about that, you
know. The Columbia project was--their involvement was to
classify the events into whether they were definitive suicidal
behaviors or not, basically, and they had a more refined
methodology than what I had used.
Then the other part of that is that Dr. Hammad's analysis
from a statistical standpoint is more sophisticated than what I
did. So----
Mr. Walden. But the outcome was the same, wasn't it?
Mr. Mosholder. The results were very similar.
Mr. Walden. Thank you. I now recognize the gentleman from
Michigan, Mr. Stupak, for questions.
Mr. Stupak. Thank you, Mr. Chairman. Doctor, Ms. DeGette
asked a question about not being allowed to testify at the
Advisory Committee. Is it your understanding that Dr. Graham
has not been allowed to testify at the Accutane Advisory
Committees?
Mr. Mosholder. I am not--I don't have direct knowledge of
the Accutane Advisory Committees.
Mr. Stupak. Okay. When we talk about these anti-
depressants, Paxil, Zoloft, Prozac, etcetera, we are talking
about SSRIs, which is selective serotonin reuptake inhibitors.
Correct?
Mr. Mosholder. Correct. There are also--in the group of
drugs that were looked at, there are some so called atypical
anti-depressants which are not SSRIs.
Mr. Stupak. Sure. Let me show you a document. We will give
the doctor one and the rest of the committee members a copy of
this document. I am going to show you three of them, but the
first one is a September 19, 2001, FDA pharmacology/toxicology
consultation.
In there, they are reviewing three previously unreported
Accutane studies, and a pharmacologist reported--and I am on
page 3, the last paragraph, sort of the conclusions. It is a
seven or nine-page document there, but on page 3 there are
conclusions, and I am quoting now. I think it is the second to
last line. ``Although possible psychiatric correlates of
excessive serotonagenic function cannot be ruled out, it should
be noted that increased serotonagenic function is presumed to
be the mechanism of action of a major class of anti-
depressants, the SSRIs, i.e., selective serotonin reuptake
inhibitors.''
Since the excessive serotonic function discovered with
Accutane use mimics the SSRIs of these anti-depressants, I as
you then: Do you believe that this relationship between
Accutane and the SSRIs warrant the same type of notification to
patients, to the parents, consisting of an informed consent, a
clear and concise package warning, a Med Guide, and a
certification of the physician and the registry of all
patients, as is recommended for Accutane? Do you think we
should have that same kind of notice, if we are talking about
SSRIs which somehow, some are similar to function we find in
Accutane?
Mr. Mosholder. That is a good question. As I understand it,
you are suggesting that a risk management program----
Mr. Stupak. That has been recommended for Accutane, which
Accutane, according to this consult 3 years ago, talks about
SSRIs and the mechanism which is similar--it is the same thing
we are talking about right here with Paxil and Zoloft and
Prozac.
So if we are going to have that kind of a recommended
warning for Accutane, shouldn't we have that kind of
notification or warning to patients who are using these anti-
depressants that again have the SSRI function in them?
Mr. Mosholder. That is something I haven't really thought
about. I guess that would be going beyond the boxed warning and
more----
Mr. Stupak. Sure, it is.
Mr. Mosholder. The real issue being how can we be sure that
patients----
Mr. Stupak. Have the full information before they make this
decision. Right? As you said earlier talking to Mr. Chairman,
the benefits and the risks have to be known before you can have
had the whole thing--before a parent should make that decision.
Correct?
Take a look at the second document I showed you there. This
document, if you look, is a PET scan of the orbital frontal
cortex in the area of the brain that mediates depression. The
PET scan is of a 17-year-old, and the brain starts--17-year-old
brain. It starts with baseline of the orbital frontal cortex,
and then it shows this area of the brain after 4 months on
Accutane. Please note the changes. As demonstrated in color,
the brain after 4 months on Accutane, there's some clear
differences.
The PET scan clearly shows changes in the brain after 4
months. The researcher took PET scans of Accutane patients and
patients who received a different oral antibiotic. The
researcher took a baseline PET scan of all the patients' brains
and then again at the 4 month stage of their Accutane or oral
antibiotic treatment.
Some of the Accutane patients showed a pronounced
difference in the brain's metabolism in the area that we
recognize causing depression.
Since the FDA in their previous memo has equated Accutane
with SSRIs, and we know from this research that, while
metabolic changes are occurring in the brain of Accutane user,
then my question is this. Is the FDA, by allowing anti-
depressants be used in young people, creating another situation
like we have in Accutane where these drugs are destroying part
of the brain, destroying young people, but the evidence is
ignored as not being scientifically established and, therefore,
the drug manufacturer continues to market their products,
despite the research which suggests that the drugs are actually
destroying a person's brain, causing depression, and is doing
more harm than good? Based on the PET scan, research of this
metabolism that is going on in the brain may or may not be
reversible. Can the brain regenerate itself to repair the
damage done by the SSRIs? What are we telling parents whose
children have not improved after taking the anti-depressants?
That the drug their children are taking may have actually
destroyed part of the brain?
You and I don't have the answers to this, but in summation:
Since there appears to be an established link, at least in one
research project, by giving our children Accutane and these
SSRIs, Prozac, Zoloft and Paxil, we may actually be causing
more harm than good in the brains of young people.
Should the FDA--and here is my question. Should the FDA
prevent the use of these drugs in children until these very
serious questions are answered? I think it is the same
question--maybe we have a little bit of evidence here that Mr.
Barton didn't have--that Mr. Barton asked you about the risk
versus benefits, and I think in response you said to him, risk
is never justified in dealing with suicidal behavior.
So if we have some evidence here showing changes in the
brain in Accutane, which is equated to the previous documents
SSRIs, should we not be very cautious on continuing to
prescribe these SSRIs to young people under the age of 18 until
we answer these questions?
Mr. Mosholder. Well, I would say that the findings from--
actually from the clinical trial data--you know, without
turning to even neuroimaging, one can look at the clinical
trial data, and that would certainly give one pause about the
usefulness of these drugs for children and adolescents for
depression.
It is also true that we don't know nearly enough about the
long term effects of these anti-depressant drugs or other drugs
on children and adolescents who are growing and developing.
Mr. Stupak. Well, as you said, we don't know enough about
it. So as I said in my opening statement, shouldn't we really
err on the side on caution? You know, suicide is final, and we
have had a number of suicides related to these SSRIs and, say,
with Accutane. I mean, if there is a question here as to the
safety, and to date this is probably the only evidence we have
showing a change in the brain in some of these Accutane
patients which equate to your SSRIs--if we have brain changes,
until we answer these questions, if it is reversible, can the
brain rehabilitate itself, grow new cells, shouldn't we really
be very, very cautious in how we use these drugs, and should we
not even consider not prescribing to young people under age 18?
I asked that same question of the drug manufacturers 2
weeks ago, and they really wouldn't give me an answer. They
thought it was still okay to prescribe drugs to people under
18, even though the jury is still out, as they wanted to say.
Shouldn't we err on the side of caution here?
Mr. Mosholder. Well, my own opinion is, as I said before,
that we should be mindful of the fact that the best data, the
best evidence for benefit is limited to the single drug,
Prozac, at least in terms of depression. Obsessive compulsive
disorder is a different story, but for depression.
So that faced with the question of possible harm, on the
one hand, and then lack of evidence of benefit, on the other,
that should certainly be part of the evaluation of whether or
not to use the drugs.
I am not prepared to say that the drugs shouldn't be used
in children.
Mr. Stupak. I believe you got one more document there. My
time has almost run out. Let's go to that. In dealing with
pediatric studies, and again we are still in question here,
dosage is usually a question as to the proper amount that
should be given, of the amount, the percentage, things like
that.
For example, in Accutane we know that the dosage is way too
high, and in one FDA source--in fact, it is there with you--it
states that the Accutane formula dose may be 240 times more
than necessary for safe treatment, and that was followed up
with discussions to have Hoffman La Roche do a dosage study
and, as far as I know, it was never done.
So my question is: Since these anti-depressants and
Accutane have sort of been linked here today, has there been
shown to be--has the FDA given any thought to determine whether
proper dosage is given to children and adolescents with these
anti-depressants, because they were developed for adults. So
are we dealing with the proper dosage when we are dealing with
young people and adolescents?
Mr. Mosholder. Well, that is a very good question, and
unfortunately, to the best of my recollection, the clinical
trials that we have for the anti-depressants in children were
done with what we call flexible dosing where it is left up to
the clinician/investigator to determine the dose within a
certain range.
So there might have been one or two exceptions to that, but
what is really needed is a study in which patients are assigned
to a specific dose, and then both the benefits and the side
effects can be compared to get a judgment of what the best dose
is.
So there is clearly--apart from even figuring out if the
drugs are effective in children, there is clearly more need for
data on the proper dosage.
Mr. Walden. I want to thank the gentleman.
Mr. Stupak. Thank you. Mr. Chairman, I ask that those three
documents referred to by Dr. Mosholder and given to the
committee be made part of the record.
Mr. Walden. Without objection.
[The documents referred to follow:]
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Mr. Stupak. Thank you.
Chairman Barton. Thank you.
Mr. Walden. Dr. Mosholder, given the new TAD study on
fluoxetine, do you believe that that raises any issues parents
and physicians should be concerned about relative to
suicidality?
Mr. Mosholder. My opinion is that it does raise some
concerns about that, and as I was saying earlier, when I did my
initial--well, actually, the March consult document didn't have
the TADS study, and it looked at sort of conveniently the one
drug that had the best efficacy for depression, also didn't
seem to have this risk of increasing suicidal events, which
made a certain amount of sense. But I think now it is a little
different picture that, although the TAD study again showed
that Prozac is effective in ameliorating the symptoms of
depression, it suggests there is a certain number of patients
who have an increased risk of suicidal behaviors or thoughts at
the same time.
So there is both a risk and a benefit, in other words.
Mr. Walden. Do you recall what the suicidality rate was in
the TAD study and how that compares to the other studies?
Mr. Mosholder. As I recall from Dr. Hammad's analysis, the
relative risk, as we call, which is--or risk ratio is between 4
and 5. I can look that up.
Mr. Walden. And what does that mean to a layperson like me?
Mr. Mosholder. Well, one way that we measure these risks is
to do what we call a risk ratio, and that is--I guess the
simplest way to explain would be with a brief example. A study
with 100 patients on drug, 100 on placebo, if one had 10
suicidal events on drug and 5 on placebo, the ratio would be 10
out of 100 to 5 out of 100, or 2.
So we would say that that relative risk is 2, and that is--
and as I recall, in the TAD study it's actually higher than
that.
Mr. Walden. And is that a--is 4, if that was the number, is
that one that should raise a flag? I mean, you do this work all
the time.
Mr. Mosholder. Well, I think it raises a flag, and it has
to be judged against the benefit. so that there is a study in
which in the same study, you can look at the benefits and the
risks simultaneously.
Mr. Walden. All right. The question is: Does it suggest a
point of underreporting in the other studies?
Mr. Mosholder. No, I'm not sure that is the--I'm not sure
the answer is as simple as that. There are some differences
between the TAD study and the other studies that might or might
not account for the different in the data. It is kind of hard
to tell after the fact.
Mr. Walden. Could you turn to Tab 11 in our notebook there.
This is an e-mail dated October 2, 2003. Mary Willy who is your
direct supervisor--correct?--in the Office of Drug Safety at
that time, suggests to the Neuropharm Division and others that
you should present your Paxil suicidality conclusions that were
first presented in September to a Pediatric Advisory
Subcommittee meeting that was meeting in October.
Then Russell Katz writes back to her and states: ``We
recognize that some folks outside the Division have concluded
there is enough of a signal already established to make some
sort of a meaningful statement about the data, but we haven't,
and we think that publicly presenting part of the data in its
current state has the great potential to be misleading and
uninformative.''
Do you agree with Dr. Katz' statement that publicly
presenting your data and conclusions you reached at that time
has the great potential to be misleading and uninformative?
Mr. Mosholder. Well, my opinion was--and that of Dr. Willy
at the time was that we thought it could be done and might have
been useful, which is why she proposed it. But as you see,
there was a difference of opinion about that.
Mr. Walden. You know, it strikes me that when word came
over from Europe that there may be a problem here, they went
right to you quickly and said we have to act quickly.
I guess what is troubling to us is it appears there was a
fairly long delay between the time you did your quick review,
your consult, came back and said I see some problems here, if I
am characterizing that correctly, and then when it finally gets
presented up the chain. It seems like somebody put a brake on
somewhere. Did you ever feel that way?
Mr. Mosholder. You know, it is really hard to be specific
and say that--I'm not sure I have much of an answer to that,
really.
Mr. Walden. All right. Did you present at that October
Pediatric Advisory Committee meeting?
Mr. Mosholder. No.
Mr. Walden. Throughout the fall of 2003, did you continue
to work on this consult and, if so, can you briefly describe
what you were looking at?
Mr. Mosholder. During that fall, what I was doing was an
analysis of the responses from the other anti-depressant
manufacturers. As you recall, in July they had been asked to
reproduce GSK's methods that found the problem with Paxil. So
we wanted to--for comparability purposes, we wanted to have
that reproduced by each of the other manufacturers.
We received that information in the late spring/early fall
of 2003, and that is what I was working on.
Mr. Walden. You were reviewing all those data?
Mr. Mosholder. Yes.
Mr. Walden. Would those data have been ready for the
October presentation? Were you ready?
Mr. Mosholder. For the October presentation, it would not
have been the--what we would have had at that point would have
paralleled the regulatory briefing that I had given in
September to CDER management.
Mr. Walden. Okay. So at the end of October, the FDA noticed
a public Advisory Committee meeting for February 2 and 3, 2004.
Was it your understanding that you were going to present at
this meeting on the topic of your consult and what your
findings were regarding suicidal behavior in these pediatric
clinical trials?
Mr. Mosholder. Yes, that was my understanding.
Mr. Walden. That's what you were going to go do. Did the
fact that in October 2003 Neuropharm decided to involve
Columbia University in reclassifying the events provided by the
companies mean that you were to stop working on your consult?
Mr. Mosholder. I remember wondering that and discussing it
with Dr. Willy, my team leader, and we decided that at that
point I had gone far enough and had devoted a lot of time to
this project that it made most sense just to have me finish
with my analysis, which was the one that I completed the draft
in December.
Mr. Walden. So it was your understanding, both your consult
and any work that Columbia did would be pursued simultaneously?
Mr. Mosholder. Correct, although the timeline--it seemed
obvious that the Columbia--it seemed obvious pretty early that
the Columbia data would not be ready for analysis and
presentation by February 2.
Mr. Walden. But it was important enough that you wanted to
get answers sooner than that?
Mr. Mosholder. Yes, which is not to say that it had to be
either one or the other, but both efforts were continuing full
speed, you know, as far as I was concerned.
Mr. Walden. Were you involved in the planning meetings for
the February 2 Advisory Committee meeting?
Mr. Mosholder. Yes, I was.
Mr. Walden. When did you complete your final meta analysis
of all the data from the SSRI pediatric clinical trials?
Mr. Mosholder. As I recall, my draft was turned in to my
management around mid-December.
Mr. Walden. Of 2003?
Mr. Mosholder. Of 2003. I made some refinements to it in
the subsequent couple of months.
Mr. Walden. And basically--correct me if I am wrong, but
didn't those data, or didn't your findings show a 1.9 or 1.89
times more likely serious suicide-related event on drug than
placebo?
Mr. Mosholder. Yes.
Mr. Walden. Across the trials. Right?
Mr. Mosholder. That's correct, yes.
Mr. Walden. All right. And didn't you recommend interim
measures?
Mr. Mosholder. Yes. I recommended--I wasn't very specific,
I realize, but I had in mind some kind of interim measures to
announce that there could be a problem.
Mr. Walden. Did you feel a sense of urgency?
Mr. Mosholder. Yes, I did.
Mr. Walden. To get this information and your findings out?
Mr. Mosholder. Yes, I thought it was--and that was one of
the points I made at the September regulatory briefing, that
these drugs are widely used in this population, and so that it
was an important public health issue.
Mr. Walden. Did you reclassify any of the events that the
sponsor gave? That is, did you change the classification from
serious to nonserious or discount it completely?
Mr. Mosholder. What I did for my meta analysis, I took the
events which had been identified by each sponsor, using GSK's
method, and then the result that I emphasized was the subgroup
of those events which also met a regulatory definition for
seriousness. That is a definition that--it is in the Code of
Federal Regulations. It is something that each sponsor
designates when they report the studies to the FDA as to
whether or not a particular adverse event is serious or not.
Mr. Walden. And didn't your consult focus on serious
suicidal events?
Mr. Mosholder. Yes, it did.
Mr. Walden. Including the famous girl slapping face?
Mr. Mosholder. Well, that was not a serious event which
was----
Mr. Walden. So that wasn't----
Mr. Mosholder. Well, that was the rationale that, without
being able to do anything as elaborate or sophisticated as the
Columbia University project, as a first cut to eliminate some
of the questionable cases, I took the subgroup that met the
criteria for seriousness, which in this case is mostly either
life threatening or resulting in hospitalization.
Mr. Walden. Okay. So the girl slapping face scenario was
not even included in your data that resulted in a 1.9 times----
Mr. Mosholder. No.
Mr. Walden. I mean, you were pushing the upper end here in
terms of suicidality issues then. Is that right? My reading as
a layperson.
Mr. Mosholder. Well, it was an attempt to hone in on the
events that were clinically meaningful.
Mr. Walden. But it also says there are other events below
that, including the girl slapping face situation that--I guess
my point is, that could be occurring out there in adolescents--
--
Mr. Mosholder. Yes.
Mr. Walden. [continuing] are not even in your data. That is
not a criticism. I am just trying to get the range here.
Mr. Mosholder. Well, I did look at it with the broader
category, too, but I thought the more important result was with
the subgroup of the serious events.
Mr. Walden. Indeed. My time has long since expired. I turn
to my colleague from Colorado.
Ms. DeGette. Thank you, Mr. Chairman. Dr. Mosholder, if you
could turn to Tab 67 of the notebook in front of you, do you
see that statement? It is entitled Written Statement.
Mr. Mosholder. Yes.
Ms. DeGette. Was this statement prepared by you?
Mr. Mosholder. Yes, it was.
Ms. DeGette. Can you tell me how you came to prepare that
document?
Mr. Mosholder. I was--well, this is a statement that I
provided to the Office of Internal Affairs, and this was
pursuant to an interview that I had with two Special Agents of
the Office of Internal Affairs regarding the San Francisco
Chronicle story about my analysis of the suicidal events.
Ms. DeGette. Did those agents ask you to prepare that?
Mr. Mosholder. Yes, subsequent to the interview they asked
me to provide a written statement.
Ms. DeGette. And that is how you came to prepare that?
Mr. Mosholder. Yes.
Ms. DeGette. Okay. And that statement was under oath.
Correct?
Mr. Mosholder. It was given----
Ms. DeGette. It was an affidavit?
Mr. Mosholder. Right. That's correct, yes.
Ms. DeGette. And what it was about was the circumstances
surrounding the removal of your analysis of the incidence of
pediatric suicidality in clinical studies of anti-depressants
from the agenda of the Advisory Committee meeting that we
talked about, and also the conversations that you had with the
San Francisco Chronicle reporter about that analysis and the
decision to omit it from consideration by the Advisory
Committee. Is that right?
Mr. Mosholder. That is correct.
Ms. DeGette. And so what this written statement was
attempted to be was an accurate account of the events as you
knew them about the presentation and the decision to cancel
that presentation, and also about your contacts with the
reporter. Right?
Mr. Mosholder. That is correct, and importantly, to include
the statement that I did not divulge the information to the
reporter.
Ms. DeGette. Right, and you wanted to--so part of what you
wanted to do was set out a chronicle of the events, including
how and why and in what way you communicated with this
reporter. Right?
Mr. Mosholder. That is correct. And that was part of the
request that they gave me to include in the statement.
Ms. DeGette. Okay. Now when did you provide that statement
to the OIA?
Mr. Mosholder. I believe it was--it was middle of March, I
think maybe March 15.
Ms. DeGette. That is the information I've got as well. Did
there come a time when the U.S. Senate Finance Committee made
inquiries regarding the events described in your statement?
Mr. Mosholder. Yes, that's correct.
Ms. DeGette. And when did you know about that? How did you
find out about that?
Mr. Mosholder. I believe I saw a news report in late March
of this year.
Ms. DeGette. And then were you contacted by the Office of
Legislative Affairs?
Mr. Mosholder. Yes, I was, when the Senate Finance
Committee investigators wanted to arrange an interview.
Ms. DeGette. So it was sometime after March 15?
Mr. Mosholder. That's correct.
Ms. DeGette. Okay. Did you meet with folks from the Office
of Legislative Affairs subsequent to the TV report that you saw
or the media report?
Mr. Mosholder. Yes. We had a couple of preparatory
meetings, as I recall, to prepare me for the Senate Finance
Committee interview.
Ms. DeGette. Okay. Was that with Patrick McGarry and Karen
Meister?
Mr. Mosholder. I believe they were some of them.
Ms. DeGette. And there were others as well as them?
Mr. Mosholder. Yes. We had a series of meetings, and I am
not entirely clear on who precisely was at which meeting, but
there was a number of them.
Ms. DeGette. Okay. Doctor, take a look at Exhibit 64, which
is an e-mail from Ms. Meister to you regarding a May 3, 2004,
meeting in Mr. McGarry's office. Do you see that memo, Tab 64?
Mr. Mosholder. Yes.
Ms. DeGette. There are some people who are copied on that
e-mail: Ann Hennig, Donna Katz, and Kim Dettlebach. Do you see
those names?
Mr. Mosholder. Yes.
Ms. DeGette. Do you know those individuals?
Mr. Mosholder. Yes, I do.
Ms. DeGette. Do you know who they are?
Mr. Mosholder. Ms. Hennig works with the CDER Office of
Executive Programs, as I believe it is called. Ms. Katz and Ms.
Dettelbach are, as I understand, with the Office of Chief
Counsel at FDA.
Ms. DeGette. Okay. Now can you tell me what the subject of
that meeting was?
Mr. Mosholder. As I recall, it was a preparatory meeting
for my Senate Finance Committee interview.
Ms. DeGette. And after that meeting, were there exchanges
of various revisions to the written statement that you talked
about a little while ago that you had prepared earlier that was
to be provided to the Senate Finance Committee?
Mr. Mosholder. Yes. That became an issue, and I can explain
it this way. Having given the statement under penalty of
perjury, as we said, I had a legal interest, and my attorney
confirmed this, in being consistent with that statement. So
that----
Ms. DeGette. And telling the truth, because you were under
oath.
Mr. Mosholder. Yes. And also not even inadvertently
contradicting a previous statement. So----
Ms. DeGette. A previous statement made by you?
Mr. Mosholder. Right. So to ensure my own consistency and
knowing that the Senate Finance Committee would be asking about
the same sequence of events, it was to my advantage to make use
of that statement for the Senate Finance Committee
investigation as well.
So I wanted to provide them with a copy of the statement as
sort of my official record.
Ms. DeGette. Right, your take on what happened, to the best
of your recollection.
Mr. Mosholder. The issue was that at that time the Internal
Affairs investigation, as I understand it, was still an open
investigation, and apparently FDA's policy or the executive
branch policy is not to reveal the existence of such
investigations. So that I was advised to redact the statement
so that it didn't have any reference to the Internal Affairs
investigation.
Ms. DeGette. And they also wanted you to take the names
out?
Mr. Mosholder. Right. The other issue was personal privacy
of not revealing the names of other people who were subject of
an Internal Affairs investigation. So although I was free to
reveal my own involvement, but that it wouldn't be appropriate
to divulge other people who were subject to that same
investigation.
Ms. DeGette. And were you willing to make those redactions?
Mr. Mosholder. I said that I was uncomfortable redacting
the document in a way that it wasn't transparent that it had
been redacted.
Ms. DeGette. So you didn't mind taking out the names or the
reference to the internal investigation, but you wanted the
document to reflect that it had been altered. Correct?
Mr. Mosholder. That is correct.
Ms. DeGette. And they wanted to alter it so that there
would be no record of the redactions. Correct?
Mr. Mosholder. That is my understanding. That is how I
understood it, yes.
Ms. DeGette. Now ultimately you decided not to sign the
revised document that they had sent you. Correct?
Mr. Mosholder. Well, I said that, when I went to the
Finance Committee for my interview, that I preferred to use my
version, which indicated that the document had come from a
previous document, and in the--actually, what happened was in
the interim the Internal Affairs investigation was closed. So
that that made that issue moot. So I was able to ultimately
provide the Finance Committee with my affidavit, only minus the
names for personal privacy.
Ms. DeGette. Okay. Take a look at Exhibit 57. That is an e-
mail from Donna Katz to you with copies to various people. Do
you see that there?
Mr. Mosholder. Yes.
Ms. DeGette. Now attached to that e-mail is a copy of the
written statement, your written statement, with lines through a
number of sentences, and a copy where the deletions had been
made. Do you see that?
Mr. Mosholder. I see the--I only have the copy with the
deletions indicated.
Ms. DeGette. All right. We are going to hand it to you.
Apparently, it is not attached in the notebook, but do you
recall seeing a draft of a document that Ms. Katz wanted you to
look at?
Mr. Mosholder. Yes. That is actually the situation I just
described.
Ms. DeGette. Right, and here it is.
Mr. Mosholder. Thank you.
Ms. DeGette. Is that the document?
Mr. Mosholder. Well, this is the document showing where the
lines have been dropped. Yes.
Ms. DeGette. Right, where she wanted to redact it, and in
fact, her e-mail to you says, ``Andy, I have taken a look at
your written statement and made some suggested edits. Given
this will be a new document created to give to the Senate
Finance Committee, albeit based on an earlier document, I think
it is cleaner to make this a stand-alone document, i.e., to
include everything in it that is current and you would like to
include, and just delete out anything you would like to leave
out. I don't think it is necessary to indicate that this
document represents a version of the earlier one by noting that
the things that have been omitted. This simply invites the
Committee to ask further questions about what was omitted in
the earlier document. Please let me know if you have any
questions, etcetera. Thanks, Donna.''
Is it your understanding that, had you signed the revised
statement, it would have been submitted to Senator Grassley and
probably also this committee without notation regarding its
alteration?
Mr. Mosholder. Well, it wasn't a matter of signing it, but
the plan was that I would provide this to the Committee at the
start of my interview with them. So----
Ms. DeGette. Right. So if you had gone alone with this,
this redacted document without the--I mean the lines would have
been taken out. It would have been cleaned up, and that is what
would have been given to the Senate and also probably to us,
without notation of the things that had been taken out. Right?
Mr. Mosholder. That is my understanding of what was
proposed.
Ms. DeGette. And that is what you objected to?
Mr. Mosholder. Yes. I said I was not comfortable with that.
Ms. DeGette. Okay. Now take a look at Tab 58. What that is,
your reply to Ms. Katz the same day, which says, attached is a
version of the statement that you say you would have been
comfortable with. Right?
Mr. Mosholder. Yes, that's correct.
Ms. DeGette. And the e-mail reads: ``Thanks very much,
Donna. Your version is actually very similar to the one I came
up on my own this a.m. See attached. Although it might be
cleaner to do so, as you say, I am uncomfortable with
concealing from the Committee the fact this is not a new
document. Accordingly, I prefer to use the version I edited as
in the attached e-mail which otherwise incorporates all the
edits we have discussed. Thanks, Andy.'' Right?
Mr. Mosholder. Yes.
Ms. DeGette. And it is clear that you chose against the
wishes of Ms. Katz and, I assume, the other lawyers to revise
that document in such a way as to put the interest of
Congressional committees on notice the document had been
altered. Right?
Mr. Mosholder. Well, that was my intent.
Ms. DeGette. Right. Thank you very much, Mr. Chairman.
Mr. Walden. The Chair recognizes the gentleman from
Michigan, Mr. Stupak, for 10 minutes.
Mr. Stupak. Thank you. Did you incur legal expenses while
you were doing all these interviews with your Internal Affairs
and all this?
Mr. Mosholder. I did obtain legal representation. In point
of fact, I have a Federal employee liability policy which
provided for that. So my only expense was the insurance
premium.
Mr. Stupak. I can see an internal investigation on
something about some newspaper leak or something, but sounds
like here, and I think Ms. DeGette was being much too polite,
you were being squeezed here to change your testimony. Correct?
Mr. Mosholder. I'm not sure I would----
Mr. Stupak. I was police officer for 12 years. I would have
squeezed you and got it, too, you know. I mean, look, let me
ask you this. Go to Tab 89.
Mr. Mosholder. I'm sorry. Eighty?
Mr. Stupak. Eighty-nine, please. It is a June 16 letter
from Representative--I guess it is Senator Grassley to the FDA,
and on the fourth page the letter states--it is on Tab 89. It
says on page 4: ``Perhaps most troubling, however, was the fact
that the OND attempted to have Dr. Mosholder present reporting
rates of suicidal thoughts rather than the available clinical
trials data on anti-depressants in children which form the
foundation of his analysis.''
Can you please clarify the difference between the reporting
rates of suicidal thoughts and available clinical trials data?
Which is more reliable and relevant?
Mr. Mosholder. A reporting rate is a term we use when we
have spontaneous reports obtained through the MedWatch program,
and as the enumerator. Then that is divided by some measure of
the number of prescriptions in the U.S.
The problem with reporting rates is that it is usually
assumed we only have only a small fraction of the number of
events that are actually occurring in the population.
Mr. Stupak. Well, clinical trial data is far more reliable
than reporting rates. Right?
Mr. Mosholder. That is correct. When----
Mr. Stupak. And isn't it true that you were asked to
present the reporting rates instead of the clinical trial rates
or clinical trial data?
Mr. Mosholder. You could put it that way. That is true,
yes.
Mr. Stupak. Okay. Then why did you choose not to present
the reporting rates instead of your clinical trials data?
Mr. Mosholder. Well, this was an issue we had considerable
internal discussions about in preparation for the February 2
meeting. Ultimately, we in the Office of Drug Safety felt that,
given that suicidal behaviors are part of the reason why the
patients would be receiving the drug in the first place, giving
a rate of such events really is not very useful information,
and that the better data is done from trials where there could
be comparisons.
Mr. Stupak. So the better data is from the clinical trials
data, and they were requesting, pressuring you--whatever word
you want to use--to use the reporting rates and not the
clinical trials data. OND asked you to present reporting rates
instead of the clinical trials data. They wanted you to soften
your conclusions.
Mr. Mosholder. Well, at that point I was not presenting the
clinical trials data at all.
Mr. Stupak. But it was in your paper, your affidavit, if
you will. So you had it. Correct?
Mr. Mosholder. In my presentation to the Advisory Committee
February 2 I presented simply a number of reports, as I recall,
without the reporting rates in the end.
Mr. Stupak. Right, but you used clinical trials data,
because it is more reliable.
Mr. Mosholder. Yes. My opinion is that is better data. Yes.
Mr. Stupak. And OND wanted you to use reporting rates
instead of clinical trials data. Correct?
Mr. Mosholder. That is correct that they asked for that.
Mr. Stupak. Correct. And the reason for that is it softens
your conclusions that you put down in this paper, the
affidavit. Isn't that correct?
Mr. Mosholder. I'm not----
Mr. Stupak. Let me put it this way. The numbers look better
if you use reporting rates as opposed to the more reliable
clinical trials data. Isn't that correct?
Mr. Mosholder. My own opinion--well, that was a concern of
the Finance Committee investigator. My own opinion is that the
reporting rates simply are not informative. You can interpret
it as an attempt to--I wouldn't go----
Mr. Stupak. I'm not trying to put words here, but look it,
we established that the clinical trials data is more reliable
than the reporting rates. You were asked to change your
clinical trial data to reporting rates, which is not as
reliable. The reason to do that is then your affidavit, your
conclusions are not as firm and solid. It is a softening of
your conclusions, is it not? Softening is my word, not yours.
Mr. Mosholder. Well, I would say that the reporting rates
are inconclusive. There are no conclusions that you can draw
from reporting rates, in my opinion. So----
Mr. Stupak. Then why would OND want you to use reporting
rates, if they are not as solid, not as reliable?
Mr. Mosholder. Well, again there was difference of opinion
about that. My understanding was that it was for completeness,
because ordinarily this had been done and----
Mr. Stupak. How do you get completeness if you don't use
the most reliable data?
Mr. Mosholder. Well, that was----
Mr. Stupak. Completeness is the conclusion that one wishes
to draw from the report that you did, completeness in the eye
of the beholder. Right?
Mr. Mosholder. Well, my own preference would have been to
present the clinical trial data. Yes.
Mr. Stupak. Correct. Okay. Reporting rates--to your
knowledge, how many other instances were reporting rates
provided when more reliable data was available? Is this a
common thing? You medical officers do your reports. You look at
the most reliable evidence, which may be your clinical trials
data, and then you are told, well, geez, don't use that, let's
look at the reporting rates, and let's use reporting rates as
opposed to clinical data? Does that occur fairly often at the
FDA?
Mr. Mosholder. Not that I can recall, for just those
reasons, that situations where reporting rates are useful are
for very rare events that wouldn't necessarily be part of the
reason why the patient was receiving the drug. So that it----
Mr. Stupak. Absolutely. I agree with 1000 percent. Clinical
trial data is always better than reporting rates. My question
is: In the past, to your knowledge, has the FDA pressured
medical review officers who review the drugs and deal with the
data all the time to change from clinical trial data to
reporting rates?
Mr. Mosholder. I am not aware of any comparable situations,
personally.
Mr. Stupak. Your statement you gave here today--did the FDA
have to approve your statement you are giving here today before
the committee, your written statement?
Mr. Mosholder. No, they did not.
Mr. Stupak. Okay. If we do this labeling, packaging
labeling that was suggested in the Advisory Committee, will you
be involved in that process?
Mr. Mosholder. Not to my knowledge.
Mr. Stupak. I think someone may have asked you this, but
let me just clarify this.
What is your impressions of Dr. Hammad's study?
Mr. Mosholder. Well, I think the important point is that it
is very consistent with the findings I had in my analysis.
Mr. Stupak. That was my second question.
Mr. Mosholder. You know, it lends strength to the finding.
Mr. Stupak. So you would--Dr. Hammad's study is good work,
and you would agree with it?
Mr. Mosholder. Yes, and in many respects it is more
sophisticated than my first crack at the data.
Mr. Stupak. And it confirmed what your initial findings
were? Dr. Hammad's report confirmed what your initial
preliminary report showed. Correct?
Mr. Mosholder. That is my--my own biased opinion is that it
did confirm it, yes.
Mr. Stupak. Someone, I think, asked you this one, too, on
Tab 15 in which Dr. Avigan writes on your consult, ``Andy,
great job.'' If Dr. Avigan thought you did a great job with
your analysis, why did he later issue a dissenting memo to your
consult? It is in Tab 15.
Mr. Mosholder. Yes. I believe Dr. Avigan did not feel that
the data were ready to make the--or was sufficiently conclusive
to make the recommendations that I made in my consult.
Mr. Stupak. So you went from great job to being
inconclusive?
Mr. Mosholder. Well, to be fair, he did say that--at the
time of the first draft, I remember him telling me that we
would have to think about the recommendations some, but in the
end he felt that the data were not persuasive enough to endorse
my recommendations.
Mr. Stupak. Thank you, Mr. Chairman.
Mr. Walden. Thank you. Dr. Mosholder, I want to refer you
to Tab 78, if you would, sir, and go to--this is a memo. You
were the medical officer on review and evaluation of clinical
data. It is dated 12/13/96, received 12/16/1996, to Sulvay
Pharmaceuticals regarding Luvoxamine maleate.
Mr. Mosholder. Maleate, yes.
Mr. Walden. Thank you.
Mr. Mosholder. Or Luvox.
Mr. Walden. Thank you. That is even easier. I want to refer
you, though, to the second page, and it says: ``it's of
interest that in the adult studies the incidence of agitation
was 2 percent and 1 percent for fluoxomine and placebo,
respectively, while the pediatric study, the corresponding
incidences were 12 percent and 3 percent. That is, the risk
ratio for adults was two and for children was four. It is
possible this reflects a real difference in adverse reactions
between adults and children. There is an emerging literature
pointing to behavioral reactions to SSRI drugs in children.''
Then you make some references there or some references are made
here. ``It may be that this is a reaction to SSRIs that is more
prominent in children than adults. Further data would help
clarify this.''
Now I think what is interesting about this, this is a
December 1996 memo. The review was completed in February 1997.
Was this a flag you were raising in 1997?
Mr. Mosholder. Well, as I said, this was one of the very
first pediatric clinical trials we had seen with this class of
drugs, and although there had been some other reports,
apparently--I don't recall that reference at this point, but it
seemed to be raising the question of whether the behavioral
adverse effects might be different for kids versus adults.
Mr. Walden. Right. And you also said this is also reflected
in Pfizer's recently submitted study of Certraline in the
treatment of juvenile OCD as well in that reference. I guess
the reason I asked is it looks like from this documentation,
perhaps others, that this was sort of coming up as an issue
back in 1996-1997.
I wonder, as we go into these pediatric clinical trials,
could they have been designed better to go look at this issue
of suicidality in children and adolescents? Should we have
picked up on that sooner?
Mr. Mosholder. Well, that is a good question. Historically,
these two, as I recall, were the first actual studies we had
with this class of drugs in kids. So it suggests that a pattern
was starting to emerge. We, of course, didn't get more data
until several years later, but the----
Mr. Walden. But should the FDA have sought more data in the
way they designed the clinical trials for children?
Mr. Mosholder. Well, the question being, as we were writing
the request for pediatric studies, part of the pediatric
exclusivity, could we have done more to get at this issue.
Well----
Mr. Walden. In retrospect.
Mr. Mosholder. Yes, in retrospect, you know, perhaps more
attention could have been given to that. On the other hand,
these trials had done nothing special to look for this type of
event, and it seemed to be turning up. So that would be on the
side of saying routine adverse event monitoring was sufficient
to turn up this possibility.
Mr. Walden. Were you aware that apparently Dr. Knudsen also
had some warnings that go back to 1996?
Mr. Mosholder. I recall the----
Mr. Walden. For Zoloft.
Mr. Mosholder. [continuing] something about that at the
time. Then, of course, in preparation for this hearing I've
been reminded of that. Yes.
Mr. Walden. I guess that the question we keep going back to
is: Should this signal have been spotted sooner?
Mr. Mosholder. Well----
Mr. Walden. Because it raises the issue, are there other
signals that are bouncing around out there on other drugs being
prescribed off-label for people that we are not catching. How
do we fix the system, I guess, is part of it. Should we have
spotted this one sooner? Should FDA?
Mr. Mosholder. Well, one always wants to spot a problem as
soon as possible, of course. The issue here, I think, at least
in my own mind, was that we were lacking clinical trials in
children until the past few years, that the Luvox and Zoloft
studies were really sort of on the forefront of that, and so it
was more just a plain lack of data rather than lack of any
specific attention to it.
Mr. Walden. Okay. And I guess--but if we designed trials
right, you would have the data. You would have had the data.
Right?
Mr. Mosholder. And in fact, that is what we have currently.
Mr. Walden. And I guess what I also want to make sure of is
that, when we do have the data and they are evaluated by people
of your credibility, that those data then are applied
appropriately and the results are put out there appropriately.
I am troubled by an article that appeared in the August 7,
2004, British Medical Journal, and it states that Dr. Thomas
Laughren reported the relative risk ratios of all the anti-
depressants evaluated at the Pediatric Drug Advisory Committee
meeting, and that it was--``it was Dr. Mosholder's conclusions
and not the data that were withheld.''
Do you agree with Dr. Laughren's reported
characterizations?
Mr. Mosholder. Is this what was----
Mr. Walden. This is the article. He also says--you will see
in the second graph on this particular page--I'm sorry, second
column, the last paragraph on the page, both the raw data and
Dr. Mosholder's interpretation ``were imperfect,'' said Dr.
Temple, adding that some of the behaviors labeled suicidal were
highly suspect and could have been accidents, such as a child
``who hit her head with her hand.'' FDA officials acknowledged,
however, that some cases classified as accidental injury could
be suicide related. Because of this, they have gone on then to
Columbia University.
That is why I raise that issue about whether or not your
study included the incident of the girl slapping her head,
because it didn't include that, did it?
Mr. Mosholder. I included it in one analysis but not the
result that I----
Mr. Walden. But not in the results, not in your
conclusions.
Mr. Mosholder. Yes.
Mr. Walden. And so why would then Dr. Temple tell this,
allegedly, I suppose--it is printed here--say that that may be
part of the problem here, that it is imperfect. Did you think
your conclusions were imperfect?
Mr. Mosholder. Well, I'm not sure I can give an unbiased
answer to that. I think there was----
Mr. Walden. Well, do you think--let me ask this. Do you
think his characterization of your consult is correct?
Mr. Mosholder. I think we have had some--perhaps some
communications issues where I am not sure that it was--I
perhaps could have done more to make it obvious that I was
trying to get away from the question of the clinically trivial
events, if you will, such as the slapping in the face.
Mr. Walden. And I know we are putting you in a tough spot
here with some of these folks that are, you know, your
superiors sitting right behind you. I mean, I don't envy that
position. Trust me. But these are critically important issues
we have to get to.
Was your data analysis fully and fairly presented at the
February 2004 Advisory Committee meeting and, if not, what
should have been presented? What was presented, first of all,
since you didn't do the presentation?
Mr. Mosholder. As far as the clinical trial data, Dr.
Laughren gave the presentation of that.
Mr. Walden. Was it full and fair?
Mr. Mosholder. It did not include all of the results or
data that I had in my draft presentation.
Mr. Walden. I guess the point is did it include the most
important recommendations?
Mr. Mosholder. Well, it didn't include--well, apart from
the recommendations, the data I think that I would have
included--let me put it that way--would----
Mr. Walden. If you had been there presenting it, what would
you have included that wasn't included?
Mr. Mosholder. I would have included the analysis of the
serious subgroup of suicidal events and the meta analysis where
the data was combined across studies. I think that--if I were
doing or if I had a chance to do the presentation, that is what
I would have included.
Mr. Walden. So the way you would have presented it would
have painted a much more serious situation to that Advisory
Committee than the way it was painted, when it comes to the
risk of suicidality in adolescents and children? Is that
accurate?
Mr. Mosholder. I guess we will never know what the Advisory
Committee might have made of----
Mr. Walden. No, no, no. The difference in the two
presentations.
Mr. Mosholder. I think, if I had been doing it, it would
have perhaps been more obvious.
Mr. Walden. The chairman at the outset of this hearing
thanked you on behalf of the committee for your work, and I
think our country feels the same way. I know you have been
honored many ways.
Somebody told me you had been selected, too, to be the ABC
Person of the Week. Is there any truth to that?
Mr. Mosholder. I was told that I was nominated, but I did
not run.
Mr. Walden. Well, there is always next week, I guess.
All right. We are going to add, without objection, this
newspaper article from the British Medical Journal, August 7,
2004, to the record. Without objection, so ordered.
[The newspaper article follows:]
[GRAPHIC] [TIFF OMITTED] T6099.011
Mr. Walden. Do you have further questions? We have been
called to votes on the House floor, and it would--Mr. Stupak,
do you have anymore questions for this witness at this time?
Mr. Stupak. No. I just thank Dr. Mosholder for being here.
Mr. Walden. Thank you. And, Dr. Mosholder, we would like
you to stay with us, even though we probably won't have you on
the next panel. We would like to have you available, should
there be some questions that we need to seek your expert advice
on. So if you could stay with us.
We are going to recess the committee until after these
votes. There are four of them, which probably tells me it will
be 45 minutes before we are back here. So it is a good time for
everyone to go grab a quick bite, and we will reconvene the
committee immediately after those votes have concluded.
The committee is in recess.
[Brief recess.]
Mr. Walden. I am going to call this hearing back to order
and ask our next panel of witnesses to come up: Dr. Robert
Temple, Food and Drug Administration; Dr. Paul Seligman, Food
and Drug Administration; Dr. Thomas Laughren, Food and Drug
Administration; Dr. Tarek Hammad, Food and Drug Administration;
and Dr. James Knudsen, Food and Drug Administration. Please
come up to the witness table, if you would.
You are aware the committee is holding an investigative
hearing and, when doing so, has the practice of taking
testimony under oath. Do you have any objection to testifying
under oath? Do any of you have an objection?
Let the record show they all indicated they have no
objection.
The Chair then advises you that, under the rules of the
House and the rules of the committee, you are entitled to be
advised by counsel. Do you desire to be advised by counsel
during your testimony today? Mr. Knudsen? Could you turn on
your mike, sir, and then we will need you to identify your
counsel. Dr. Knudsen.
Mr. Knudsen. My name is Dr. James Knudsen.
Mr. Walden. Okay. Yes, you actually have to get kind of
close to that. Sorry. If you could identify for the record, Dr.
Knudsen, your counsel, please.
Mr. Knudsen. My counsel?
Mr. Walden. Oh, I thought you said you wanted to be
represented by counsel.
Mr. Knudsen. No, I did not.
Mr. Walden. Okay, fine. No? Okay. Dr. Temple? Dr. Laughren?
Mr. Laughren. No, sir.
Mr. Walden. Dr. Seligman?
Mr. Seligman. No.
Mr. Walden. Okay. So let the record show, none of them is
being represented by counsel.
In that case then, would you please rise and raise your
right hand, and we will take your testimony under oath. Let the
record show, they all indicated yes.
[Witnesses sworn.]
Mr. Walden. Thank you. You may be seated.
You are now under oath, and you may now give a 5-minute
summary of your written statement, and we will start with Dr.
Knudsen.
Mr. Walden. Dr. Hammad? No opening statement. Dr. Temple?
Actually, I am not sure your mike is on yet.
Mr. Temple. Now?
Mr. Walden. There it is, sir, yes. Thank you, and welcome.
TESTIMONY OF JAMES KNUDSEN, FOOD AND DRUG ADMINISTRATION;
ACCOMPANIED BY ROBERT TEMPLE, FOOD AND DRUG ADMINISTRATION;
PAUL SELIGMAN, FOOD AND DRUG ADMINISTRATION; THOMAS LAUGHREN,
FOOD AND DRUG ADMINISTRATION; AND TAREK HAMMAD, FOOD AND DRUG
ADMINISTRATION
Mr. Temple. Mr. Co-Chairman, I guess, and members of the
committee, I am Robert Temple, CDER's Associate Director for
Medical Policy. I welcome the opportunity to participate in
this hearing on FDA's regulation of pediatric uses of anti-
depressants.
My colleagues and I recognize that the entire discussion of
the past year has been very painful and difficult for people--
both for people whose loved ones have committed suicide while
on an anti-depressant and for people whose family members are
seriously depressed and are uncertain as to what they can do
for them.
Today I will briefly review the importance of detecting and
treating depression in children, the available treatments and
recent efforts to encourage studies of drugs in children, the
history of the concern, the subject of this hearing, about the
possibility that anti-depressants might provoke suicidal
thinking or behavior, and FDA's evaluation and data--of the
data from the pediatric depression studies.
Throughout my testimony and later, I will want to emphasize
an important concern that we had from the beginning of this. We
were concerned that overemphasis or premature conclusion about
an increased risk of suicidality related to anti-depressant use
could discourage treatment of serious pediatric depression,
which is a potentially life threatening condition.
At the same time, failure to take adequate note of the risk
could lead to inattention to the possibility for emerging
suicidality or to too casual use of the anti-depressants.
We dealt with this concern by making the public fully aware
of the issue and of the data that led to our concern, but we
thought it was responsible to withhold an agency conclusion
about what the data showed until it had been fully evaluated.
Depression in children is a serious mental illness that
affects up to 2.5 percent of children and 8 percent of
teenagers. In the U.S. there are about 1600 suicides in
teenagers per year, many of them in people who are diagnosed as
having depression.
The difficulty of obtaining good data on the effectiveness
and safety in drugs in children is well recognized. A provision
of the Food and Drug Administration Modernization Act which was
renewed in the Best Pharmaceuticals for Children Act in 2002
provides 6 months of patent extension to sponsors who carry out
pediatric studies that have been requested by the FDA.
This provision has enormously stimulated the conduct of
these studies, and it was FDA's analysis of the depression
studies submitted under these laws that led to the question of
whether the drugs could cause suicidality in children.
Specifically, review by Dr. Mosholder of adverse effects
collected under the term emotional lability in five Paxil
studies that were submitted under the Act detected an excess of
such cases, some of which appeared to represent suicidal
thinking or behavior in patients.
I can't emphasize too strongly that, although as you will
hear there were some disagreements on our part with some of Dr.
Mosholder's conclusions or whether they were right, this
discovery, this observation was of immense value and has kicked
this whole thing off. So let there be no question about whether
that was an important observation.
A request for a more focused analysis of the Paxil
suicidality data led to a further suggestion of an increased
rate of suicidality in the Paxil treated patients, and this was
more credible because the analysis was better than their
initial one.
FDA issued a Public Health Advisory on June 19, 2003,
describing the results of the Paxil evaluation and stating
that, although FDA had not completed its evaluation, we
recommended that Paxil not be used in children and adolescents
to treat major depressive disorder.
Subsequently, the Review Division asked all manufacturers
of newer anti-depressants for an analysis that was similar to
what GlaxoSmithKline had done for Paxil, and this was provided
by late September 2003. These reports were sent to Dr.
Mosholder and were also considered by the Review Division.
On October 27, 2003, FDA issued an updated Public Health
Advisory, again noting the suggestion of excess suicidality in
anti-depressant treated patients and the need for further data
and analysis.
The Review Division had been examining the data submitted
by the sponsors, too, as had Dr. Mosholder, and had significant
concerns about it. It, therefore, began in September-October
2003 to make arrangements to have the reported suicidality
events reviewed and reclassified by the Columbia Department of
Psychiatry.
Our concern was that the companies had cast a wide net in
seeking cases of suicidality, of suicidal thinking or instances
of self-harm, but not all such cases--for example, a
superficial cutting--represent attempted suicide.
I also want to say that I am somewhat embarrassed about my
BMJ quote from before, because at least by the time that came
out, I was well aware that Dr. Mosholder had excluded cases
like that. I think that reflected an earlier conversation. So
there is no question that he did exclude many such things, and
the banging of the head. So I feel bad about that. However,
remained concerned that the cases themselves needed close
evaluation, and I can talk later about how those data were
collected and why we thought they needed that.
Given our conclusion that they needed to be looked at
closely, we concluded that a blind expert classification of the
cases was needed.
In addition, we sent the Columbia reviewers narrative
descriptions of additional adverse reaction cases that had not
been included by the companies, because we thought there might
be excess--might be cases of suicidal behavior or thinking in
there, and that proved to be correct.
It is worth emphasizing that we had no idea what the
results of the reclassification would be. We didn't know
whether it would strengthen the findings or weaken the
findings. We had no way of knowing and no expectation, and not
to state the obvious, no preference. We just wanted to get at
what the right answer was.
At a February 2, 2004, Advisory Committee meeting we
presented the results of the company submissions, as you have
heard before, study by study, in part to make the point that
the results were very variable from one study to another, and
from one drug to another. But many of the drugs clearly showed
an increased risk of suicidality. That's the sum of suicidal
behavior and suicidal thinking.
We noted to the committee our concerns with the data
submissions and explained why we considered additional review
by Columbia necessary.
We also acknowledged that some in the agency thought the
results were, in fact, definitive and could be a basis for
change in labeling to discourage use of the drug, except for
Prozac, in children.
Although no specific question was put about this to the
committee, discussion indicated that they clearly understood
the agency's reservations, and they in fact expressed doubt
that anything arising from this kind of data collection would
be useful, a conclusion that they modified at the most recent
Advisory Committee.
The Advisory Committee recognized that, whatever the
relationship of anti-depressants to suicidality, it was
perfectly clear even then that the period after initiation of
treatment for depression was of great concern and that
physicians needed to be warned about this, the need to be
careful and make close observations.
On March 22, we asked manufacturers of anti-depressants to
add warning language to their labeling and issued a third
Public Health Advisory describing our request. The new warning
emphasized the critical importance of observing newly treated
patients for emerging suicidality or other problems.
All manufacturers added this warning to their labeling by
late summer. We have no received the reclassified cases from
Columbia and analyzed the data.
The analysis by Dr. Hammad was presented to the Advisory
Committee on September 13, 2004. The analysis included the
study you have heard about, the TAD study, a new study of
Prozac carried out by the National Institutes of Mental Health.
The analysis showed that, as a group, the anti-depressants
studied, both SSRIs and the so called atypicals, increased the
risk of suicidality. There was variation from drug to drug and
variation from study to study, but the roughly twofold
increased risk was reasonably consistent across drugs. As has
been pointed out, there were no actual suicides in these
trials.
At the September 13-14 Advisory Committee meeting, the
combined Pediatric and Psychopharm Drugs Advisory Committees
agreed with FDA's conclusions that the data in aggregate
indicated an increased risk of suicidality in pediatric
patients, and made several critical recommendations.
First, they believed the conclusion should apply to all of
the studied drugs, even though it was more prominent in some
than others. They also strongly urged that we apply it to any
new anti-depressant and to the older anti-depressants,
including the tricyclics. They thought that partly because the
logic seemed to be that this is a property of anti-depressants,
and they were quite concerned that people would be driven to
the tricyclics, which are rather more dangerous.
They did not believe the anti-depressants, other than
fluoxetine,should be contraindicated in children, and
repeatedly expressed concern that these drugs may be valuable
even if that has not been shown, and they were quite aware that
it had not yet been shown.
They strongly supported a patient and family directed Med
Guide which we had suggested to them, and two-thirds of them
thought the new warning information should be boxed.
On September 17 we announced publicly that we generally
support the recommendations and had begun working on new
labeling to reflect that. The term generally applies only to
the thought that we are going to read closely what they said
collectively about the boxed warning, and think about it.
Obviously, two-thirds of them thought that was reasonable,
but the discussion indicated concern that over-discouraging use
was potentially very dangerous, too, and they wanted a balance.
So we are going to be thinking about that.
I appreciate the opportunity to present these remarks, and
I look forward to your questions.
I am aware that you have also invited Dr. Russell Katz to
appear here this morning. Unfortunately, he is not able to
attend because a member of his family is having surgery today.
He will be happy to answer any questions you have for him in
writing or speak with your staff at a later date. Thank you.
Mr. Walden. We appreciate that, Dr. Temple. We were aware
of that, obviously, too, and did not want to interfere in his
very difficult time.
[The prepared statement of Robert Temple follows:]
Prepared Statement of Robert Temple, Director, Office of Medical
Policy, Center for Drug Evaluation and Research, U.S. Food and Drug
Administration
introduction
Mr. Chairman and Members of the Subcommittee, I am Dr. Robert
Temple, Director, Office of Medical Policy for the Center for Drug
Evaluation and Research (CDER) at the U.S. Food and Drug Administration
(FDA or the Agency). We appreciate the opportunity to discuss FDA's
review of the safety and efficacy concerns in anti-depressant drugs for
use in pediatric populations.
background on depression
Depression is a serious mental illness that affects the way nearly
19 million adult Americans feel, think, and interact. While everyone
experiences occasional sadness, particularly in response to loss or
adversity, a person with depression has persistent symptoms that can
significantly interfere with their ability to function. People with
depression cannot merely ``pull themselves together'' and get better.
Depression cannot be willed or wished away.
The two most severe types of clinical depression are major
depressive disorder (MDD) and bipolar depression, which is the
depressed phase of bipolar disorder. Within these types, patients
experience variations in the severity and persistence of mental
symptoms associated with these disorders. A person experiencing MDD
suffers from, among other symptoms, a depressed mood or loss of
interest in normal activities that lasts most of the day and nearly
every day, for at least two weeks. Such episodes may occur only once,
but more commonly occur several times in a lifetime. People with
bipolar disorder cycle between episodes of major depression, similar to
those seen in MDD, and highs known as mania. In a manic phase, a person
might act on delusional grand schemes that could range from unwise
business decisions to romantic sprees. Both MDD and bipolar disorder
can lead to suicide. The treatment of the two conditions is quite
different. In general, anti-depressants alone are not an appropriate
treatment for bipolar disorder.
depression in the pediatric/adolescent population
According to a 2000 National Institute of Mental Health (NIMH) Fact
Sheet on Depression in Children and Adolescents, depression affects up
to 2.5 percent of children and about eight percent of adolescents in
the United States. These disorders often go unrecognized by families
and physicians because behaviors associated with depressive disorders
may be seen as normal mood swings typical of a particular developmental
stage. In addition, health care providers may be reluctant to
prematurely ``label'' a young person with a mental illness diagnosis.
At the February 2, 2004, meeting of FDA's Psychopharmacologic Drugs
Advisory Committee (PDAC), Dr. Cynthia Pfeffer of Cornell University
addressed the issue of pediatric depression and its treatment. She
noted that pediatric depression is very common and often recurrent, is
often accompanied by very poor psychosocial outcomes for children and
adolescents, and is associated with high risk for suicide and substance
abuse. She reported that in 2001, about 1,600 15 to 19-year-olds
committed suicide in the U.S. Suicide is the third leading cause of
death in the U.S. in this age group and accounts for more deaths in
this age group than all other major physical conditions combined.
At that meeting, Dr. David Shaffer of Colombia University reported
on rates of suicidal ideation (thinking about suicide) and suicide
attempts. He obtained his information from large community studies,
particularly the Youth Risk Behavior Study (YRBS), a study carried out
by the National Center for Health Statistics. In this study, officials
from the National Center interviewed a broad population of between
15,000 and 20,000 high school students every two years using self-
reporting measures. Based on this data, it was determined that suicidal
ideation in high school students is extraordinarily common. Almost 20
percent of American high school students think about suicide. Suicide
attempts are also very common. Experts report that the overall rate is
about nine percent. Only about a quarter of these attempts are brought
to medical attention. It is widely recognized that adolescents are
frequently reluctant to disclose suicidal thoughts or even suicide
attempts to parents or others. There are about 4,000 female suicide
attempts for every female suicide death, and about 400 male attempts
for every male death.
Dr. Shaffer also showed rates of pediatric suicide over several
decades. The rate has fallen by about 25 percent over the last decade,
the period in which the use of anti-depressants has grown steadily.
This association does not prove that the increasing use of anti-
depressants is the cause of the decline in suicide, but it is at least
suggestive.
drugs for treating depression
Existing anti-depressant drugs influence the levels of one or both
of two neurotransmitters in the brain: serotonin and norepinephrine.
Older medications--tricyclic anti-depressants (TCAs) and monoamine
oxidase inhibitors (MAOs)--affect the activity of both of these
neurotransmitters. The disadvantage of the older medications is that
they can be difficult to tolerate due to significant side effects. MAO
use may also be subject to dietary and medication restrictions. TCAs
and MAOs are of limited value in the pediatric population because of
serious, potentially life-threatening adverse events. These include
tachycardia, convulsions, and shock-like coma. Moreover, TCAs are a
potential tool for adolescents attempting to commit suicide because
overdose can cause serious and protracted cardiac arrhythmias.
Newer medications, such as the selective serotonin reuptake
inhibitors (SSRIs), have fewer side effects than the older drugs,
making it easier for people to continue treatment. They have become
very widely used to treat depression, especially in the pediatric
population. FDA approved Prozac, the first SSRI, for adults, in
December 1987, and for children in January 2003. Experts believe that
SSRI drug products work by increasing the level of the hormone
serotonin in the brain. There were no approved drugs for the treatment
of depression in children before the January 2003 Prozac approval.
anti-depressant treatment and suicidality
Suicidality in the context of treating patients with depression and
other psychiatric illnesses has been a genuine concern and a
longstanding topic of debate. In fact, for many decades, anti-
depressant labeling carried the following standard language under the
``Precautions'' section of the label alerting clinicians to the need to
closely monitor patients during initial drug therapy due to concern for
the possible emergence of suicidality:
Suicide: The possibility of a suicide attempt is inherent in
major depressive disorder and may persist until significant
remission occurs. Close supervision of high-risk patients
should accompany initial drug therapy. Prescriptions for [name
of drug] should be written for the smallest quantity of tablets
consistent with good patient management, in order to reduce the
risk of overdose.
This standard precaution statement did not explicitly warn of the
possibility that anti-depressant drug products have a causal role in
the emergence of suicidality early in treatment. Several mechanisms
have been proposed to explain the clinical observation that some
depressed patients being treated with anti-depressants, particularly
early in treatment, have an increase in suicidality. In September 1991,
FDA convened a meeting of the PDAC to discuss this issue. At that
meeting, Dr. Martin Teicher, a psychiatrist from Harvard Medical
School, proposed various mechanisms to explain the emergence of
suicidality early in treatment of depression:
Roll back phenomenon: anti-depressants with prominent energizing
effects might actually increase suicidal behavior in severely
depressed patients who are suicidal but also have psychomotor
retardation and are thus inhibited from acting on their
suicidal thoughts.
Paradoxical worsening of depression: in rare cases, the patient's
depressed mood might actually worsen as a result of anti-
depressant treatment.
Akathisia (inability to sit still): some anti-depressants are
associated with akathisia, which might lead to suicidal
behavior in certain depressed patients.
Induction of anxiety and panic attacks: some anti-depressants may
induce anxiety and panic attacks, and these might lead to
suicidal behavior in certain depressed patients.
Stage shifts: anti-depressants may lead to switching the patient from
depression into mixed states in bipolar depressed patients,
possibly leading to suicidality.
Insomnia: insomnia associated with certain anti-depressants might
lead to suicidal behavior in certain depressed patients.
While all of these theories have some plausibility, it is difficult
to know whether these mechanisms are real. In addition, proposing a
mechanism is quite different from actually demonstrating that there is
a causal association between anti-depressant use and suicidality. It
might be possible to demonstrate that anti-depressants cause an
increase in suicidality through randomized clinical trials, but these
trials would need to be quite large because suicidality is not common.
It might be possible to pool results of many trials, but if this
involves results from studies of different drugs, the question remains
whether some drugs could behave differently from others. Furthermore,
assessing this risk in uncontrolled data is particularly difficult
because depression itself causes suicidality. In any given case, one
cannot usually distinguish whether the suicidality occurred because of
the drug or despite it.
anti-depressant-induced suicidality in adults
Thus, the question of whether anti-depressants can provoke
suicidality has been the subject of considerable discussion. With
regard to the adult population, the debate intensified in 1990 when Dr.
Teicher and several colleagues published a paper describing six adult
patients with depression who, in their view, became suicidal because of
treatment with Prozac. This paper and subsequent discussions led Eli
Lilly, the manufacturer of Prozac, to conduct new analyses of data from
their controlled trials for Prozac to look for suicidality. These
events also led FDA to fully re-evaluate its spontaneous reports
database to determine whether we could observe a signal of increased
risk.
During a September 1991 PDAC meeting, family members raised
concerns about suicide by loved ones whose deaths they attributed to
Prozac. Representatives from FDA, NIMH and Lilly also gave
presentations. FDA gave an update on the very substantial number of
spontaneous reports of suicidality in association with Prozac use, but
also noted the marked increase in reporting following the publication
of the Teicher paper and the publicity about the paper. A
representative from NIMH gave their perspective on the issue,
essentially making the case that depression is a serious disorder that
itself is associated with suicidality, and arguing that the data
available to date did not support the view that anti-depressants
further increase the risks of suicidality in this population. Finally,
Lilly presented the results of its analysis of data pooled over its
extensive clinical trials, revealing no signal of increased suicidality
in association with the use of Prozac. Following these presentations, a
majority of the Advisory Committee members concluded that there was no
clear evidence of an increased risk of suicidality in association with
Prozac, and did not recommend any changes to Prozac labeling.
Over the next several years, researchers accumulated additional
data as new anti-depressant drugs came to market. All of these
additional data related to the treatment of adults. In recent years,
several groups have conducted pooled analyses of data on completed or
attempted suicides from these studies in an effort to identify a
possible signal of risk from active treatment. They have also searched
for risk signals from patients assigned to a placebo group, since some
have challenged the use of placebo controls in a disease with
potentially serious outcomes. Arif Khan, a psychiatrist from the
Northwest Clinical Research Center, and other researchers published a
paper in 2000 based on adult data obtained from FDA reviews. Dr. Khan
concluded that the risk of completed suicide was the same, regardless
of treatment assignment. A similar study reached the same conclusion.
FDA researchers also analyzed completed suicides in 234 randomized
controlled depression trials of 20 anti-depressant drug products. Based
on all our analyses to date of these data, we reached a similar
conclusion: there does not appear to be an increased risk of completed
suicide associated with assignment to either active drug or placebo in
adults with MDD.
anti-depressants and suicidality in pediatric patients
Whether anti-depressant drug use causes suicidal thinking or
behavior in pediatric patients (or adults) is a critically important
question that we must answer in a careful, thoughtful manner. A
premature conclusion or emphasis in either direction could have adverse
consequences for those who are suffering from depression. Missing or
understating a signal of increased risk of suicidality could result in
greater reassurance than is warranted about the safety of these drugs,
insufficient attention to the patients being treated, and perhaps too
casual use of the drugs. On the other hand, overstating the risk could
result in overly conservative use of these drugs or excluding their use
for the pediatric population, and inadequate treatment of a potentially
fatal condition. Below we discuss the origins of the concern that anti-
depressants could provoke suicidal ideation in children.
use of anti-depressants in the pediatric population
Many people have expressed concern about pediatric use of products
approved for MDD in adults where clinical trials in children were
negative. Prozac is the only product for which efficacy has been
established sufficiently to meet FDA's standards for approval in the
pediatric population. To date, clinical trials evaluating six other
current generation anti-depressants approved for adults have not met
FDA's standards for establishing efficacy in the child/adolescent
population. Nevertheless, there is widespread belief among treating
physicians that these products do in fact work and that the
``negative'' results are in fact inconclusive. Negative trials are not
necessarily informative in MDD trials because they may be an indication
of inadequate trials rather than evidence of benefit.
Because Prozac is the only product for which efficacy has been
establish for treatment of pediatric/adolescent MDD, it is often the
first product prescribed by a physician. However, in 30-40 percent of
cases, Prozac does not work for the patient. In such cases, it is
standard care for physicians to prescribe one of the other current
generation anti-depressants approved for adults. The older medications,
tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors
(MAOIs), have not been approved for use in pediatric/adolescent
population. Moreover, as noted previously, they are of limited value in
the pediatric population because of serious, potentially life-
threatening adverse events. They may cause life-threatening arrhythmias
in overdose or even at normal doses in individuals who are unable to
efficiently metabolize these drugs.
fdama and bpca stimulate new pediatric suicidality data
The question of suicidality arose in the course of FDA's review of
clinical trials of anti-depressants in children. When Congress enacted
the FDA Modernization Act (FDAMA) in 1997, it provided incentives to
manufacturers to conduct pediatric clinical trials. Section 111 of
FDAMA authorized FDA to grant additional marketing exclusivity (known
as pediatric exclusivity) to pharmaceutical manufacturers that conduct
studies of their drugs in pediatric populations. To qualify for
pediatric exclusivity, sponsors must conduct pediatric studies
according to the terms of a Written Request from FDA and submit the
results of those studies in a new drug application or supplement.
Congress renewed this authority in 2002, in the Best Pharmaceuticals
for Children Act (BPCA).
BPCA contains important, new disclosure requirements. For studies
other than those submitted under the BPCA, the Agency generally may not
publicly disclose information contained in investigational new drug
applications, unapproved new drug applications, or unapproved
supplemental new drug applications. Only after a new drug application
or supplemental new drug application is approved can the Agency make
public certain summary information regarding the safety and
effectiveness of the product for the approved indication. However,
section 9 of BPCA regarding the dissemination of pediatric information
gives the Agency additional disclosure authority and differs from FDA
regulations that generally preclude the Agency from disclosing to the
public information in an unapproved application. BPCA requires that, no
later than 180 days after the submission of studies conducted in
response to a Written Request, the Agency must publish a summary of
FDA's medical and clinical pharmacology reviews of those studies.
Moreover, we must publish this information regardless of whether the
action taken on the pediatric application is an approval, approvable,
or not-approvable action. Thus, although under FDAMA information on
pediatric studies conducted in response to Written Requests is not
available until after the supplemental application is approved, under
BPCA, a summary of FDA's medical and clinical pharmacology reviews of
pediatric studies, conducted in response to a Written Request issued
under BPCA, is publicly available irrespective of the action taken on
the application.
bpca written requests for anti-depressants
Prior to the enactment of BPCA, under the pediatric exclusivity
authority of FDAMA, FDA issued seven Written Requests to manufacturers
of drugs approved for the treatment of depression (Prozac, Zoloft,
Remeron, Paxil, Celexa, Serzone, and Effexor). The sponsors of three of
these drugs (Prozac, Zoloft, and Remeron) performed the studies and
submitted the reports of their studies before FDAMA expired on January
1, 2002 (and thus, before BPCA took effect). The manufacturers of two
of these drugs, Prozac (which has been approved for the treatment of
pediatric depression) and Zoloft (which was studied but not approved
for the treatment of pediatric depression) received pediatric
exclusivity for having conducted studies. The third sponsor, the
manufacturer of Remeron, did not receive pediatric exclusivity. Under
FDA's general disclosure provisions regarding the availability of data
and information in approved applications, information on the approved
pediatric use of Prozac is publicly available at: http://www.fda.gov/
cder/foi/nda/2003/18936s
064_Prozac.htm. Just as it has for other product approvals, FDA posted
this information because we granted approval for Prozac for use in
treating pediatric depression. The pediatric data for Zoloft and
Remeron would not normally be available for public disclosure because
their pediatric supplements have not yet been approved. However, FDA
nonetheless asked the sponsors to allow us to make summaries of these
studies public. The sponsors agreed to our request and summaries are
now available on FDA's website at: http://www.fda.gov/cder/pediatric/
Summary
review.htm.
Following enactment of BPCA in January 2002, FDA determined that
the provisions of this new law should apply as broadly as possible to
outstanding Written Requests for which studies had not yet been
submitted. In a July 2002 letter, the Agency notified drug sponsors
with outstanding Written Requests issued under FDAMA that FDA
considered those Written Requests to be reissued under BPCA. In its
July 2002 letter, FDA further advised manufacturers that any studies
submitted in response to the reissued Written Requests would be subject
to the terms of the BPCA, including, among other things, the provisions
governing public availability of study summaries. However, the Written
Requests for three anti-depressants (Paxil, Celexa, and Serzone) were
not considered as reissued under BPCA in July 2002 because the
manufacturers had already submitted their pediatric studies to the
Agency before FDA issued its July 2002 letter (albeit after BPCA was
enacted). Therefore, FDA considered the studies for Paxil, Celexa, and
Serzone, to have been submitted under FDAMA; did not consider their
Written Requests to be reissued, and did not apply the public
disclosure provisions of BPCA to these studies. Nonetheless, the Agency
has received permission from the sponsors of these drugs to post
summaries of the safety and effectiveness reviews of their pediatric
studies on FDA's website, and this information appears at: http://
www.fda.gov/cder/pediatric/Summaryreview.htm.
Only one of the outstanding and reissued Written Requests under
BPCA was for studies relating to the treatment of pediatric depression.
This Written Request was for Effexor. FDA granted pediatric exclusivity
for this product and posted the study summaries on the FDA Pediatric
Summary Review website, according to the requirements of BPCA. No new
Written Requests for anti-depressants have been issued since the
passage of the BPCA.
We want to emphasize that although these anti-depressants have all
been shown to be effective in adults, in its Written Requests FDA asked
manufacturers to conduct two pediatric studies because we knew from
experience that it is very difficult to show the effectiveness of anti-
depressants in children. In all studies submitted in response to
Written Requests, no completed suicides occurred in the trials.
Nonetheless, FDA reviewers of these Written Requests identified a
suicidality concern during the course of their review.
results of the paxil written request
FDA has been reviewing the results of anti-depressant studies in
children since June 2003 after an initial report on studies with
paroxetine (tradename, Paxil) appeared to suggest an increased risk of
suicidal thoughts and actions in the children given Paxil, compared to
those given placebo. During the review of the supplemental new drug
application submitted by GlaxoSmithKline (GSK) for the use of Paxil in
children, FDA reviewers noted a greater number of adverse events coded
under the term ``emotional lability'' in patients treated with Paxil
compared to the placebo group. FDA reviewers in the Division of
Neuropharmacological Drug Products (DNDP) of FDA's CDER noted this in
some, but not all, of the Paxil studies. The reviewers also noted that
the actual events coded under this term included suicidal thoughts and
attempts as well as a wide range of other events.
In an effort to better understand these events and to focus on
suicidal thoughts or behavior, DNDP asked the sponsor to reanalyze its
data and better characterize the adverse events identified under the
term ``emotional lability.'' This FDA request resulted in additional
work by GSK and a report on suicidality, submitted first to the UK
(UK), and, shortly thereafter, to FDA.
gsk approach to accumulating paxil summary data
GSK's re-analysis of the Paxil data focused exclusively on placebo-
controlled trials (of which there were six). This has been FDA's focus
as well. As noted earlier, in their original pediatric supplement, GSK
classified adverse events suggestive of suicidality (as well as various
other behavioral events) under the general term ``emotional lability.''
In response to our request for a separate approach to better identify
events that suggested suicidality, GSK conducted searches to find
events of potential interest. GSK's adverse event data was in an
electronic file that allowed them to search for text strings that
suggested suicidality, e.g. ``overdose,'' ``suic,'' ``hung,'' ``cut,''
etc. The company conducted a blind evaluation of all events detected by
this text search to select those considered possibly suicide-related. A
subset of these events that could represent self-harm was then
classified by GSK as suicide attempts. GSK's examination of events was
limited to those occurring within 30 days of the patient's last dose.
GSK submitted its report to FDA on May 22, 2003. This report
suggested an increased risk (Paxil vs. placebo) of various thoughts and
behaviors coded as events considered ``possibly suicide related.'' In
addition, there was a suggestion of increased risk for the subgroup of
events that met the sponsor's criteria for ``suicide attempts.'' The
signal for increased risk was clearest in 1 of the 3 trials involving
pediatric patients with MDD.
It is important to note that these analyses were difficult because
investigators used a large variety of terms to describe what might have
been suicidal behavior and provided variable amounts of detail when
identifying these events. The standard assessments of depression used
to evaluate effectiveness all had an item indicating suicidal thoughts,
and an evaluation of these scales showed no increased suicidality
compared to placebo. However, the trials were not designed to focus on
the question of suicide risk with drug treatment. To address this
concern, we plan to develop guidance for subsequent trials that will
lead to a standard nomenclature and assessment by investigators.
initial response to signal of increased risk of suicidality for paxil
The reaction to the GSK report by the Medicines and Healthcare
Regulatory Agency (MHRA) in the UK was to issue a public statement
explicitly stating that Paxil ``should not be used in children and
adolescents under the age of 18 years to treat depressive illness,''
and to institute a labeling change contraindicating Paxil in pediatric
MDD.
On June 6, 2003, Dr. Russell Katz, the director of DNDP, asked the
Office of Drug Safety (ODS) to perform a consult review of the newly
submitted GSK safety data.
Dr. Katz requested that ODS assign Dr. Andrew Mosholder as the
primary reviewer for the consult because Dr. Mosholder had previously
been involved in reviewing data on the safety and efficacy of anti-
depressants and had generated the original request to GSK. On June 19,
2003, FDA issued a public health advisory stating that: ``Although FDA
has not completed its evaluation of the new safety data, FDA is
recommending that Paxil not be used in children and adolescents for the
treatment of [major depressive disorder].''
FDA also requested data similar to that submitted by GSK from the
manufacturers of eight other anti-depressant drugs that were studied in
children. On July 22, 2003, the Agency sent requests for data to the
manufacturers of the following drugs: Prozac, Zoloft, Luvox, Celexa,
Wellbutrin, Effexor, Serzone, and Remeron. In those letters, we asked
manufacturers to identify suicide-related events for their pediatric
studies in a blinded manner using two search strategies. We modeled our
request to these manufacturers on the approach used by GSK, and asked
manufacturers to conduct an electronic search for text strings relevant
to suicidality similar to the approach employed for Paxil. We also
asked manufacturers to blindly search narrative summaries for any
serious adverse events to identify additional instances of ``suicide-
related events.''
fda re-review of data from pediatric supplements for other anti-
depressants
While waiting for the various manufacturers of anti-depressants
other than Paxil to respond, we went back to the adverse event data in
the pediatric supplements for the other eight drugs to re-examine the
question of suicidality. Our major question was whether there were
other anti-depressants with possible signals of increased risk for
suicidality, as was observed for Paxil.
There were several limitations to this re-examination. First, the
methods for detecting and coding events were not standard across these
studies. Second, because we wanted to have categories similar to those
used for the Paxil data for purposes of comparison across drug
programs, we classified events described in the adverse event listings
for these drug programs into two categories: ``possibly suicide-
related'' and ``suicide attempt.'' One obvious flaw in this approach
was that FDA's reviewer was not blinded during this reclassification
process. Nevertheless, we believed this re-examination of summary data
might shed some light on the possibility of signals emerging from other
anti-depressant programs. We discovered that there were signals of
increased risk of suicidality for patients assigned to drugs other than
Paxil. We also found that the findings were not consistent across the
studies, even for individual drugs.
august 2003 effexor labeling change and fda's response
While we were beginning to receive responses to our requests for
summary data from the sponsors for the other anti-depressants, Wyeth
Pharmaceuticals, the manufacturer of Effexor and Effexor XR, decided to
make labeling changes for its products to address reports of
suicidality and hostility. Sponsors have the authority to make changes
to strengthen labeling to address safety issues without prior FDA
approval. This action was based on the company's re-analyses of data
from the Effexor pediatric trials. The labeling change was the addition
of a statement to the ``Usage in Children/Pediatric Use'' section in
the ``Precautions'' section of the label to note increased reports of
hostility and suicidality. This labeling change was accompanied by an
August 22, 2003, ``Dear Health Care Professional'' letter noting the
findings and noting that these products are not recommended for use in
pediatric patients.
In September 2003, the UK MHRA issued a regulatory response on
Effexor similar to its response to the report on Paxil suicidality
data. It issued a public statement advising prescribers against the use
of Effexor for the treatment of pediatric MDD. This statement was
accompanied by a labeling change to contraindicate the products for
that pediatric indication. FDA did not take any specific regulatory
action on Effexor because we viewed the data as preliminary. Like data
for other anti-depressant drug products, it required a more detailed
review.
september 2003 fda internal regulatory briefing
An important milestone in our consideration of the pediatric
suicidality data was the September 16, 2003, internal briefing for
upper level CDER management. This briefing occurred at a time when we
only had a preliminary review of the summary data for Paxil and a crude
internal re-analysis of suicidality data from the other pediatric
supplements. We had not yet received and reviewed the requested new
analyses from all the sponsors of pediatric drugs.
There were several agreements reached at this meeting, including
two that were of particular importance for our further plans to address
this issue. We recognized that we had cast a very broad net to attempt
to capture events of potential interest for possible suicidality. This
was appropriate, but it meant that individual cases needed closer
examination to determine what they actually represented. Our first
conclusion was that it would be useful to try to have all events of
potential interest blindly reclassified by outside experts in
suicidality in order to have greater confidence in what the signals
represented. This conclusion eventually led to the Columbia
Classification Project, described in greater detail below. Second,
because it was apparent that there was inconsistency in the signals of
suicidality among the individual studies of the various drugs, we also
concluded that it would be useful to attempt to obtain patient-level
data sets for all of these trials. This would permit analyses that are
more refined and allow adjustments for potentially important
covariates. These agreements strongly influenced the subsequent course
of our efforts to better understand these data.
responses to fda's request for summary data for other anti-depressants
The responses to FDA's request for summary data for all of the
anti-depressants arrived by late September 2003. These responses were
received within DNDP and forwarded to Dr. Mosholder in ODS as they
arrived, over roughly a six-week period. Unfortunately, as we began
reviewing these responses, it became clear that different sponsors had
interpreted the July 22, 2003, request differently. This caused us to
doubt whether all eight manufacturers used similar approaches in
selecting, classifying, and presenting cases of suicidality for review.
There was also a concern, due to the methods used by the manufacturers
to search their database, about the possibility that manufacturers had
not captured all adverse events of potential interest.
This impression was confirmed when we spoke to individual
manufacturers about their approach to our request. In retrospect, the
algorithm we had provided to search for potential events and select
patients experiencing those events was not sufficiently detailed to
result in a common understanding. This discovery presented a major
hurdle in our evaluation of these data, because we needed to have
confidence in the thoroughness and uniformity of the methods used to
gather and classify these cases. We realized that we would need to be
more certain that manufacturers captured all relevant cases, and that
the relevant cases were appropriately classified.
Greater certainty on this point was necessary to accurately assess
the ability of these drugs to provoke suicidality. For example, we did
not receive complete descriptions of how manufacturers conducted
searches or why manufacturers included or excluded individual cases. In
at least one case, the search for and classification of cases was not
conducted in a blind manner to avoid bias. In another case, what
appeared to be a strong signal in our preliminary analysis of the
previously submitted data became a weak signal on re-analysis by the
manufacturer. In all, we concluded that we needed to better understand
the classification and analysis process.
fda decision on independent reclassification of cases
FDA also was concerned about case definition and selection by
manufacturers in response to our July 22, 2003, letters. We noted
substantial differences across different drug products in the selection
of cases included as suicide attempts. Some sponsors decided to include
essentially all captured events as suicide attempts, even though there
was clearly not enough information in some of the cases to justify such
a classification.
For example, there was concern about a number of the adverse events
classified under the category ``possibly suicide related.'' In one
case, a young girl slapped herself on the face and researchers coded
this as a suicide attempt. A number of other events coded as ``suicide
attempts'' involved children who had engaged in superficial cutting
behavior and children who had ingested small numbers of pills in sight
of parents. Such events, while of concern in their own right, would not
necessarily be an indication of suicidal behavior.
This confirmed the view reached tentatively at our September 2003
internal regulatory briefing of the need to have potential events
blindly reclassified by an independent group. Although we briefly
considered doing this internally, we rejected this idea because FDA did
not have the expertise in suicidality to conduct such a large
reclassification effort. Furthermore, most employees who might
logically participate in such an effort had already seen many of the
cases. These reviewers could also be biased because they were aware of
the treatment assignment (drug or placebo).
further requests for data/initiate the ``columbia'' study
Thus, we began to look outside the Agency and initiated a series of
discussions with outside experts. Although we found several experts
interested in such an effort, there remained the problem of who could
coordinate this work and establish methods and criteria for
reclassification.
Columbia University not only had well-recognized expertise in
adolescent suicidality, but also had developed an approach to
classifying events that possibly were representative of suicidality,
and this approach precisely fit our needs. We conducted extensive
discussions with this group in order to establish a contract to
accomplish this reclassification of cases and to work out the details
of a standard approach to finding all relevant cases and setting up
categories for the reclassification effort that would meet our needs.
Additionally, as we reviewed the summary data provided by the
various sponsors in response to our July 22, 2003, letters, we again
noted an inconsistency in results across trials, even within individual
programs, that we had observed in our re-review of the pediatric
supplements. To further address this issue, on October 3, 2003, DNDP
requested patient-level data sets from all manufacturers of the nine
anti-depressant drugs. The availability of these more detailed data has
permitted FDA to perform a more refined analysis, taking into
consideration possible imbalances across study groups in these trials.
In order to ensure that we had a complete capture of all relevant
events that might possibly be related to suicidality for these trials,
we issued follow-up requests to our
july 2003 letters; these requests were made on november 24 and december
9, 2003.
This complete set of narratives was sent to Columbia University for
review by a panel of international pediatric suicidality experts. This
group was assembled to undertake a blinded review of the reported
behaviors using a rigorous classification system.
fda's october 2003 updated public health advisory and talk paper
FDA issued an updated Public Health Advisory and Talk Paper on
October 27, 2003, based on our assessment of the pediatric suicidality
data at that time. Although we indicated that preliminary data
suggested an excess of reports of suicidality for several anti-
depressant drugs, we noted the need for additional data and analysis.
We also noted that we intended to bring this issue to an advisory
committee meeting. We advised caution in the use of any of these drugs
in treating pediatric MDD, and reminded prescribers of the standard
language already in anti-depressant labeling alerting clinicians to the
need for close supervision of high-risk patients, particularly during
initial onset of drug therapy.
december 2003 uk mhra action on anti-depressant treatment of pediatric
mdd
The UK MHRA made a public announcement on December 10, 2003,
indicating that, in addition to its earlier statements regarding the
contraindications of Paxil and Effexor in pediatric MDD, it was now
also contraindicating all SSRI anti-depressants except Prozac for this
condition. This announcement noted that the risk to benefit profile
could not be assessed for Luvox, and that, the risk to benefit profile
is favorable in pediatric MDD for Prozac only. Serzone and Wellbutrin
are not approved drug products in the UK. Remeron is an approved
product in the UK, but MHRA has offered no specific comment on the
pediatric data for this drug.
fda's february 2, 2004 advisory committee meeting
FDA uses advisory committees to gain expert advice about scientific
and public health issues and/or regulatory decisions. In preparing for
an advisory committee meeting, scientific team leaders, supervisors and
managers--seasoned regulatory scientists with drug development and
public health expertise--exercise scientific judgment in synthesizing
issues to be brought before advisory committees. This process is
designed to ensure that an advisory committee considering an issue is
provided with sufficient data and information to fully discuss the
issues.
While CDER was conducting its more in-depth review of the data from
the pediatric clinical trials, planning was also under way to hold a
meeting of the PDAC on
February 2, 2004. Because the BPCA mandates a review of the post-
marketing safety data for products that have been granted pediatric
exclusivity, this meeting was convened to review the post-marketing
safety reporting for a number of products (not limited to anti-
depressants). One of the drugs scheduled for discussion at the February
2, 2004, Advisory Committee meeting was Paxil.
In planning for the discussion of the safety of the use of Paxil in
children, the Agency initially intended to broaden the PDAC meeting to
include a discussion of the Agency's review of the safety concerns
arising from the data on the use of anti-depressants in children, as
these concerns were clearly of public interest. However, as the reviews
and meeting planning progressed, it became clear that the additional
analyses of the data from the clinical trials of anti-depressants in
children, particularly the Columbia analysis, would not be completed in
time to present the Agency's final assessment of these data at the
Advisory Committee meeting.
The Agency decided to proceed with the plans to discuss the post-
marketing safety data for Paxil at the meeting, to brief the Advisory
Committee on the Agency's progress in evaluating data from the clinical
trials of anti-depressants in children, and to solicit advice and
comment regarding the Agency's plans for further analyses. The plan
included returning to the Advisory Committee for another meeting once
the Agency's more definitive analyses of the clinical trial data were
complete. This would allow us to solicit Advisory Committee input
before taking further regulatory action.
While CDER was moving ahead with plans for the February 2, 2004,
Advisory Committee meeting, Dr. Mosholder was nearing completion of his
review of the data from the clinical trials provided in response to our
July 22, 2003, request. Based on his review, he believed that the
available data were sufficient to reach a conclusion about an
association between the use of anti-depressants and suicidality in
children and to recommend additional regulatory action, without the
need for the more in-depth case classification or analyses that had
already been initiated by DNDP. Dr. Mosholder shared his conclusions
with his supervisors and with the DNDP/ODE I review team involved in
reviewing this issue. The review team and Dr. Mosholder's direct
supervisors did not agree that the available data were sufficient to
reach a conclusion and believed that definitive action should await the
re-analysis by Center staff using the Columbia data. There was a
discussion within the DNDP/ODE I review team, as well as higher CDER
management including Drs. Katz, Laughren, and Temple, as to whether
Dr. Mosholder's scientific and regulatory conclusions on the data
should be presented in some form at the February meeting, given that
they did not represent the Agency's (but rather an individual staff
member-s) determination; it was concluded that they should not be.
However, at the February 3, 2004, meeting, Dr. Laughren did present
the data that led Dr. Mosholder to his conclusions, although not in
detail. These data plainly showed an excess of suicidality in
individual studies and across the studies as a group.
Dr. Laughren also explained the Agency's reservations about the
classification.
Dr. Katz also acknowledged in his presentation to the Advisory
Committee that some reviewers had reached a conclusion that the data
were sufficient to conclude that there was a link between anti-
depressant use and suicidality in children. The Agency did not present
Dr. Mosholder's conclusion in detail because of concerns that this
would have given his determination the appearance of an Agency position
before the Agency had made such a determination. This could have been
harmful to the public health because it might have led patients who
were actually benefiting from the use of these drugs to inappropriately
discontinue therapy with potentially dire consequences, or to avoid
treatment when it might be the best option.
Senior CDER staff believed that the best way to serve the public
health on this very complex and important issue was to: 1) disclose the
available publicly releasable safety data during the Advisory Committee
meeting; 2) describe the limitations of those data in supporting a
definitive conclusion; and, 3) describe the Agency's plans to further
evaluate the data. The Agency realized its responsibility to the public
to find the right answer to this question. A premature conclusion that
these drugs are harmful (when used in the pediatric population) that
does not hold up during a more careful review would be a disservice to
the public health given the serious and potentially life-threatening
nature of severe depression. This is of particular concern since there
are no acceptable therapeutic alternatives for health care providers
and their pediatric patients with depression.
cder's decision-making process on safety issues
CDER's decision-making process is designed to ensure that
regulatory actions or policy formulation take into consideration an
array of perspectives and concerns designed to advance public health.
The process requires that primary reviewers, team leaders, supervisors,
and managers work together effectively.
In the free and open discussion of CDER issues within a scientific
and regulatory environment, we expect differing professional judgments/
opinions. Individual employees are strongly encouraged to discuss their
views with co-workers. A number of opportunities are available to
discuss and resolve scientific differences and enhance decision-making.
These include meetings among review teams, meetings with the
supervisory and management chains within the Center and Agency,
meetings with sponsors, CDER regulatory briefings and Advisory
Committee meetings.
It is never the goal of these discussions to pressure or convince
reviewers to reach any particular conclusion, or to reach a different
conclusion that they have already reached, but only to provide a forum
for a free exchange of views by all. After considering all of the
relevant data and arguments, individual reviewers are expected to write
reviews that reflect their best judgment. If their supervisor disagrees
with their conclusions and/or recommendations, the supervisor documents
the disagreement, and the resolution of the disagreement, in the
official administrative file on a matter.
fda's march 2004 advisory: new warning statement in labeling
At the February 2, 2004, Advisory Committee meeting, experts raised
concerns about the possible relationship between anti-depressant drug
products and suicidal behavior and suicidal ideation and supported a
labeling change to warn of possible suicidality. On March 22, 2004, FDA
responded to these concerns by issuing a Public Health Advisory and
asked manufacturers of Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro,
Wellbutrin, Effexor, Serzone and Remeron to include a warning statement
in their labeling recommending close observation of adult and pediatric
patients treated with these drugs for worsening depression or the
emergence of suicidality.
In this statement, the Agency informed the public that symptoms
such as anxiety, agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, and mania have been
reported in adult and pediatric patients who are being treated with
anti-depressants for MDD. We warned that patients who experience one or
more of these symptoms might be at an increased risk for worsening
depression or suicidality. The Agency pointed out that we did not know
whether the drugs increased suicidality but warned that medications may
need to be evaluated and perhaps discontinued when symptoms are severe,
abrupt in onset, or not part of the patient's presenting symptoms. FDA
urged health care providers to instruct patients, their families, and
their caregivers to be alert for the emergence of agitation,
irritability, and the other symptoms described above, as well as the
emergence of suicidality and worsening depression, and to report such
symptoms immediately to their health care provider.
``columbia'' study results
The Columbia group submitted its completed review to FDA in July
2004. FDA then developed its analysis of the pediatric suicidality data
based on the case classifications provided by Columbia University.
While there were findings among these data suggestive of an increased
risk of suicidality for some of these drugs, inconsistencies remained
in the results, both across trials for individual drugs and across
drugs. Thus, an overall interpretation of these findings represented a
substantial challenge to the Agency. The Agency brought these findings
to the Psychopharmacologic Drugs and Pediatric Advisory Committees in
September 2004 for further consideration.
fda's august 2004 advisory: agency plan to present data to advisory
committees
As part of its commitment to keep the American public fully
informed about the status of its review of data concerning the use of
anti-depressants in pediatric patients, on
August 20, 2004, FDA informed the public of its detailed plan to
present new data to the Psychopharmacologic Drugs and the Pediatric
Advisory Committees. This new data, which FDA posted on its website,
included the Agency's interpretation and analyses of pediatric
suicidality data based on information obtained from the Columbia Study.
In addition, the Agency sought advice on appropriate regulatory
actions, such as labeling changes to ensure that the labels of anti-
depressants used in pediatric patients reflect the most recent
information obtained from current studies and analyses.
As we noted previously, FDA also announced that it posted
additional summaries on its web site of pediatric efficacy studies for
drugs that have been studied for depression in pediatric patients.
These summaries are for Paxil, Celexa, Serzone, Zoloft and Remeron.
Although specific new labeling language has yet to be developed, FDA
will work to assure that the labels of the anti-depressants used in
pediatric patients reflect the most recent information obtained from
these studies and analyses.
fda's september 13-14, 2004 advisory committee meeting
On September 13 and 14, 2004, a joint meeting was held between the
Psychopharmacologic Drugs and Pediatric Advisory Committees to consider
the occurrence of suicidality in the course of treatment of pediatric
patients with various anti-depressants. The primary focus of FDA's
presentations at the September 2004 meeting was to provide committee
members with (1) a detailed description of FDA's approach to evaluating
and analyzing the pediatric suicidality data, and (2) the results of
this work. The Agency also included presentations on related studies,
in particular, several pertinent epidemiological studies and TADS
(Treatment of Adolescents with Depression Study). Committee members
heard presentations by both FDA staff and experts in pediatric
suicidality from the academic community outside of FDA.
The overall consensus of the committee was an endorsement of FDA's
approach to classifying and analyzing the suicidal events and behaviors
observed in the controlled clinical trials. Committee members expressed
their view that the new analyses increased their confidence in the
results. Further, the committee members concluded that the finding of
an increased risk of suicidality in pediatric patients applied to all
the drugs studied (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa
Wellbutrin, Luvox and Serzone) in controlled clinical trials. In
addition, the members:
recommended that the products not be contraindicated in this country
because the Committees thought access to these therapies was
important for those who could benefit;
recommended that the results of controlled pediatric trials of
depression be included in the labeling for anti-depressant
drugs;
recommended that any warning related to an increased risk of
suicidality in pediatric patients should be applied to all
anti-depressant drugs, including those that have not been
studied in controlled clinical trials in pediatric patients,
since the available data are not adequate to exclude any single
medication from an increased risk;
reached a split decision (15-yes, 8-no) regarding recommending a
``black-box'' warning related to an increased risk for
suicidality in pediatric patients for all anti-depressant
drugs; and
endorsed a patient information sheet (``Medication Guide'') for this
class of drugs to be provided to the patient or their caregiver
with every prescription.
fda's september 17 announcement regarding ssris
On September 17, FDA announced that the Agency generally supports
the recommendations made to the Agency by the Psychopharmacologic Drugs
and Pediatric Advisory Committees regarding reports of an increased
risk of suicidality (suicidal thoughts and actions) associated with the
use of certain anti-depressants in pediatric patients. FDA has begun
working expeditiously to adopt new labeling to enhance the warnings
associated with the use of anti-depressants and to bolster the
information provided to patients when these drugs are dispensed.
effectiveness data for anti-depressants in pediatric mdd
To date, much of the focus has been on pediatric suicidality and
the safety of anti-depressant drug products. However, it is also
important to consider the efficacy data for these drugs because a risk-
benefit assessment is important to clearly understand the benefit side
of this equation. Of the seven products studied in pediatric MDD
(Prozac, Zoloft, Paxil, Celexa, Effexor, Serzone and Remeron), FDA's
reviews of the effectiveness data resulted in only one approval
(Prozac) for pediatric MDD. (In January 2003, FDA approved Prozac for
the treatment of children and adolescents ages 7 to 17 for depression
and obsessive-compulsive disorder.)
Overall, the efficacy results from 15 studies in pediatric MDD do
not support the effectiveness of these drugs in pediatric populations.
It is understandable that people might conclude that these data show
that the drugs, except for Prozac, have no benefit in pediatric MDD. We
think that conclusion is premature, however.
There are many reasons, other than lack of effectiveness, for
studies to fail to show benefit. This phenomenon is a particular
problem in depression, and even more so in pediatric depression.
To begin with, in adult MDD programs for drugs approved for this
indication, the overall failure rate for studies that appear in every
respect to be adequate trials is about 50 percent. This indicates that
showing effectiveness in depression is not easy. In fact, because we
expected this difficulty, our Written Requests to sponsors asked for
two studies, not the one that would have been more typical.
Additionally, the history of pediatric MDD studies with the
tricyclic anti-depressants (TCAs) is uniformly negative. This finding
may have several possible explanations, including flaws in study design
or conduct, or the possibility that TCAs simply do not work in
pediatric MDD. It is also possible, however, that there is even greater
heterogeneity among pediatric patients who meet criteria for MDD than
is true for adults. If true, this would also work against study success
in pediatric MDD.
Finally, the context in which sponsors conducted these studies may
not have been ideal. Sponsors do not need positive results when
conducting a study in response to a Written Request in order to gain
exclusivity. The studies simply must be conducted according to the
terms of the Written Requests, and the results submitted to meet
deadlines specified in those requests. We are not suggesting that
sponsors of these studies did not design and conduct them with good
intent and according to high standards. We merely point out that the
failure of a drug registration trial to show a drug effect represents a
more significant loss for the sponsor (i.e., the non-approval of the
drug) than the failure of a study in response to a Written Request. We
do not know whether this could have influenced the conduct of the study
in subtle ways that might have worked against getting a positive
result, e.g., in recruitment of patients. As an example of how our
thought process has changed since the time we issued the Written
Requests, if we were to make a Written Request today for an anti-
depressant, we would ask that the trial include a Prozac arm as well as
placebo to confirm the ability of the study to demonstrate
effectiveness. .
Nevertheless, the failure of most of these programs to show a
benefit in MDD heightens the concern about the drugs ability to induce
suicidality. The burden is clearly upon those who believe these drugs
do have benefits in pediatric MDD to design and conduct studies that
are capable of demonstrating such benefits. The problem for
practitioners is what to do in the face of the uncertainty.
Practitioners must consider the generally negative findings in the
context of several other facts.
In all but one of the failed drugs, there were only two studies in
pediatric MDD. For the remaining failed drug, there were three
pediatric MDD studies. Among the failed drugs, there was one drug where
one of the two studies was positive (Celexa), and two others (Zoloft
and Serzone) where the results, while negative by our usual standards,
were at least trending toward positive in one of the two studies.
It has been observed that the published literature gives a somewhat
different perspective, suggesting more positivity in two of these
programs. A published paper describes one of the Paxil studies as
positive on most of the secondary endpoints, while acknowledging that
it failed on the primary endpoint. Another paper describes the Zoloft
program as positive, based on a pooling of two similarly designed
studies that, when looked at individually, failed. As noted, except for
Prozac, we do not believe effectiveness has been shown for any agent in
pediatric MDD.
conclusion
FDA was the first to identify a concern about suicidality in
several of the submitted pediatric studies. We evaluated the data
closely and raised serious questions about its adequacy. We then took
the initiative to acquire further relevant data from sponsors and used
expertise outside the Agency to access the reports of suicidality
thoroughly. FDA's assessment on this issue is designed to achieve the
most scientifically rigorous review possible. The Columbia University
classification project has provided the Agency with a credible basis
for analyzing the risks of these drug products.
The results of pediatric depression studies to date raise very
important problems. First, the poor effectiveness results, except for
Prozac, make it very difficult for practitioners to know what to do to
treat a very serious, life-threatening illness. While we believe that
these drugs may be effective in children, studies have not shown this
to be true. Second, and of equal importance, the analyses we initiated
in 2002 appear to show that the drugs in the pediatric controlled
depression trials can lead to suicidal behaviors or thinking. While no
suicides occurred in the trials, suicides certainly have been reported
in treated patients, and the devastating results of these suicides were
a critical part of the February 2, 2004, Advisory Committee meeting.
FDA generally supports the recommendations that were recently made
to the Agency by the Psychopharmacologic Drugs Pediatric Advisory
Committees regarding reports of an increased risk of suicidality
associated with the use of certain anti-depressants in pediatric
patients. FDA has begun working expeditiously to adopt new labeling to
enhance the warnings associated with the use of anti-depressants and to
bolster the information provided to patients when these drugs are
dispensed.
Thank you for inviting us today to discuss this important subject.
We would be glad to answer your questions.
Mr. Walden. Dr. Laughren, do you have an opening statement,
sir?
Mr. Laughren. No, I don't.
Mr. Walden. Okay. Dr. Seligman?
Mr. Seligman. No, I don't.
Mr. Walden. Thank you. Well, we appreciate all of you here
today to share with us this information as we continue to look
at what happened in this area and maybe what needed to happen,
and where we are today and where we will be when the FDA makes
it decision relative to the Advisory Committee's
recommendations.
Dr. Knudsen, could you turn in our big binder there to Tab
71 and 72? While you are looking at that, these are the two
versions of a letter under your signature sent to Pfizer
Pharmaceuticals on March 19, 1996, Tab 71 and 72.
Tab 71 has a FAX cover page filled out in someone's
handwriting to Martha Brumfield of Pfizer from James Knudsen.
The top of that page indicates it was sent at 10:18 and shows
FDA Neuropharm on it as well.
Does this appear to be your handwriting on the FAX cover
sheet, sir?
Mr. Knudsen. It does appear to be.
Mr. Walden. It does. Okay. The letter attached to this FAX
has lots of typographical errors in it as well as different
fonts being used for various words. If you would turn to Tab
72, it appears to be the same letter in substance as Tab 71.
However, the typos are removed, and the font is consistent. The
letters alone have a different FAX time Sent stamp on them, and
show them coming from a different section of FDA. Yet does the
signature on both these letters appear to be yours?
Mr. Knudsen. Tough question, isn't it? They appear to be,
but then again--yes, they appear to be. Back in 1996 when I
was--my penmanship may have been a bit better than now. It
varies somewhat. But I will answer the question as it appears
to be. I have to equivocate a week bit, just because of the
duration of time and the instability of my penmanship.
Mr. Walden. All of our penmanship tends to suffer with age,
sir.
Mr. Knudsen. Thank you so much.
Mr. Walden. Was it your practice to send a draft letter to
a pharmaceutical company requesting information, then resend a
cleaned-up version later on, though? Would you have sent it as
a draft and then send a different version later?
Mr. Knudsen. No, I don't--I mean, once again I have to
preface a statement by, regrettably, this was done in 1996. So
it is somewhat precarious for me to forage around in the
limited gray matter that is available to answer that
concretely.
Mr. Walden. Is it a practice you recall doing throughout
your career? Do you usually send a draft and then another?
Mr. Knudsen. I do not--no, I do not usually send a draft
and another. That's correct.
Mr. Walden. I mean, this wouldn't be a normal practice, I
wouldn't think.
Mr. Knudsen. No. That's correct.
Mr. Walden. Okay. I don't know. I mean, I'm not the best
speller in the world, but----
Mr. Knudsen. Well, quite frankly, I chatted with this--I
mean, last week I talked with the subcommittee staffers, and I
was rather appalled at what--with the typographical mistakes. I
am rather fastidious most of the time. There are periods
whereby I could deviate from that, but I mean, this is--this
being Tab 71 is a mess. Draft or otherwise, I wouldn't be
sending it to Martha, best I can recall anyway.
Mr. Walden. I understand that. Do you have any explanation
for the fact that two versions of this letter exist?
Mr. Knudsen. No, but I suspect others do. I am unable to
come up with an explanation.
Mr. Walden. Were you able to find this letter in the files
at FDA?
Mr. Knudsen. I checked--no, to answer your question. I did
check the document room. My own files are in--not trying to
generate excuses, but they are in boxes which I invite you to
my office and it is extremely difficult to even find a box. But
they are all there. We are getting ready to relocate. So maybe
with another 40 days and 40 nights I could find it.
Mr. Walden. Well, should there have been a copy of this
letter in the NDA files?
Mr. Knudsen. I would--yes, and I would have kept a copy
myself in my Certraline file. I keep everything.
Mr. Walden. Your files are in boxes?
Mr. Knudsen. I as unable to locate it in the document
room----
Mr. Walden. Right.
Mr. Knudsen. [continuing] when I was there. I checked in a
cursory way in my office, just trying to find the Certraline
file that I have. In fact, I did find the Certraline file,
parts of it, but I could not locate this particular document.
Mr. Walden. Where did you obtain a copy of your March 19,
1996, letter, and which version did you see?
Mr. Knudsen. I obtained two copies, one from the Division.
Mr. Walden. The Division?
Mr. Knudsen. HFD, the Division I am in, the day before I
left to go to Maine. I took it with me, in addition to other
things, other documents, and then the subcommittee members sent
via Federal Express another document. I mean the same one.
Mr. Walden. Another copy of that same document?
Mr. Knudsen. Yes, sir. Yes, sir.
Mr. Walden. And where did the agency get the version they
sent to you?
Mr. Knudsen. I did not inquire.
Mr. Walden. Dr. Temple, do you know?
Mr. Temple. I could be wrong about this. My understanding
is that Dr. Knudsen got a copy of the letter from the
committee. Maybe I'm wrong about that.
Mr. Knudsen. Yes, I just said that.
Mr. Temple. And that we never were able to find it in our
files and got it from Pfizer.
Mr. Walden. There you go. So you had to go to Pfizer to get
it?
Mr. Temple. Yes.
Mr. Walden. That's what you provided to the committee.
Right?
Mr. Temple. I'm not sure, but we could not--what I am sure
of is that we were unable to find a record of this letter
anywhere in our files. That, I am sure of. I am not sure about
the rest.
I should say that it is unusual. Letters don't ordinarily
go out under a medical officer's signature. They would
ordinarily go out under Dr. Katz's signature or Dr. Lieber's or
whoever was in charge at the time, and a copy would be in the
New Drug Application, in the file. So this was unusual.
Mr. Walden. All right. Dr. Knudsen, was it your practice as
a medical review officer in 1996 to directly correspond with a
pharmaceutical company on a matter you were reviewing, and then
request information or did you need to apprise any of the
supervisors of your request for additional information from the
pharmaceutical company?
Mr. Knudsen. It was not my practice to do so.
Mr. Walden. So you would have--was it your practice to tell
your colleagues or supervisors that you were seeking such
information from a pharmaceutical company?
Mr. Knudsen. Correct, 86 to 95 percent of the time. There
is always a slight opportunity for me to--I mean, once again, I
mean, I answered the question as best I could that it is not my
practice to do so. In fact, I received my copy from the
Division via--of course, I guess the Division received it from
Pfizer. I wasn't aware of that. I had no need to question that
anyway. I just wanted to take some materials with me to Maine.
Mr. Walden. Isn't it a requirement of FDA regulations these
types of correspondent documents be kept on file by the agency?
Mr. Knudsen. Yes.
Mr. Walden. All right. And yet in this case, that doesn't
appear to be what happened. Right?
Mr. Knudsen. That is correct.
Mr. Walden. All right. In these letters, you state ``We
note that there appears to be an increased frequency of reports
of suicidality in pediatric adolescent patients exposed to
Certraline compared to either placebo or Certraline treated
adult OCD patients. If this is, in fact, the case, what would
be a plausible explanation?'' That is what is in the letter
that you signed or you think you signed and sent to Pfizer.
You asked for summary tables from Pfizer to compare data
from adult and pediatric patients in their data base. Is it
fair to say that you wrote this letter to Pfizer because you
noticed an increase in suicide related behavior in the
pediatric OCD trials relative to the rates in the adult trials,
and that that was of concern to you? Is that why you wrote this
letter to Pfizer?
Mr. Knudsen. Yes.
Mr. Walden. All right. And was it of enough concern that
you wanted answers from the company?
Mr. Knudsen. Correct.
Mr. Walden. And approximately 10 days after you sent this
letter to Pfizer, you complete a safety update to Zoloft. We
have put selected pages of your safety review at Tab 81, 81, if
you want to refer to that, sir.
In your safety update you note on page 15 that, ``In the
small pediatric adolescent pool population of OCD patients, the
incidence of suicidality in the Certraline treated patients was
fivefold greater than the adult OCD Certraline treated
patients.''
You go on to note that 4 of 6 Certraline pediatric patients
had comorbid depression and, ``Depression is an important risk
factor for suicide.'' You then cite an article published in the
Journal of American Academy of Child and Adolescent Psychiatry
that indicated--that also noted the same phenomenon with kids
being treated with Prozac.
What did you do other than note these concerns in the
safety update? Where did you take it from here?
Mr. Knudsen. I was trying to see whether or not that was
instrumental in my sending the letter to Pfizer, just to garner
some additional information. This was March 28, 1996. The
letter to Pfizer was October, was it?
Mr. Walden. I think the letter to Pfizer, you will see, is
dated March 19.
Mr. Knudsen. March 19, before.
Mr. Walden. So like 9 days later----
Mr. Knudsen. Well, in fact, in reviewing the NDA, this was
a final document that was signed off, the one that--the
document in Tab 81. So prior to finalizing this document, Tab
81, I found this information to be--at the time anyway,
certainly of concern to me to make some further inquiries to
Pfizer, and realizing, of course, when I finalize this
document, I believed that Pfizer had not responded yet to this.
Mr. Walden. That would be correct, based on the timeline I
have seen. But 9 days before you wrote to Pfizer asking for
this additional information, why didn't you include in this
update the fact that you were awaiting additional information
from the company to explain the fivefold increase? Would that
have been a prudent thing to do?
Mr. Knudsen. Yes, it would have been.
Mr. Walden. Well, my time has expired. I will now recognize
the ranking member of the subcommittee at this time, the
gentlelady from Colorado.
Ms. DeGette. Thank you very much. Dr. Temple and Dr.
Laughren, I am wondering if you can tell me, knowing what you
know today, do you believe that Dr. Mosholder's initial
conclusions about the increased risk of suicidality exists in
pediatric populations taking anti-depressant medication to
treat MDD? Dr. Temple?
Mr. Temple. The reanalysis that Columbia did, did not
change the overall direction of the results. So----
Ms. DeGette. So your answer would be yes?
Mr. Temple. Would be yes. Dr. Hammad's analysis and Dr.
Mosholder's are slightly different analyses, but in fact the
relative proportions of suicidality are similar to what Dr.
Mosholder found.
Ms. DeGette. What about you, Dr. Laughren?
Mr. Laughren. Yes, I agree. The relative risk for both
analyses is roughly twofold. So it is essentially the same.
There are some differences across drugs. The signal gets a
little stronger for some drugs, a little weaker for others, but
overall I agree that it is roughly the same result.
Ms. DeGette. There was about 8 months between his findings
and when, I think, the FDA took action. I guess my question to
both of you: Do you wish that the agency would have taken him
more seriously and allowed him to present the findings so that
we could have warned parents and physicians about the increased
suicidality rates instead of waiting these 8 months?
Mr. Temple. Let me say a few things. Our concern, as I said
before, was that the action we take be based on the best
possible data. Let me describe the kind of data we had here.
The usual way we expected to evaluate increased suicidal
risk is by looking at the scales that patients in trials are
given that ask them how suicidal they are. Dr. Laughren in his
comments on Dr. Knudsen's review points out that we are going
to have more data on this question.
Those analyses revealed nothing in any of these trials.
There was no increased suicidality by that measure. What we got
was something unexpected, namely the adverse reaction reports,
when interpreted, when translated, revealed an excess of these
suicidal behaviors. What we had very little experience with was
what those things mean.
We thought, as we looked at them, that somebody--that
people expert in interpreting these behaviors needed to look at
them. Dr. Mosholder specifically in his review says he did not
try to reevaluate each of these cases, because he was no longer
blinded. That conclusion----
Ms. DeGette. But Dr. Mosholder also said that he only
looked at the most--I'm not a researcher, but he only looked at
the most serious cases and, in fact, Dr. Temple, you yourself
in your opening statement said that the comment you had made
about the face slapping you now regretted that, because he
didn't take those things into account.
Mr. Temple. Let me explain. He had--in response to the
concern that these cases might not be a true bill, might not be
what they seemed to be, he offered several approaches. One was
to only look at the serious cases. That is clear, and you can
see in his review, if you look at the cases that were included
and not included, that many of the trivial cases were excluded
by the decision to look only at the serious cases. That is
perfectly true.
There were, however, additional cases where you didn't know
what they meant, and he was in no position to reevaluate them.
Let me just----
Ms. DeGette. I apologize, but they only give me 10 minutes.
So if you can make your answer concise, I would appreciate
that.
Mr. Temple. Okay. I wanted to explain one other point about
it.
Ms. DeGette. Very briefly.
Mr. Temple. He also said that, if there is noise in the
system, if it is inaccurate, that would tend to hide a finding
rather than to create one, and that is true.
What is also true, however, is if there was a bias toward
interpreting certain things that the drugs do, like agitating
people or making them hostile, as suicidality, that could give
you the wrong picture. It could cause you to think there were
suicidal events when, in fact, they were not.
That is why we thought we needed an independent look at
these cases in----
Ms. DeGette. Okay. But at the time that Dr. Mosholder came
up with his findings, there was already the British study that
had come out earlier that year.
Mr. Temple. No, the British were using the same data we
were.
Ms. DeGette. Right, but they had concluded this increased
risk of suicidality.
Mr. Temple. But we don't know that they----
Ms. DeGette. But I mean there were two.
Mr. Temple. Let me make it clear. There was nothing wrong
with Dr. Mosholder's analysis, the ratios he designed, any of
those things. That is not----
Ms. DeGette. Well, right. In fact, it has now turned out he
was completely right.
Mr. Temple. No, that is not at issue. What was at issue was
what the cases were, whether they really showed suicidality,
and to answer that question you either have to look at them
closely or decide that they could not have been biased.
Ms. DeGette. Well, let me ask you this. In the spring or
summer of 2003, Wyeth came to the FDA, and they wanted on their
own--we heard this in the last hearing--to strengthen warnings
on Efexir, and the FDA asked them not to do that. Is that
right?
Mr. Temple. Not quite. They were allowed to do that, and
they did it until we created a new stronger warning or--you can
call it strong or not--a different warning in march of 2004.
That warning was in the warning section. It prominently said
you really need to watch patients, and we thought that was a
more trenchant warning. That was in response to the Advisory
Committee.
Ms. DeGette. Okay. Now do you think that the FDA is going
to adopt this most recent recommendation about the black box
warnings?
Mr. Temple. Our public statement said that we were going to
do all the things they said. We want to think about the
conversation they had about the black box. It is true it was 15
to 8, but there were a lot of people that said a lot of things.
You know, I don't want to----
Ms. DeGette. Does that mean no?
Mr. Temple. No, it absolutely doesn't mean no. It means we
haven't finished our decision yet. We want----
Ms. DeGette. Well, what is the FDA's goal with respect to
labeling of these anti-depressants for off-label use for
pediatrics? What is the goal at this point, knowing the
information you know about increased risk of suicidality?
Mr. Temple. Well, we are unquestionably going to explain
that the drugs themselves appear to be--are associated with or
cause an increased risk of suicidality. That is a given. The
only question is what form it will take.
The discussion the Advisory Committee had was----
Ms. DeGette. What kinds of forms do you have that you can
take with it?
Mr. Temple. Oh, you could put a warning--I mean, the
alternative, you could put a warning in dark print, something
like that, or you can put it in a box. Those are probably the
two choices.
Ms. DeGette. So the choice would be to put it on the
bottle. No?
Mr. Temple. No, no.
Ms. DeGette. To put it on the box?
Mr. Temple. Well, a box warning is the very first thing you
read in the label.
Ms. DeGette. Right. Open it up.
Mr. Temple. A warning comes a little bit later. Those are
prominent, too, and we sometimes do one and sometimes do the
other. The particular----
Ms. DeGette. If there is a black box, that has to be in the
advertising, too. Right? So if Zoloft has an ad, it has to have
a warning, may cause suicidality in pediatric use, or something
like that.
Mr. Temple. Yes. The contents of the black box would have
to appear, but----
Ms. DeGette. It seems to me you would want to do that.
Mr. Temple. Wait, wait, wait. The content of the warning
would have to be there, too.
Ms. DeGette. Well, sure. I understand, but that's the
effect of a black box versus some of these other warnings.
Right?
Mr. Temple. No. The requirement for advertising is you have
to balance the information. If there was a prominent dark print
box, that would have to be there, too. I'm not trying to
discourage a black box. I am just trying to reflect the fact
that people who spoke to us were concerned that people who were
at risk of killing themselves would not be treated if we scared
people too much.
I'm not saying I agree with that. We put the idea of the
black box before the committee. You know, we are not shrinking
from it, but they said multiple things.
Ms. DeGette. Well, I would imagine you would share my
concern. My concern is that off-label prescription of these
nonapproved drugs for pediatrics with, at best, no effect on
these depressed kids and, at worst, increased risk of
suicidality will continue unabated. I would assume that is the
FDA's role to decide that. Right?
Mr. Temple. One of the problems with off-label use and not
having enough data is that you don't know what the answer is.
The Advisory Committee--many, many people said we know how the
studies came out; they are not impressive; they weren't able to
show effectiveness. But they clearly were concerned that maybe
as a second line drug these drugs probably should be available
and probably worked in people.
That is not the same as knowing, because we know the
studies largely failed.
Ms. DeGette. I think we can probably all agree that it
would help to have more clinical trials in this area, would it
not?
Mr. Temple. Yes, but they--Again, I am talking for them. I
am not telling you what we decided to do. They were very
concerned that we would scare people so much that people who
didn't respond to, say, Prozac wouldn't use it or would be
afraid to use it, and they were afraid of the consequences.
They were worried about them.
You know, these are expert people who treat these
conditions. They know a lot more about it than I do.
Ms. DeGette. Can I just ask you a question. Do you think it
would be a good idea if we had more clinical trials so we could
get more data on what the effects of these anti-depressants
are, or should we just rely on faith?
Mr. Temple. Oh, no, we live by getting more data. We can't
always manage to get it.
Ms. DeGette. Can you require more clinical trials as part
of your ongoing effort?
Mr. Temple. That is going to be an interesting question. We
have a number of thoughts about how to do further studies,
which I would use up your 10 minutes if I told you, but I would
be glad to.
Ms. DeGette. It's okay. It's already over.
Mr. Temple. No, we think there needs to be more data. For
example, we were very impressed with the TAD study. It was a
very informative study done by NIMH. We are going to be talking
with them, see if we can convince them to do some more stuff.
Ms. DeGette. Great. Now what about the companies? Are you
going to require--what we learned in the last hearing:
Pharmaceutical companies are making millions and millions of
dollars from this off-label prescription of these anti-
depressants.
Would it be reasonable for the FDA to require further
studies by the companies?
Mr. Temple. It is reasonable, and whether we can--well,
there is a question of our authority. Whether we will be able
to require further studies when they will perfectly happily say
we think it is a settled question, we don't want the drug used
in children--we are perfectly happy to say safety and
effectiveness in children hasn't been demonstrated, and they
are perfectly happy to say that, as you pointed out.
Ms. DeGette. Because they can still sell these drugs.
Mr. Temple. Whether we will be able to persuade them to do
more studies is not known to me. We definitely----
Ms. DeGette. Well, can't you hold the pediatric exclusivity
stick over their head?
Mr. Temple. Unfortunately, no. They have done what they
were supposed to do under the law. They have done the trials we
asked for, and pediatric exclusivity has been now granted.
Ms. DeGette. So if you have these recalcitrant drug
companies who are refusing to do more studies because they can
just blithely say, well, we don't like this off-label use
anyway, we don't----
Mr. Temple. To be fair, they haven't refused yet.
Ms. DeGette. Okay.
Mr. Temple. I'm not optimistic. That's all.
Ms. DeGette. They might agree to do it, but if not, it
would seem to me it would be in the FDA's interest then, and
this is within the FDA's authority, to require the strongest
possible warnings so that doctors and parents understand the
risk to pediatric patients.
Mr. Temple. There is no question there is going to be a
strong warning. The other thing is we suggested to the
committee that there ought to be patient labeling, a so called
Med Guide, and they totally agreed with that.
We also told them that we didn't think a Med Guide works
unless you create what is called unit of use packaging, so that
it is always handed out, and I am on lengthy record as saying
we are going to require that, which we will. But we did all of
those things. It needs to be a strong warning.
Ms. DeGette. And staff points out to me, the FDA could
counterindicate this drug and stop it form being prescribed,
period.
Mr. Temple. Well, we couldn't. They could still prescribe
it. We don't control what people do. The Advisory Committee was
unequivocal, voted overwhelmingly and uniformly that they did
not think a contraindication was appropriate, for the reasons
that I have just given. They think, without data, without
evidence that these drugs actually work, they think they need
to be available.
Ms. DeGette. Excuse me, sir. Let me just say, it seems like
circular reasoning. We don't have the data to say what we
should do, but we can't make them get the data. So we are just
going to go along. I would suggest we work together. Do you
need statutory changes, whatever you need? We need to get a
grasp on this, and I think part of it is getting more data.
My time has long expired. Thanks for your comments.
Mr. Temple. Can I throw one more thing out? The data were
not uniformly negative. There was one positive trial with a
drug called Cetalopram, and there were a couple of trials that
were close, not entirely negative.
So it is not out of the question that these drugs can be
shown to work.
Mr. Walden. Are you talking about efficacy or suicidality?
Mr. Temple. Efficacy.
Mr. Walden. Well, I am going to go to Mr. Ferguson in a
second. But you could also require that the trials that show no
efficacy be published. Right? Be printed? Doctors could be
notified? Couldn't you require that?
Mr. Temple. That is a difficult question. Published?
Absolutely not. We have no control over publication.
Mr. Walden. I'm sorry. I used the wrong term. Couldn't you
require that on a label it says no efficacy?
Mr. Temple. I believe we can, yes.
Chairman Barton. Would the gentleman yield before you go to
Mr. Ferguson? I just want to follow up on that question very
briefly.
Mr. Walden. Certainly, Mr. Chairman.
Chairman Barton. Dr. Temple, is the FDA now changing its
criteria for approval to say, if it can be shown that it is not
out of the realm of question that it might be shown to work,
that you are going to approve it? I've never heard such a----
Mr. Temple. We are not approving it. I am trying to reflect
the views of the experts we had on our Advisory Committee.
Chairman Barton. I understand that.
Mr. Temple. They know perfectly well that these drugs have
not been shown, according to our standards, to work. There is
no question about it. I totally agree with that conclusion.
That is not the same as knowing they don't work, and they were
frightened at the prospect that people would not be able to use
the drugs in----
Chairman Barton. I understand that.
Mr. Temple. That's all.
Chairman Barton. One reason your agency has such high
esteem in the public is because, almost without exception, all
the time drugs or medical devices don't get approved until it
has been shown without a shadow of a doubt that they do work
unless it is some cancer therapy or orphan drug where you
develop some sort of an informed consent that the situation is
so dire that the patient is going to die unless almost a
Biblical miracle occurs.
That statement you just said, to just cavalierly say, well,
we can't really say that in some cases it might work, just
boggles my mind.
Mr. Temple. I'm obviously not communicating. There is no
question that these drugs have not met the standard for
approval. I don't want to approve them. I cherish the standard.
I think the 1962 Act was one of the greatest pieces of
legislation in all the world's history.
That is not the same as saying that anyone who uses a drug
off-label is doing the wrong thing. The requirement for
approval has to meet--there is a threshold set for approval,
and I think that is entirely appropriate. I value it
enormously, and I don't even believe it doesn't apply in orphan
drug cases, in cancer drugs either.
But the fact is that data comes in a smear, in a range, and
what may not be anywhere close to what we would need for
approval may inform some people or convince them that they
ought to give something a try. I'm just saying that is a fact.
I am not saying it is a good thing or a bad thing.
What I am saying is that our Advisory Committee was
uniformly concerned that people who hadn't responded
appropriately to Prozac would have nothing available when they
were deeply depressed, suicidal, and the like. That seems a
legitimate concern, too.
That is not talking about making the drug----
Chairman Barton. I will do this on my own time.
Mr. Walden. But don't virtually every single clinical trial
show there is no efficacy for these drugs in kids and
adolescents? Isn't Prozac like the only one that shows that for
kids and adolescents, that there is any efficacy?
Mr. Temple. The results are certainly discouraging. Prozac
was three for three.
Mr. Walden. No, no. How many studies that have been done in
children and adolescents for this range of drugs showed they
had efficacy for kids?
Mr. Temple. Not counting Prozac, I assume.
Mr. Walden. Count Prozac. I don't care. How many studies
have been done----
Mr. Temple. Three Prozacs, one Cetalopram. There is a study
of Paxil in which all of the endpoints except their primary
endpoint were successful. Some people would think that shows
something. We wouldn't. We wouldn't buy it.
Mr. Walden. So you don't buy it.
Mr. Temple. I don't buy it.
Mr. Walden. All right.
Mr. Temple. Certraline published a report that said we work
when you throw our two studies together. We don't buy that, but
it is a trend in the right direction. It is not zero, and----
Mr. Walden. When it is combined, but not a stand-alone, and
I thought your own agency rejected that.
Mr. Temple. That is what I said. We do not believe that
they have shown effectiveness. Absolutely not. That is the
wrong analysis. I am just saying that is not proof that it
doesn't work. I am obviously not making myself clear. I don't
want to approve these drugs.
What the Advisory Committee expressed concern about was
that in a world of uncertainty, they thought that you need to
be able to think about using them in someone who hadn't
responded to anything else and who had no other choices. I am
not here to say that is a stupid thing to do. Those are
knowledgeable advisors.
Mr. Walden. Yield to the gentleman from New Jersey.
Mr. Ferguson. Thank you, Mr. Chairman. Dr. Temple, thank
you and your colleagues for being here today. We appreciate you
answering many, many questions that are very important
questions.
I may have missed it if someone else asked this question.
But can you tell me why Dr. Mosholder did not present at the
February 2 meeting?
Mr. Temple. Yes. We thought that the--let me just try to
think what you've heard and what you haven't heard. Our concern
was that there was uncertainty about what the cases that went
into his analysis meant. They were collected from adverse
reaction reports that were not particularly designed to look at
suicidality, and determining whether a given clinical picture
represents suicidality is not entirely simple.
The people at Columbia specialize in trying to sort those
things out, and we were aware of that. Our concern was not with
the analysis that Dr. Mosholder did, which was perfectly right,
but with the very cases that went into the analysis and whether
they were credible instances of suicidality.
So we arranged well before that meeting, the Advisory
Committee meeting, and well before his final report, we
arranged for Columbia to blindly review each of the cases and
reclassify them. We didn't want to present what appeared to be
an FDA conclusion at the February 2004 Advisory Committee.
Mr. Ferguson. Certainly, he would be capable of explaining
that himself, though, wouldn't he?
Mr. Temple. Well, no. He believed the analysis was fine.
You know, people can probably disagree about this. We didn't
think he was wrong. We thought it wasn't ripe yet. So for us
to--you know, for us to go up and say, oh, he's all wet, that
wouldn't have been appropriate, and it is not that we thought
it was wrong. We thought the cases needed to be looked at
before conclusions should be reached.
Mr. Ferguson. Isn't that the role of the Advisory
Committee, is to gather information like this and analyze it
and make a recommendation? Did you think they would be
confused? Are they an easily confused group?
Mr. Temple. The Advisory Committee was in no position to
review each of the cases. We had no capacity to ask them to do
that. That would have, you know, taken them months. When we
discussed this matter with them, they clearly sympathized with
the need to find out what these cases meant. We didn't get a
vote. So I can't prove what they thought, but they understood
the problem perfectly well, and expressed no dissatisfaction
with it.
In fact, at the most recent Advisory Committee meeting,
they said the review by Columbia was very impressive, that the
data looked better than they could have imagined, and expressed
sort of gratitude that they had something they could readily
work with.
Mr. Ferguson. Wouldn't the committee be equipped to analyze
the arguments? Isn't that what they are supposed to do?
Mr. Temple. Well, that's sort of what I am saying. It
wasn't a matter of making arguments. We didn't have a counter-
argument. We didn't think that Dr. Mosholder's review was
wrong. What we thought was that the basis for doing the review,
for creating the numbers, was imperfect, because the cases
hadn't been analyzed----
Mr. Ferguson. And the Advisory Committee couldn't possibly
understand that?
Mr. Temple. Well, I think they did understand it, and they
nodded in agreement. But they didn't vote on it. We didn't ask
them to vote.
Mr. Ferguson. They didn't hear his side. He never got to
present on February 2.
Mr. Temple. Well, let me make it clear. What----
Mr. Ferguson. They had information withheld from them.
Mr. Temple. What Dr. Laughren showed was the results of
each of the trials, many of which showed more suicidality in
the treated group than the other group. Now he didn't show
exactly Dr. Mosholder's data or the cumulative data, but it was
easy to see, and we emphasized this in the professional
advisory that we sent out, that there was more suicidality in
the treated group in many of the studies.
So they knew what the issue was perfectly well, and they
also heard from Dr. Laughren what our reservations about the
data were.
Mr. Ferguson. I am not at all satisfied with the reason why
Dr. Mosholder was somehow blocked from presenting on February
2, for the record. Let me move on.
I'd like to go to Tab 40 in the committee's binder. This is
the minutes from the February 2 meeting. Tab 40 is the minutes.
I want to go to the top of the last page of Tab 40.
Mr. Temple. Hang on.
Mr. Ferguson. Sure.
Mr. Temple. Top of the last page?
Mr. Ferguson. The last page of Tab 40, and I am quoting.
The text states: ``The committee advised the FDA to inform the
public and health care workers, including pediatricians and
family practitioners''--it goes on--``of the level of concern
regarding possible harm to a minority of children on anti-
depressants and the signs associated with the side effect.''
It is clear that the Advisory Committee wanted you to
inform the public about the risk to children, not the risk to
the general population but specifically the risk to children,
as reflected in these minutes. Is that correct? Do you agree
with that? That is what the minutes say.
Mr. Temple. Yes, but I guess we interpreted that as----
Mr. Ferguson. I am real short on time.
Mr. Temple. Okay. We put a warning that applied to both
adults and children.
Mr. Ferguson. Right. The Advisory Committee seemed to
indicate--they were specific to children, not the general
public. That is what it says. That is what the minutes say.
Right? Why didn't you issue an advisory specific to the side
effects in the pediatric population?
Mr Temple. Because the same side effects occur in adults.
Remember, this--we did not write a conclusion that the drugs
increased the risk of this, because we thought that was
premature, and the committee didn't tell us otherwise. But the
possibility that people being given these drugs get worse when
they are given them is a phenomenon that has been observed in
both adults and children. We thought the warning should apply
to anybody being started on these drugs.
Mr. Ferguson. But if the committee says in their quotation,
in the quote from the minutes, from your minutes, the possible
harm to a minority of children on anti-depressants and the
signs associated with the side effect, why not issue a warning
specific to children?
Mr. Temple. Even though we thought the same warning should
apply to adults?
Mr. Ferguson. Why not? What's the harm? Why not?
Mr. Temple. Well, in the labeling what would we say about
adults?
Mr. Ferguson. We consider children and adults different in
all sorts of ways. You do, too. The side effects in children
are different from the side effects in adults. Right?
Mr. Temple. Yes. This was a statement----
Mr. Ferguson. There is a reason we test on pediatric. There
is a reason we do tests on kids and different tests on adults.
We don't extrapolate one to the other necessarily.
Mr. Temple. Right, but----
Mr. Ferguson. We do tests on both.
Mr. Temple. But the potential for getting worse when you
are starting therapy is a phenomenon of both adults and
children.
Mr. Ferguson. Okay. Are the side effects different in
children and kids--between children and adults?
Mr. Temple. Well, we now think that they are, because we
have seen no increase in suicides in adults with a very large
data base, but we now believe there is an increase in suicidal
thinking and behavior in children. But that is what we know
now, and the new labeling will surely say that.
Mr. Ferguson. Okay. I am going to keep going, because we
are kind of getting fuzzed over here. To me, it is mystifying
that, given this information, that you would not have issued--
particularly, because this is what the Advisory Committee
seemed to be saying, that you wouldn't have issued a warning
specific to kids. Let me move on.
The minutes go on to note that the committee is concerned
that the public does not know that a strong majority of
randomized controlled trials of SSRIs do not demonstrate
superiority over placebo in the treatment of major depression
in children and adolescents.
Did you address this concern publicly and through a
labeling change?
Mr. Temple. We did not introduce a labeling change. All the
labeling----
Mr. Ferguson. Why not?
Mr. Temple. Well, what the labeling all says is that safety
and effectiveness in children has not been demonstrated, and
the new warning moves that statement forward to the warning
language.
Mr. Ferguson. What warning?
Mr. Temple. The warning that all of the drugs got in
March--sorry, after the Advisory Committee meeting.
Mr. Ferguson. You're talking about the March 22?
Mr. Temple. We asked for it in March. It was all
implemented by about August, I think.
Mr. Ferguson. Okay. Which is Tab 44. So it just seems to me
that the agency first tries to determine what information that
the Advisory Committee can handle, for instance pulling Dr.
Mosholder, not allowing him to present his data and information
to the committee, and then when they make a recommendation,
when the Advisory Committee makes a recommendation, you
disregard the recommendations that they make.
Mr. Temple. I don't agree that we disregarded it. The third
paragraph of the thing you just showed me says that anxiety,
agitation, panic attacks, etcetera, have been reported in adult
and pediatric patients being treated with anti-depressants. I
mean, adults are people, too. We thought this is a risk that
applies to all people who are started on an anti-depressant.
Mr. Walden. Would the gentleman yield?
Mr. Ferguson. I will yield. I am mystified that, given what
is going on with this issue, that you seem to be incapable or
refuse to decipher the difference between effects on kids and
effects on adults. I will yield to the gentleman.
Mr. Walden. Really, I think, what you are asking is: If you
knew it affected children and adults, but you also knew it
affected kids more than adults.
Mr. Temple. We didn't think we knew that at the time.
Mr. Ferguson. And worse, more and worse.
Mr. Walden. Dr. Mosholder indicated that in his study. This
came out--when did this come out, 2004? This came out in
February 2004. Right? You own agency began flagging this in
1996 and 1997.
Mr. Temple. We did not think it had been established--
again, you have heard the debate about that. Obviously, Dr.
Mosholder thought it was well established. We did not think it
was established that there was a special risk in children, but
we knew that both adults and children started on therapy, early
in therapy, can have all these things, including increased
suicidality. That is what we wanted to warn about.
We did not say at this time that there was an increased
risk in children.
Mr. Walden. Are you acknowledging that there is an
increased risk in adults?
Mr. Temple. Increased risk compared to no treatment?
Mr. Walden. Right.
Mr. Temple. No. We don't know that.
Mr. Walden. So there is no increased risk of suicidality in
adults who are on anti-depressants in the trials?
Mr. Temple. We have done analyses of suicides now, and we
don't see anything like that. Dr. Mosholder presented at the
last Advisory Committee an analysis of the Paxil adult data
using exactly the same approach that was used in the children.
That showed no increase in suicidality in the adults. So at
this time, that appears to be different, but it remains true
that, whether there is an increase or not, increased suicidal
behavior and thinking does occur early in therapy.
Mr. Ferguson. Mr. Chairman, could I reclaim the time that I
don't have left for one more question?
Mr. Walden. Yes, sure.
Mr. Ferguson. I want to just go to one more, Tab 49, which
is your statement, the FDA's statement from September 16 on the
recommendations of the Psychopharmacologic Drugs and Pediatric
Advisory Committees. These are the recommendations from
September.
Mr. Temple. I'm sorry. Which am I looking at now?
Mr. Ferguson. Tab 49.
Mr. Temple. Forty-nine? Sorry. Okay.
Mr. Ferguson. My question is: Given the fact that, in my
estimation, you seem to have, No. 1, tried to control the
information that the Advisory Committee was getting; No. 2,
seemed to disregard the Advisory Committee's recommendations
that they made back in February.
What assurance do we have that these recommendations from
September will be followed or adopted?
Mr. Temple. Well, you have the statement about what we are
going to do, and in a couple of weeks you will see the labeling
change.
Mr. Ferguson. No, no, no, no. The statement says the FDA
general supports the recommendations that were recently made.
That is--I mean, my gosh, this is Washington. That could mean
anything.
Mr. Temple. Well, let me make it clear. We had some
discussion of this before we came in. The only thing we want to
think further about is the box, for reasons that I explained
before and would be glad to explain again. All the rest of the
recommendations are----
Mr. Ferguson. I heard the conversation about the box.
Mr. Temple. All the rest of them are clearly going to be
implemented. We, frankly, suggested half of them.
Mr. Ferguson. Okay. You said in the New York Times on
September 14, ``I think we now--I think that we now all believe
that there is an increase in suicidal thinking and action that
is consistent across all the drugs.'' And you have the Advisory
Committee saying 15 to 8 that they think the black box is a
good idea.
I mean, that is almost the override of a veto. I mean, 15
to 8 is substantial. What is left? What is the problem?
Mr. Temple. Well, you have to have been to a lot of
Advisory Committees to notice this, but as much as anything
else, you want to hear the words people use to explain why they
think what they think and what the reservations are. All I am
saying is we are going to look at what those are.
I am not predicting that we won't buy the black box. My
guess is we probably will, but we owe the people who spoke and
tried to advise us a look at what they said.
Mr. Ferguson. If there is a vote on another issue that is
15 to 8, is it generally adopted or is it something that is not
adopted or do you kind of think about it for a little while
longer?
Mr. Temple. Yes, that is a very hard thing to answer, but
divided committees recommending approval or not approval--when
it is reasonably close, we don't necessarily go by the
majority, you know. You sort of have to read what people say
and----
Mr. Ferguson. Is 15 to 8 reasonably close?
Mr. Temple. Well----
Mr. Ferguson. That is a whitewash.
Mr. Temple. There is no question the majority of the people
thought that it ought to get a box, and they overcame in
recommending that their concern that use of the drugs would be
over-discouraged.
Mr. Ferguson. Recommending a black box is a pretty big
deal. That is not taken lightly. Right?
Mr. Temple. We understand it. One of the questions we asked
them is should we put a black box on it. We put it on their
table so that we could hear their opinion, and we wanted their
opinion and their discussion on the pros and cons, and how they
came to pro, in spite of certain reservations and concerns is
extremely informative.
Mr. Ferguson. You have almost a two to one vote on a--you
don't see a black box on too many drugs.
Mr. Temple. You see them on a fair number. We are not
saying that we don't want to do it or don't plan to do it. We
just owe that one some thought. That's all.
Mr. Ferguson. I'm done. Thank you. I yield back.
Mr. Walden. Thank you. I now turn to the gentleman from
Michigan, Mr. Stupak, for questions.
Mr. Stupak. Thank you, Mr. Chairman. This black box--where
is it going to go?
Mr. Temple. Black boxes are always the first thing in
labeling.
Mr. Stupak. Where is the label? Is that for health care
professionals or do people get a chance to see that?
Mr. Temple. Sorry. The label refers to the package insert
that is written for physicians.
Mr. Walden. Mr. Stupak, I erred. I was committed to the
chairman to go to him, because he has to go to mark-up.
Mr. Stupak. That's all right.
Mr. Walden. Could you----
Mr. Stupak. Go ahead, Joe.
Mr. Walden. Mr. Chairman.
Mr. Stupak. But let me just clarify that. That black box
only goes to physicians. It doesn't go to the general public?
Mr. Temple. Right. There will be an equivalent emphasis in
the patient labeling, what is called a Med Guide, that we were
also very strongly advised to create. So that will be very
prominent in that form, too.
Chairman Barton. I apologize for going out of order, but
we've got a mark-up on the waste bill upstairs. I thank the
courtesy of Mr. Stupak.
Dr. Temple, have you ever run for any political office?
Mr. Temple. No.
Chairman Barton. Do you follow Presidential politics?
Mr. Temple. Oh, yes.
Chairman Barton. Okay. You are aware there is going to be a
debate next week between President Bush and Senator Kerry.
Mr. Temple. So I've heard.
Chairman Barton. How would you feel if you were really
looking forward to that and at the last moment the news
reported that it had been decided that Senator Kerry couldn't
represent himself in the debate, that Congressman Joe Barton
had been appointed to represent Senator Kerry's views in the
debate with President Bush about who is qualified to be the
next President of the United States?
Would you think that was a fair thing to do or an unfair
thing to do?
Mr. Temple. Unfair thing to do.
Chairman Barton. Unfair thing to do. So when the decision
was made that Dr. Mosholder could not present his findings last
February, nobody was allowed to even hear what his findings
were, but that when it was finally decided that his findings
could be presented last week or the week before last, somebody
else did it, and somebody else did it who probably disagreed
with his findings. Was that fair or unfair?
Mr. Temple. He presented his findings. He compared his
findings with the new findings.
Chairman Barton. Oh, Dr. Mosholder did present his--I was
told he did not.
Mr. Temple. Well, the primary analysis was done by Dr.
Hammad on the new data, but what Dr. Mosholder did was show how
the analyses were similar and different.
Chairman Barton. Well, now I want to be fair. When I'm
wrong, I'm wrong. I was told that Dr. Mosholder did not get to
present his own findings. That is apparently not true?
Mr. Temple. When do you mean now?
Chairman Barton. Well, there have been two Advisory
meetings, one last February that I----
Mr. Temple. Oh, I think I misunderstood you. In the most
recent Advisory Committee----
Chairman Barton. There have been Advisory----
Mr. Temple. A couple of weeks ago.
Chairman Barton. There was an Advisory at the beginning of
this year in February. Then there was another Advisory just a
couple of weeks ago. Isn't that correct?
Mr. Temple. Yes. At the February meeting, he did not
present his analysis. If that is what you mean, that is true.
That is what we talked about.
Chairman Barton. Well, at that meeting did anybody present
any of his findings?
Mr. Temple. I see. I understand. That sort of depends on
what you mean. The results of the numbers, the number of
adverse--of suicidality events were shown, study by study, not
Dr. Mosholder's analysis, by Dr. Laughren. I mean, these are
the data that we had that were submitted to us. Those were
presented. They showed an excess in some studies, not an excess
in other studies, and they did not----
Chairman Barton. Which meeting are you talking about?
Mr. Temple. The February 2004 meeting.
Chairman Barton. But he was not there?
Mr. Temple. He was there, but he didn't present the
results.
Chairman Barton. He was there, but he wasn't allowed to
speak.
Mr. Temple. Yes.
Chairman Barton. Publicly allowed to speak.
Mr. Temple. He presented other data, but he didn't present
the--he didn't present the analysis of the controlled trials in
depression.
Chairman Barton. Well, I would argue that that was unfair.
Now let's fast forward to a couple of weeks ago. There was
another Advisory meeting. Was he allowed to present there?
Mr. Temple. Yes.
Chairman Barton. Unencumbered?
Mr. Temple. Unencumbered.
Chairman Barton. Okay. So then I was misinformed on that. I
was told that he was not allowed at the second meeting to
present, that his data was presented, I believe, by Dr.
Laughren. That was at the first one? Okay. Well, then I was
misinformed.
Mr. Temple. At the first one Dr. Laughren presented
somewhat different data that were basically derived from the
same data bases. We didn't try to present Dr. Mosholder's
views. We just tried to show why we were worried about these
things in the first place.
Chairman Barton. Well, my main point, and I think it is
still valid: If somebody is viewed as credible, which Dr.
Mosholder was initially when he was appointed, when he was
still in the Pharmacological Neuropharm Directorate. He was
picked to do the review, apparently because they felt he was
the best qualified. Now I understand that he later got
transferred to a different division or different directorate.
Mr. Temple. He moved voluntarily. We didn't want him to go.
Chairman Barton. Okay. He moved voluntarily. Anyway, he was
no longer in that group.
Mr. Temple. We consider that a loss for us.
Chairman Barton. Okay. Well, we agree on that. We agree on
that. You know, if he was the one who was picked to do the
initial review, he should be the one that is picked to do the
presentation of the data. We, I think, all agree up here that
the impression is that he wasn't allowed to present, because
higher-ups disagreed with him and wanted to muzzle him.
Mr. Temple. Well, what higher-ups thought was that the data
weren't ripe for presentation, because they needed the analysis
of the cases by the Columbia group, and you know, it is always
a difficulty when there is disagreement about something like
that. But the people at the next level have responsibility for
making that decision.
We thought it was potentially dangerous for the community
to present prematurely what appeared to be an FDA conclusion.
You know, I am positive people can argue that judgment, but
that is what the judgment was.
Chairman Barton. Well, we all agree that the best advocate
for a position is normally the person who is actually most
responsible for developing the position. You agreed with me
that Senator Kerry would be a little hacked off if Joe Barton
got to present his position, because if I was doing the
presenting and I say, now this is what Senator Kerry said but
this is really what I think ought to be, you know, and every
time President Bush said something, I'd say, well, I have to
oppose that, but you know, really I do agree with you, it
wouldn't be a very good debate.
Mr. Temple. This may be more nuance than is safe, but it
wasn't that we disagreed with him. What we thought was that the
data weren't ready. So what I didn't want to do----
Chairman Barton. Why wouldn't you let the Advisory
Committee--it's not like you are making a presentation to the
unwashed like Members of Congress. You are making the
presentation to a technical advisory committee of experts that
you yourself--not you personally perhaps, but the FDA has
picked.
They certainly ought to be able to determine the nuances of
the data and, if they are really on their toes, they are going
to ask him a lot of very pointed questions trying to pick out
any flaws in his presentation.
Mr. Temple. We could probably have done that and offered
our own critique and then let them choose. What we were worried
about, you know, for better or for worse, is that it would
appear to be an FDA conclusion and that we thought it was
premature, and we thought that was not the right thing to do
and was potentially a bad thing for the community.
I think Dr. Laughren has been trying to--can I let him?
Mr. Laughren. Can I just try and clarify?
Chairman Barton. Yes, sir. This is an open hearing. We are
not going to muzzle anybody.
Mr. Laughren. Okay. You know, let me just say, first of
all, that we fully appreciate Dr. Mosholder's role in this. As
Dr. Temple pointed out, he was the one who discovered the
signal initially, the potential signal in the Paxil pediatric
supplement back in 2002, and alerted us to this problem with
the way the data were coded that led to the report from Glaxo
in May 2003. And everyone agrees that he was the right person
to begin looking at those data.
What he did, he looked at the Paxil summary report, which
was the first one. In the meantime, he began looking back at
the pediatric supplements for the other drugs while we were
waiting for data from the other drugs and made a very important
contribution at the internal regulatory briefing in September.
The focus--our focus changed dramatically over the course
of the fall, as we started looking at the cases and recognized
that there might be a problem in understanding--in whether or
not they all represented suicidalities. That was one major
theme we were pursuing.
We were also concerned about case finding. We recognized,
as again we started looking at these documents, that we may not
have gotten all the cases, and that is why late in the year we
issued additional requests for more cases from the companies.
A third theme that we were pursuing was getting what is
called patient level data so that we could try and understand
the striking differences between trials.
So this was our focus, and gradually it became clear that
we were going to have to do our own analysis of the data, based
on this more complex dataset. That is why Dr. Mosholder's role
changed during that period of time. So----
Chairman Barton. Are you saying he wasn't competent to do
that?
Mr. Laughren. No, I'm not--well, I'm not saying that. We
had the expertise to deal with----
Chairman Barton. Who is we?
Mr. Laughren. Well, the Neuropharm Division, in particular
the safety team, Dr. Hammad.
Chairman Barton. And Dr. Hammad is not in the direct line.
He is kind of a staff auxiliary advisory to the main chain of
command in the Center. Is that not correct? I mean, his job is
to kind of double check everybody else?
Mr. Laughren. No, no, no. He did the primary analysis, the
definitive analysis that we presented to the Advisory Committee
last week.
Mr. Temple. There is a group called the Safety Group in
Neuropharm that specializes in doing safety analyses, and he is
a member of that group. He, too, is actually moving to the
Office of Drug Safety.
Chairman Barton. But Dr. Hammad's--I looked at a flow chart
to try to figure out who everybody is, and my understanding is,
of the group that is here, Dr. Temple is the biggest dog and is
an Associate Director, and Dr. Laughren reports directly to
you, and Dr.----
Mr. Temple. Well, Dr. Katz who couldn't be here is the
Division Director, one of three in the office that I run.
Chairman Barton. You report to him. Right?
Mr. Temple. He reports to me, and Dr. Laughren reports to
Dr. Katz.
Chairman Barton. And Dr. Hammad is in a staff group that is
not in the direct chain. Is that correct?
Mr. Temple. No. Well, there's two Psychopharm groups, one
of which is headed by Dr. Laughren, and there is a safety group
that reports the same way as Dr. Laughren does, to Dr. Katz,
and Dr. Hammad is in that group.
Chairman Barton. Okay. Well, I have kind of gotten off on a
rabbit trail here. My time has expired. Let me refocus this
again to the members of this subcommittee who have really no ax
to grind except that we want the very best for the American
people, and in this particular case we don't want children
taking anti-depressant drugs if there appears to be quite a bit
of evidence that, not only does it not help them, in some cases
it actually hurts them, increases the risk of suicidality.
Time after time in reviewing the documents and reviewing
the transcripts and the testimony, you know, it really does
appear to me that the FDA has gone out of its way to short
circuit the findings of Dr. Mosholder and create this counter-
argument that you epitomized earlier when you said, well, if
there is some evidence that it might help some people some of
the time, why should we stop it, which seems to me exactly
contrary to what the normal FDA standard is, that if you can't
show that it helps a lot of people all the time, we shouldn't
allow it.
Mr. Temple. I was trying to describe what our Advisory
Committee of people in the field who actually do this were
worried about.
Chairman Barton. I am just really puzzled about that.
My last thing, again back on Dr. Mosholder: Is it true
that, when ABC contacted him to say that they were considering
him for man of the week, that higher-ups at FDA tried to stop
that? Is there any truth to that?
Mr. Temple. I have no idea. I can't imagine that we would
try to stop it, but I do imagine that it might have to get
cleared, something like that. But I have no knowledge of this.
Chairman Barton. Would Mr. Mosholder--you are still under
oath. Do you know for a fact if anybody at FDA, when you were
asked to be man of the week for ABC, either did not clear that
or tried to prevent that?
Mr. Mosholder. Actually, I had a conversation about that
with Dr. Seligman, whose chair I just took, and Dr. Seligman
had some reservations about it. In my mind, too, was at that
time I had been asked to be a witness at this hearing, and I
had some concerns about whether it would be unseemly, because
being person of the week involves an on-air interview, whether
that would be unseemly coming just a few days before this
hearing.
Chairman Barton. So who withdrew? Did you withdraw?
Mr. Mosholder. I withdrew. Yes.
Chairman Barton. You withdrew. You didn't--I am going to
ask Dr. Seligman as soon as he retakes his seat what is
concerns were.
Dr. Seligman, we just heard from Dr. Mosholder that, after
talking to you, he withdrew from consideration for ABC man of
the week, which I would think would be something the FDA would
want, that they would want their employees being men and women
of the week to show that they are doing good deeds for the
American people.
What were the concerns that you expressed to him about
that?
Mr. Seligman. I congratulated him for his selection.
Chairman Barton. That is not expressing a concern.
Mr. Seligman. No, I know. I am just telling you what the
nature of our conversation was. I just expressed the same
concern that I express over any interaction with the media,
which is to make sure that was careful and thoughtful in his
presentation and that things he said were, you know, succinct
so that it potentially could not be taken out of context.
Chairman Barton. So did you encourage him to go forward or
did you encourage him to withdraw?
Mr. Seligman. I did neither. I did neither encourage him
nor discourage him.
Chairman Barton. Okay. Well, if ABC is listening, I would
encourage ABC to nominate Dr. Mosholder for man of the week,
because I think he is doing the kind of things that we want our
researchers and evaluators to do. So for what it is worth, the
chairman of Energy and Commerce Committee that has jurisdiction
over the FDA thinks that would have been an excellent
selection.
Mr. Walden. And Telecommunications.
Chairman Barton. My time has way expired. So with that, I
yield back.
Mr. Walden. Thank you, Mr. Chairman. Now I again appreciate
the courtesy extended by the gentleman from Michigan, and we
look forward to your questions. Mr. Stupak.
Mr. Stupak. Thank you. Dr. Temple, you said the black box
warnings goes to health care professionals hearing this and not
to the public. Are you going to do an informed consent on this
drug?
Mr. Temple. The Advisory Committee didn't vote on that
question, but talked about it and did not think that was
appropriate. The problem here is that----
Mr. Stupak. So are you going to do an informed consent or
not?
Mr. Temple. Well----
Mr. Stupak. Yes or no?
Mr. Temple. I don't think that is fully settled, but I
would say probably not.
Mr. Stupak. So we don't get the black box warning. There is
no informed consent. How are people out here going to know what
is going on with these drugs?
Mr. Temple. Sorry, I missed the first part of your
sentence.
Mr. Stupak. There is no black box warning that people will
receive. There is no informed consent. How are they going to
know that these drugs are not effective and increases
possibility of suicide behavior?
Mr. Temple. Well, patients will--with unit of use
packaging, every patient who gets the drug gets the patient
labeling, so called Med Guide. That will have a very prominent
statement--whether we box it or not, I think that hasn't been
determined yet; we don't necessarily----
Mr. Stupak. You are going to put the Med Guide, which is
supposed to be in very plain, simple English--you are going to
put that into every packet?
Mr. Temple. Yes.
Mr. Stupak. Every one?
Mr. Temple. Every one.
Mr. Stupak. Is the pharmacist going to have to dispense it
or is it going to be in every one?
Mr. Temple. No. We despair of success when the pharmacist
has to dispense it.
Mr. Stupak. Beg pardon?
Mr. Temple. We don't think it is successful if the
pharmacist has to do it. That is why we create--that is why we
insist, in some cases anyway, on unit of use packaging. Unit of
use packaging means----
Mr. Stupak. Right. Familiar with it. You indicated that--we
have heard testimony the last couple of times that everyone was
quick to say there were no suicides in clinical trials. Is that
correct? Yes or no? You can't shake your head.
Mr. Temple. I'm sorry. Yes.
Mr. Stupak. Okay. So where did you get the information on
the suicides then?
Mr. Walden. Just for our audience, we are being called for
one vote. We will wait, though, a few minutes, and then we will
recess while we make that one vote. Then we will come back. Oh,
is it two votes? Okay. Well, we will do the same drill.
Mr. Temple. There were no suicides in the 4,000 or so
patients who were in the controlled trials--in the pediatric
trials.
Mr. Stupak. Correct.
Mr. Temple. In the much larger data bases that have been
carried out in adults, there were suicides, and we have
compared the frequency of suicides on-treatment and off-
treatment in those. There, it comes out even. That is our
suicide data.
Mr. Stupak. So your suicide data would be coming from
reports from the drug manufacturers then, right, or unless it
is voluntarily----
Mr. Temple. No. These are results of trials. There have
been a lot of trials altogether. So we have 30-40,000 people.
Dr. Hammad can tell us how many.
Mr. Stupak. So the suicides were found in the adult
population. You extrapolated that to make some kind of
conclusions as to children?
Mr. Temple. No. We have reached the conclusion about
adults. We don't know that adults and children are the same. As
I said, when Paxil data in adults were examined in exactly the
same way as they were examined in children, and the children's
analysis showed a clear excess of suicidal behavior and
thinking, no similar excess was seen in adults.
I don't have a good explanation for that. I don't know why
that should be true, but that is what the result is so far.
Mr. Stupak. If you have no suicides in the clinical trials,
do you have suicides in your adverse events file?
Mr. Temple. Yes.
Mr. Stupak. With children?
Mr. Temple. Oh, yes.
Mr. Stupak. And what percentage are reported?
Mr. Temple. Well, we have no idea.
Mr. Stupak. Wasn't it true that with your adverse events
report, only about at most 10 percent are ever reported?
Mr. Temple. That is a figure commonly given, but we don't
know what the right answer is.
Mr. Stupak. In fact, FDA has used that figure many times,
somewhere between 1 percent and 10 percent.
Mr. Temple. We have used that figure to try to make rough
estimates, but that is not the same.
Mr. Stupak. What you have is only 10 percent of what may
actually be out there. We can't say with certainty, but based
upon, again, extrapolation of the data, it is basically 10
percent of the known number.
So when you do your black box warning, are you going to use
the word rarely, that suicide behavior, suicide thoughts,
suicide ideation, suicides may rarely occur with the use of
these anti-depressants in young people?
Mr. Temple. No. The results of the trials would not support
the term rare. Dr. Hammad estimated--well, it is roughly, just
roughly, 2 percent in people who get placebo and about 3.5 or 4
percent in people who get the drug. That doesn't meet anybody's
test for rare.
The excess risk is in the neighborhood of 2 to 3 percent. I
think that is the figure Dr. Hammad gets. So that would not be
called rare.
Mr. Stupak. When will you end your conversations about the
black box?
Mr. Temple. Really, within a few days, we will reach a
decision.
Mr. Stupak. Right. You have stated in your testimony, the
little bit I have been in--we have a mark-up going on upstairs;
so I am running back and forth between the two. You have stated
in your testimony that thus far these anti-depressants in
children, ``doesn't work; do not meet the standards for
approval; results are discouraging.'' Then why does the FDA
allow these anti-depressants be given to children under the age
of 18?
Mr. Temple. Well, we don't allow it. The labeling all says,
except for Prozac, that safety and effectiveness----
Mr. Stupak. Are you telling this committee, if the FDA put
on the thing that says not to be distributed to children under
18, you don't have that authority? You can't do that?
Mr. Temple. Not to be distributed?
Mr. Stupak. Not to be filled by pharmacists.
Mr. Temple. We could, for example, contraindicate the use
in people under 18.
Mr. Stupak. Yes, you could.
Mr. Temple. We could. We were advised by our committee in
the strongest way--this was not 15 to 8----
Mr. Stupak. This was the Advisory Committee. Right?
Mr. Temple. Right.
Mr. Stupak. You don't listen to advisory committees if you
don't want to anyway. Take Accutane. We have been waiting for 4
years for certification and registry. Four years, we still
don't have it. After two advisory committees tell you do it, we
are still waiting 4 years later.
The FDA does what it wants. Now the bottom line here----
Mr. Temple. I have to protest. We take--I can't speak to
the case you are referring to here. We take----
Mr. Stupak. The bottom line is you have the authority.
Mr. Temple. We could seek to contraindicate their use.
Mr. Stupak. Then if it doesn't work and increases the
possibility of suicidal behavior in people under the age of 18,
why don't you do it? Aren't you supposed to protect the safety
and welfare of the American people?
Mr. Temple. Yes, and we are not sure that your proposal or
your suggestion would protect the American public. It might
harm them.
Mr. Stupak. Well, let me just read you here. This was an
article handed out earlier today. This is the San Francisco
Chronicle, I think it was, the article. It says on paragraph,
column four, first paragraph: ``But this episode suggests that
they''--being the FDA--``reject the precautionary principle in
favor of the idea that no drug is dangerous unless it is proven
to be so.''
Mr. Walden. I believe that is the British Journal.
Mr. Stupak. The British Journal? Okay. So in other words,
shouldn't you err on the side of caution when you are talking
about increased possibility of suicidal behavior in young
people, especially when the drugs thus far has not shown to be
effective in the treatment of depression?
Mr. Temple. Well, like the Advisory Committee, I believe we
have to think about a whole bunch of things. There are--I don't
want to make more of this than they deserve, but it is very
clear that the suicide rate in adolescents has been declining
for the last 10 years, the period in which these drugs were
started.
Mr. Stupak. But you can't give the anti-depressants credit
for that, because you have said that they are not effective in
that.
Mr. Temple. No. I have not said that they are not
effective, and it is very important to recognize the
distinction.
Mr. Stupak. Wait a minute. You're saying now they are
effective in treating depression in young people?
Mr. Temple. No. What I said is that they have not been
shown to our satisfaction to be effective. That is, they
haven't been shown in well controlled studies to do the things
that you are supposed to do to be considered effective. But we
know from depression trials in adults that lots of drugs that
work can't show that they are effective every time.
In fact, more than 50 percent of all trials in adults fail.
Why they seem to fail so much in children, we don't know. It
could be they really don't work.
Mr. Stupak. You don't know.
Mr. Temple. We don't know.
Mr. Stupak. For all indications right now, we know they
don't work. We know they increase suicide behavior. Then why
don't you not allow the drugs be prescribed to children under
18 until you do know--until you do know? Isn't it more harm to
these people who may be of fragile mind, suffering from
depression, to give them something like Paxil, which is
supposed to make them feel better, and it really doesn't? Isn't
the mind then saying, geez, I had a little hope here; you gave
me this prescription, and I would be better. It doesn't work.
In fact, it is not being effective. Aren't you really putting
that person at risk, at a greater risk with a false hope that
you are giving them?
Mr. Temple. Having untreated depression is risky, too, and
we don't know----
Mr. Stupak. Absolutely.
Mr. Temple. We can't know. You can't do mortality studies
here. No one will let you do them. We don't know whether you
would be worse off or better off. The Advisory Committee was
quite convinced, but I am not going to tell you they had data
to work from. They didn't. They were quite convinced that there
are many people who are suicidal because of their disease who
would be made worse off.
I am not telling you that they know that to be true. I am
not telling you that is evidence. I am not telling you that
should lead to a claim in labeling. But I don't dismiss it out
of hand either.
Mr. Walden. If I could interrupt just a second, Mr. Stupak.
Are you able to come back after the votes?
Mr. Stupak. Sure.
Mr. Walden. In which case I would extend you another 5
minutes after the votes. We are probably down to about 7
minutes or so to go over to vote. What I would like to do is
recess the committee, return, and then I will return to you for
further questions, if that is appropriate.
The committee will stand in recess, and we would request
our witnesses to stay here as well. Thanks.
[Brief recess.]
Mr. Walden. If I could have our witnesses return to the
table, we will get started here in just a moment. I am going to
call the Committee on Oversight and Investigations back to
order.
When we left for the vote, Congressman Stupak had the
floor, and we are extending you another 5 minutes for your
continuing line of questions. So the Chair would recognize the
gentleman from Michigan.
Mr. Stupak. Thank you, Mr. Chairman.
Dr. Temple, in response to one of the questions by someone
up here, they were asking about the studies, and you said there
were some studies you could not publish concerning the anti-
depressants.
Mr. Temple. I said we can't force people to publish things.
Mr. Stupak. But can you publish them?
Mr. Temple. Well, let me describe what we can and can't do.
When we approve a new drug or a supplement to a new drug, our
reviews and things like that are all made public. They are put
on our website. If we do not approve----
Mr. Stupak. Your reviews, but not the studies?
Mr. Temple. Our reviews, not the studies. But our reviews
are quite detailed. I would modestly say there are at least as
informative as a publication in a journal, as a rule.
Mr. Stupak. Okay. So these are all approved. All these
anti-depressants are approved drugs. If another study comes
out, do you get that study? Do you receive that study?
Mr. Temple. Like if they do another study, they must be
reported in annual reports, but unless they show something bad,
they don't have to be--not much has to be done with them. If
they show something dangerous, then they have to be reported to
us promptly.
Mr. Stupak. So they are found in what is called the Annual
Progress Report or another one they call it is the
Investigative Drug Brochure. Correct?
Mr. Temple. Well, that is for a drug that----
Mr. Stupak. That is for an IND. Right?
Mr. Temple. Yes.
Mr. Stupak. Okay. In the Annual Progress Report--that is
just a summary of what they did. Right? A summary of these
studies, the drug companies send it to you: Here's what we have
done in the past year; here is where reference to our pill has
showed up in a medical journal, or something like that.
Mr. Temple. They may actually put the reprints, but I
wouldn't want to boast too much about how useful those
documents are to us.
Mr. Stupak. What if the company fails to leave out part of
the critical point that you are looking for, that something
would be dangerous, such as causing suicide or affecting the
central nervous system. They don't put it in their annual
report.
Mr. Temple. Well, if we somehow become aware of it, we can
bring various legal actions against them. You have to tell us
about things like that. There are examples where delays in
reporting to us have resulted in criminal penalties of various
kinds.
Mr. Stupak. Okay.
Mr. Temple. Of course, we do have to find out about it.
Mr. Stupak. Sure. Let me ask you this question. Is it true
that the FDA published its Public Health Advisory with a
recommended label change about worsening depression and
suicidality in patients treated with anti-depressants on March
22, 2004?
Mr. Temple. Yes.
Mr. Stupak. Okay. And who wrote the text of that label
change?
Mr. Temple. Wow. Let me ask Dr. Laughren, because he and
his people would have had a major role in that.
Mr. Laughren. The initial draft of the label change came
out of the Division, but there were a number of other groups
within the agency who had input into that, including people in
Office of Drug Safety, Office of Pediatrics and
Counterterrorism.
Mr. Stupak. Well, let me ask you this then. Who would have
been the person to sign off? Who gives it final signature? I
know you have these initial drafts.
Mr. Temple. I mean, something like that goes through parts
of the Commissioner's office for final sign-off.
Mr. Stupak. Okay. So Dr. Crawford would be the guy who
would sign off on it eventually then?
Mr. Temple. I can't say that, but someone in the
Commissioner's office would.
Mr. Stupak. If you compare the text that the FDA approved
for the labels of anti-depressants on March 22, 2004, and what
is on the labels of the anti-depressants today, would they be
the same?
Mr. Temple. It depends on how the Public Health Advisory is
written. Sometimes they are written before----
Mr. Stupak. I am talking about the March 22, 2004 Public
Health Advisory. Look at Tab 44. That might help a little bit
here.
Mr. Temple. They wouldn't necessarily be the same. You are
writing in a different way. You are trying to communicate a
little more in the Public Health Advisory.
Mr. Stupak. Well, explain this to me. Look at Tab 44.
Mr. Temple. They shouldn't be in major----
Mr. Stupak. March 22, 2004, says, and I am quoting:
``Health care providers should carefully monitor patients
receiving anti-depressants for possible worsening of depression
and suicidality, especially at the beginning of therapy or when
the dose either increases or decreases. Although FDA has not
yet concluded that these drugs cause worsening depression or
suicidality, health care providers should be aware that
worsening of symptoms could be due to the underlying disease or
might be a result of drug therapy.''
But now the actual labels say this--that is approved by the
FDA. It says, ``Patients with major depressive disorder, both
adult and pediatric, may experience worsening of the depression
and/or the emergence of suicidal ideation and behavior
(suicidality), whether or not they are taking anti-depressants
medications, and this risk may persist until significant
remission occurs. Although there has been a longstanding
concern that anti-depressants may have a role in inducing
worsening of depression and the emergence of suicidality in
certain patients, a causal role for anti-depressants inducing
such behaviors has not been established. Nevertheless, patients
being treated with the anti-depressants should be observed
closely for clinical worsening and suicidality, especially at
the beginning of the course of drug therapy or at a time the
dose changes.''
This is just one example of how March 22, 2004, labeling
warning label text is different from the labels we see on the
drugs today, and there is actually another one. My question is,
why is the March 22 language published on your website not good
enough to make it to the labels for the doctors? If you have
already weakened your March 22 recommendation--I believe you
have--how can we trust that you won't have strong, clearly
worded labels on the package that demonstrate the lack of
efficacy and the increase of risk with these drugs?
See what I am saying. March 22 you had pretty strong
warning. That is on your website. Now what we see on the
package is completely different.
Mr. Temple. I guess I think the labeling language is of
similar strength, although the words are somewhat different.
They both emphasize monitoring. They both emphasize that you
can get much----
Mr. Stupak. See, here's our problem. Most of us up here
aren't doctors. We looked at it. We read it, and we can't--we
think it is less. We think it is weaker, and then you tell us
you are going to do this black box warning, which the patients
and families aren't going to get, and the first notice they are
going to get about they are not being effective and may
actually increase suicidal behavior is when they open up their
package, because in there is going to be a Med Guide.
Isn't that a little bit too late? They have already had
their prescription. They already had it filled. They are
already there. They got it. They've spent the money. Now after
all this, now you are going to tell them, hey, wait a minute,
before you do this you ought to know this.
That is our concern up here. Sounds like we got the horse
before the cart, the cart before the horse, whatever you want
to call it. Ain't right.
Mr. Temple. That's a different question. That is why we
made sure that the Committee discussed the question of whether
there ought to be some attempt to give something out
beforehand. The difficulty with those, and we do do it
sometimes, mostly in relation to fetal abnormalities where the
urgency seems maximal, is that how you structure that, how you
get these into the office, how you get them discussed
adequately, given the current situation on how long people
spend, is not so clear.
Mr. Stupak. Right. When you discuss these, it is between
the FDA and the drug company. Is anyone there representing the
people, the patients, a public citizen or anyone like that at
these discussions that you are having on black box and all
that?
Mr. Temple. Well, these discussions aren't being held with
the drug companies either. We are going to propose labeling.
Then maybe after that----
Mr. Stupak. And then you go back and forth?
Mr. Temple. Maybe, but----
Mr. Stupak. No, no, you do, every one of them. I have never
seen a drug company yet accept a first recommendation you made
on labeling.
Mr. Temple. Well, we didn't--I mean, Tom would know best,
but I don't know how much difficulty we had with the one in
March.
Mr. Stupak. Let's go back to my original question. See, the
confusion with your March 22, what you have on the website,
people get it after they purchase drug. Why don't we just go to
an informed consent? I would strongly urge you go to informed
consent before you ever even get this, when you start treating
with these doctors, that clearly spells out like a Med Guide
would that here is what we find. And if it changes, we can
change that informed consent.
I don't want a voluntary one, because half the doctors
don't give it. We want a mandatory informed consent, especially
when dealing with young kids.
Mr. Temple. To do that, you also have to have a completely
separate distribution system. It has to be shipped directly to
the doctor or something like that. It is----
Mr. Stupak. I know doctors are busy, but if you tell them
it is a mandatory informed consent and then they are practicing
improperly, they would do it.
Mr. Temple. May be. I think what the people on the
committee thought was that the burdensomeness of it would
interfere more than they wanted with the appropriate use of the
drugs. That doesn't mean we can't consider this further, but
that is what they thought. They did talk about this a fair
amount.
Mr. Stupak. I would encourage you to do the informed
consent, and thank you for the extra time.
Mr. Walden. You are welcome. Thank you for your
participation.
Dr. Knudsen, if you would turn to Tab 73, please, sir. Do
you recall ever getting this response from Pfizer? I note it
says a desk copy to you on the bottom of the second page, I
believe.
Mr. Knudsen. I did not--I don't recall getting the response
from Pfizer that addressed that request that I had of them to
provide additional information. Once again, just because I
don't recall doesn't--let's see.
Mr. Walden. Had you gotten an official company response to
the question about suicidality, what would have been your
protocol in reviewing that response?
Mr. Knudsen. Yes. I would have read it and ascertained
whether or not they answered the questions posed to them,
whether or not they answered the questions adequately, and
often indicated what we--well, NAI, no action indicated, signed
my name.
I am not saying I did it for this one, because I do not
recall anything from them.
Mr. Walden. Right. I understand.
Mr. Knudsen. But that is how I have done it in the past.
Mr. Walden. Were you able to find any memo in the Zoloft
files you looked at, at the agency or in your own files,
evidencing that you or anyone else within the agency actually
reviewed Pfizer's response?
Mr. Knudsen. No.
Mr. Walden. Had you been satisfied with Pfizer's response,
would you have most likely written a memo to that effect, had
you been satisfied with their response?
Mr. Knudsen. It is conceivable.
Mr. Walden. I think your mike got turned off there, sir.
Mr. Knudsen. I may have put a No Action Intended--
indicated, excuse me. But, yes, I----
Mr. Walden. I mean, you would have written some response.
Mr. Knudsen. Yes. Yes.
Mr. Walden. So would you have let your supervisor know that
you had reviewed and received the company's response to a
safety question you posed? Is that standard operating
procedure?
Mr. Knudsen. I would have put my response in the box, yes.
Mr. Walden. The box?
Mr. Knudsen. Well, the mailbox for my supervisor.
Mr. Walden. Okay. Thank you. Who was your supervisor at the
time?
Mr. Knudsen. Dr. Laughren.
Mr. Walden. Okay. Dr. Laughren, do you recall ever
reviewing Pfizer's response on this issue of suicidality in
kids?
Mr. Laughren. Not at that time. I have looked at it
subsequently.
Mr. Walden. And that was because of the hearing coming up
here?
Mr. Laughren. I just learned about it as a result of
document exchanges and what-not. We did not have the letter
that Dr. Knudsen sent to Pfizer in our files. I believe we had
to get that from Pfizer.
Mr. Walden. That is our understanding. But we are talking
about Pfizer's response to that letter.
Mr. Laughren. Right, right.
Mr. Walden. But you didn't have either one, is what you are
saying. Is that in part because you don't have a record
retention policy? Dr. Temple, what is your policy for saving
documents like this?
Mr. Temple. Materials that are--go ahead.
Mr. Laughren. We did have the May--was it May 28, the date
of the receipt?
Mr. Walden. Yes, May 28, 1996.
Mr. Laughren. We did have that in our files. What we did
not have is the letter that Dr. Knudsen sent back in March. We
didn't have a copy of that letter in our files.
Mr. Walden. Oh, I see. But you did have Pfizer's response?
Mr. Laughren. It was in our files. But there was no
indication that it had been reviewed.
Mr. Walden. I see. And you hadn't reviewed it prior to the
committee bringing this to your attention?
Mr. Laughren. There wouldn't have been any reason for it to
have come to me, ordinarily.
Mr. Walden. Unless he had referenced it to you.
Mr. Laughren. Unless he had given it to me. Right.
Mr. Walden. All right, and there is no record of that.
Okay. But I guess the question is: Now you have reviewed it, do
you think it raises serious safety concerns?
Mr. Laughren. No. It basically provides additional
information that supports the view that I expressed in my
October--I think it was October 25, 1996, memo where I
commented on the issue that Dr. Knudsen raised in his March
review. It basically supports that view.
Mr. Walden. And what he raised at that time was a serious
safety concern, wasn't it?
Mr. Laughren. Well, he raised a concern that there might be
a signal of increased risk of suicidality in pediatric patients
relative to adults, but if you have seen my October 25 memo, I
believe I fully addressed that. I mean, there were a couple of
issues there.
No. 1, he was comparing risk of suicidality in adult
patients who had been scrupulously screened out for not having
depression with a group of children, many of whom had primary
depression. So it was not, in my view, a reasonable comparison.
Mr. Walden. all right. If you would turn to Tab 75, we will
send the book of tabs back your way. This is a memo that you
authored on October 25, 1996. Subject line is: You note that
``a concern about the possibility of a signal of emergent
suicidality, suicide attempts, gestures or ideation association
with Certraline used in pediatric patients was raised by Dr.
Knudsen in his 3/28/96 safety review.'' In your memo you did
not mention the fact that Dr. Knudsen requested and received
additional information from the company. Why is that? You had
no idea?
Mr. Laughren. Because, obviously, I didn't know about it.
Mr. Walden. Okay. As you know, the company's response was
May 1996, and so over 4 months before you write this memo. So
this memo gets written. This is in the file somewhere in
theory, because it is there today, and nobody reviewed it?
Mr. Laughren. Well, again I said, now that I became aware
of it very recently, I have reviewed it; and as I say, it
supports--sorry?
Mr. Walden. It doesn't raise serious----
Mr. Laughren. Well, it answers the questions that Dr.
Knudsen raised in his letter to the company. It provides
additional data and, having looked at those data, it supports
the conclusion that I am reaching in my memo, that there is no
signal.
I mean, really, the only data in that final safety update
that Dr. Knudsen reviewed back in 1996 that is relevant are the
controlled trials data for that one study in pediatric OCD.
That was roughly--that was the study that we have subsequently
reviewed, roughly 100 patients in drug, 100 patients in
placebo. There is one suicidality event. That occurs in a
placebo patient.
That is really the only data there that are directly
pertinent to the question.
Mr. Walden. Let me just read the final paragraph of this
memo. It is Tab 75. This is the one that you wrote to file. It
says: ``In summary, I don't consider these data to represent a
signal of risk for suicidality for either adults or children.
Supplements are planned for both depression and OCD in
pediatric patients, and when we have more complete data,
including Ham-D data, we can look more critically at this issue
using the now standard approach of comparing the proportions of
drug and placebo exposed patients who show worsening on Item 3,
suicidality item of the Ham-D during treatment. At the present
time, current labeling simply notes Zoloft has not been
adequately evaluated for safety and effectiveness in pediatric
patients.''
So you are saying that you are going to look at additional
studies. Right?
Mr. Laughren. Well, basically, what I am saying here is
that we would likely look at the Ham-D item. Every one of these
depression rating scales that is used in evaluating--they are
often used in OCD trials as well. They have a standard suicide
item. In the case of the Ham-D it is the Item 3.
Dr. Hammad as part of his review of these pediatric
suicidality data did look at the item scores. He looked at two
measures of the item scores, both----
Mr. Walden. But that was when?
Mr. Laughren. Well, that was recently.
Mr. Walden. Right. What happened between 1996 and recently?
Did the agency look more critically at this issue? Did you put
this in the pediatric trials for anti-depressants for kids, the
written request?
Mr. Temple. No. They all do that, though. They all do a
Ham-D.
Mr. Walden. Well, that is not my question. My question----
Mr. Temple. No, no. It did----
Mr. Walden. Now wait a minute. Dr. Temple, did the FDA
specifically in your written request ask for exploration of
this question, suicidality?
Mr. Temple. The answer is we did not. But again----
Mr. Walden. Why?
Mr. Temple. At the time we issued--prepared and issued the
written request, obviously, it was not an issue that was
prominent in our thinking. Again, keep in mind, up until this
point we had never seen a signal for suicidality in the adult
data.
Mr. Walden. But doesn't this memo indicate that this is
something you needed to look at?
Mr. Laughren. I did consider, and again, as I am saying,
looking at the data that were available in this safety update,
there was no signal for suicidality in children. The signal
that emerged for Zoloft in pediatric patients came later. It
came in the depression trials.
There was one study here, only one study,an OCD trial.
There was no signal in that trial.
Mr. Walden. All right. But your memo says, when we have
more complete data, including Ham-D data, we can look more
critically at this issue. How did you look more critically at
the issue? How did you go about getting more data?
Mr. Laughren. We have looked more critically very recently,
looking----
Mr. Walden. Very recently?
Mr. Laughren. Very recently.
Mr. Walden. See, I am looking at this gap between 1996-97
when some of these issues began to be raised by various people
in FDA.
Mr. Laughren. Well, raised but also addressed. There is no
signal in these data.
Mr. Temple. The first real signal came when Dr. Mosholder
evaluated the Paxil data.
Mr. Walden. And when was that?
Mr. Laughren. That supplement came in, in probably the
spring of 2002, and he finished his review in the fall of 2002,
and that is when we----
Mr. Walden. Didn't we already go through this with Mr.
Mosholder on a 1997 memo where this was also raised as an
issue?
Mr. Laughren. Not suicidality. That was agitation and, by
the way, that information got into labeling. That is included
in the labeling for Luvox. There was no issue of suicidality
raised in Dr. Mosholder's review.
Mr. Walden. So from 1997 to 2002, how did the agency look
more critically at the data?
Mr. Laughren. We had no--again, up until the time that Dr.
Mosholder reviewed the Paxil pediatric supplement in 2002, we
had no reason to do anything more. There was no signal.
Mr. Temple. Can I also repeat a distinction I made earlier?
We thought at the time--and you can see that in Dr. Laughren's
memo--that looking at the suicide item on a Ham-D or the
equivalent in a pediatric score would be the way to find
suicidality. That is plainly not true, because you don't see,
as Dr. Hammad's review showed--you don't see any increase in
that item even in the trials that show the increased
suicidality.
What turned out to be the place to look, which we didn't
know, was in the adverse reaction reports, and I would say we
don't know why that is. Why, if you are not feeling more
suicidal, do you have more suicidal events? I don't think we
know the answer to that. But it is very clear now that the way
to look for suicidal ideation is to, in a more structured and
better way that we have probably done up to now, look at those
events that may represent suicidal behavior or thinking, and
that the----
Mr. Walden. There is a March 1991 article, a case study
called Emergence of Self-Destructive Phenomena in Children and
Adolescents During Fluoxetine Treatment.
Mr. Laughren. Is that the King article?
Mr. Walden. I am sorry?
Mr. Laughren. I am sorry. Is that the King article?
Mr. Walden. I believe it is, yes, sir.
Mr. Laughren. Right, and that is reporting on individual
cases. Those are not controlled trials data.
Mr. Walden. Is this a peer reviewed study? Is this in
Journal of American Academy of Child and Adolescent Psychiatry?
Mr. Laughren. It very likely is. It came out around the
same time as the Teicher article reporting on a series of, I
believe, six adults being treated with fluoxetine. Again, it is
a suggestion that there might be something, but it is far from,
in any sense, definitive.
Again, we had been systematically looking at the adult data
for almost that entire decade, you know, looking at both
suicide item scores, looking at event data, and more recently
had begun to accumulate the completed suicides in adults, had
not seen a signal. So there was no particular reason why that
issue should have been on our radar screen.
Mr. Walden. Okay. So, basically, you had no reason in these
trials to even look for it, is what you are telling us? When
you put out the written request----
Mr. Laughren. They were looked at in the routine ways.
Adverse events were reported, and the item data were collected.
Again, a signal did emerge in the Zoloft data later on with the
two pediatric trials in depression, but even that wasn't
recognized until--actually, Dr. Mosholder was the medical
officer who reviewed that supplement initially. He did not
observe a signal for suicidality. it is only when he went back
during the summer of 2003 and looked at--relooked at the same
data that a weak signal emerged.
Mr. Walden. Dr. Temple, did you have the authority to ask
the companies to look at this, to keep better data so you
could, in your written request to them?
Mr. Temple. Let me be clear. You always measure the
standard suicide scores, and we have the capacity to look at
those. That is what you do in all these studies. It is how you
measure improvement.
So every time you do these studies, you get a suicidality
score, and we look at it. There isn't anything the company has
to do except give us the data. What we could have thought--what
we conceivably could have asked but didn't know to ask was a
better, more structured, more careful look at events that might
or might not represented suicidality, but we didn't know to do
that.
Mr. Walden. But didn't Dr. Laughren say that in the
depression trials you should look more critically?
Mr. Temple. We were looking at the items in the Ham-D
score, and nobody saw anything. It shouldn't surprise us that
we didn't see it, because in the very data that have created
the signal we are worried about now, you don't see any increase
in the pediatric version of a Ham-D. That is not where it shows
up, for some reason.
Mr. Walden. I guess, as I have listened to this, and I have
sat through these hearings a long time, the picture that begins
to emerge in my mind isn't a pretty one, because it is one that
says you are worried less about suicidality than in continuing
to allow physicians to prescribe a drug that most studies show
at best has no effect in treating depression in kids and
adults.
Mr. Temple. I don't agree that that is our conclusion. We
spent tremendous resources and devoted tremendous effort to
evaluate the suicidality question.
Mr. Walden. Well, when Dr. Mosholder does the review and
says I am spotting something here that is very troubling, when
you are dealing with drugs in kids that virtually every trial
shows have no effect and Dr. Mosholder is finding some link to
suicide, you--well, it seems to me, my opinion is you ended up
on the side of let them prescribe it, because they might be
okay; we don't necessarily agree Mosholder has got this right;
we are going to go run it out somewhere else and see, and take
that risk.
Mr. Temple. We didn't think we were letting them prescribe
it or not letting them prescribe it. The question we were
trying to face was do we have enough information to say there
is increased suicidality in children given these drugs. That is
what we were grappling with.
Mr. Walden. You have said earlier today that you didn't
want to discourage the prescribing of these off-label, because
they may work in some people.
Mr. Temple. That is a different question. We thought that
it was very important to get the right answer on this question.
That is correct.
Mr. Walden. Well, I will tell you, I guess that is where we
are just going to agree to disagree maybe, but if I had to err
and I saw a sign from one of my top scientists that I
handpicked to take a look at this and who I have a great
respect for, and he came back and said I have looked at the
data and I am seeing a link to suicide in kids, I'd say we
better err on the side of caution here. And maybe you got to go
peer review it, but meanwhile since most of these drugs don't
show any efficacy in kids, let's err on the side of against
suicide.
Mr. Temple. But we put out several public announcements
saying that you should be careful and that we are worried about
this. We didn't change the label, though. That is correct.
Mr. Walden. I have way overrun my time. Thanks for your
patience. I yield to the ranking member, Mr. Deutsch.
Mr. Deutsch. Dr. Temple, in an earlier point there was a
discussion regarding this issue of different sort of
contraindications for children versus adults, and you are
saying that it applies to both--you know, no separation of
warning. At what point is a recommendation that there be a
separate warning? Are there separate warnings--I mean, how
atypical is this? Is this the process? Is this the procedure?
Are there cases where you do have separate warnings?
Mr. Temple. Well, the warning language that will describe
the now documented increased--now we believe it is documented.
Maybe someone else thought it was documented before. What we
now believe is the documented increase in suicidality in
children. That will be a separate statement, because we don't
think such a----
Mr. Deutsch. What tips it to make that difference, the
separation?
Mr. Temple. Well, it isn't so much the separation, but we
now----
Mr. Deutsch. Well, the dual warning.
Mr. Temple. Well, we now believe--we have not seen such a
thing in adults. As I mentioned before, Dr. Mosholder presented
an analysis on Paxil that quite clearly does not show that
finding in an adult population, using the same methods that
showed it in pediatrics.
So you need a special warning on that subject for children,
because they are the ones who get that reaction. The warning in
March was about pay attention to people when you are starting
therapy. That is still a good warning for everybody. That still
applies to everybody.
Mr. Deutsch. I guess the question I am trying to get at is
at what point do you tip the balance and then say a separation
for children?
Mr. Temple. I don't think it is a balance. I think, as soon
as you have information that says children are different, you
do it.
Mr. Deutsch. And are you looking for that information or is
it just----
Mr. Temple. Well, one of the points of doing studies in
children is that very point, to see if they respond
differently.
Mr. Deutsch. Right, but is that only done in terms of, you
know, the incentives that we have put on in terms of increased
exclusivity based upon that issue?
Mr. Temple. The usual request for data, written request for
data, includes a request for studies of effectiveness,
pharmacokinetic studies because that can be something, and a
safety study . That is what they usually consist of.
Mr. Deutsch. Right, but generally those safety studies
don't break out children. So that----
Mr. Temple. Sorry. This is for a written request on gaining
pediatric exclusivity.
Mr. Deutsch. Right.
Mr. Temple. So that is only children.
Mr. Deutsch. Right. Right, but if it is a pediatric
exclusivity, then you would have that. But outside of that, a
pediatric exclusivity, then you would have no information.
Mr. Temple. Outside of that, it is extremely hard to get
any studies in children. That is why we have the Best
Pharmaceuticals for Children Act, because children--well, it is
extremely unusual, and most people would say it is not
appropriate, to start studies of children before you have the
drug properly worked up in adults. There's a lot of nervousness
about, you know, children can't give consent and so on.
So it has always been true, whether we have the Best
Pharmaceuticals for Children Act or before, that we expected
the pediatric studies to be done afterward.
Mr. Deutsch. If I can switch to Dr. Seligman, I have a
series of questions, but I want at least to open it up and give
you an opportunity, because my understanding, this has not been
brought up at this point, which is the investigation
regarding--I guess in response to the San Francisco Chronicle
article detailing the FDA's decision to remove Dr. Mosholder's
presentation.
If you can at least give us your perspective of why that
investigation began and the appropriateness of that
investigation.
Mr. Seligman. Certainly. Both prior to and subsequent to
the publication of two articles in the San Francisco Chronicle,
a number of staff in the Office of Drug Safety approached me
raising a concern of the possibility that there may have been
an inappropriate disclosure of confidential information to the
reporter at the San Francisco Chronicle.
Upon receipt of that information, as you have in your book,
I forwarded those concerns on to the Office of Internal Affairs
at the FDA.
Mr. Deutsch. Did you result in finding who had leaked the
information?
Mr. Seligman. I'm sorry?
Mr. Deutsch. Did you find out who leaked the information?
Mr. Seligman. No, I did not.
Mr. Deutsch. If you can turn to Tab 65, an e-mail dated
February 20, 2004, from yourself to Horace Coleman and Thomas
Doyle at the Office of Internal Affairs in which you outline
your reasons for initiating this investigation. You attached an
article, the San Francisco Chronicle article.
I assume you are familiar with the article. Is that
correct?
Mr. Seligman. Yes, I am.
Mr. Deutsch. Your e-mail states that a member or members of
the staff of the Office of Drug Safety may have inappropriately
disclosed information of a sensitive matter.
Were staff members of the Office of Drug Safety the only
people with access to the information contained within the
newspaper article?
Mr. Seligman. No, they were not.
Mr. Deutsch. But you were only concerned with the
activities of your staff?
Mr. Seligman. No, I was not.
Mr. Deutsch. Then why is the memo only talking about the
staff of the Office of Drug Safety?
Mr. Seligman. Only members of the Office of Drug Safety
raised the concern to me that such information had been
improperly disclosed.
Mr. Deutsch. Why would that be?
Mr. Seligman. Because I am their direct supervisor.
Mr. Deutsch. Right, but if you are asking Internal Affairs
to be looking for a leak in your office--I mean, the leak would
only be within that particular group of people?
Mr. Seligman. I don't believe I stated that I thought the--
that is correct. I did say that I am concerned that a member or
members of the staff of the Office of Drug Safety may have
inappropriately disclosed information. I did state that,
although in my interview with the Office of Internal Affairs, I
did point out that there were clearly others who had access to
such information as well.
Mr. Deutsch. If you turn back to Tab 66, the report of the
investigation, on page of that report it notes that you named
five employees of the ODS who had been called at home by
Waters. How did you know that these five individuals had been
called at home?
Mr. Seligman. They either came to me or they reported such
to my deputy, Dr. Anne Trontell, who informed me of that
information.
Mr. Deutsch. And apparently another ODS employee, David
Bram, merely because he had been very vocal in the past
regarding the scientists' findings being suppressed--did you
call--again, is that--we are trying to understand why--I mean,
were you suspicious of people within your own group for any
particular reason because of actions like that?
Mr. Seligman. As I indicated in the interview, the
investigator asked me whether there were people of whom I had
particular concern in the office, and I indicated as such, that
there were such individuals.
Mr. Deutsch. If you turn to the conclusions on page 6, you
will note the initial conclusion was that no evidence was found
that classified or proprietary information from the FDA was
released. In fact, the release of the classified or proprietary
information is the only basis to initiate an investigation into
a leak. Is that correct?
Mr. Seligman. That is correct.
Mr. Deutsch. So let me just again follow up on Tab 69. The
fourth page of that exhibit is headed by the date 5/7/04. This
is a document which Horace Coleman of the Office of
Investigation noticed that he is closing the case, and further
noticed that he had to ask you to contact Dr. Mosholder to
assure him that he was not a specific target of this
investigation, that OIA found no evidence to indicate that
classified or proprietary information had been released and
that OIA was closing the investigation.
Why did Mr. Coleman need to have you assure Dr. Mosholder
that he had not been the target of this investigation?
Mr. Seligman. I don't know the answer to that question, but
I did reassure Dr. Mosholder of that fact.
Mr. Deutsch. On that same page, Dr. Coleman notes that he
had advised you that he would also contact the CDR Director
Galson to advise him of the above information. Since Galson had
left the office to attend an awards ceremony, he would be
requesting his director, Terry Vermelion, to reach out and
debrief Director Galson.
This raises several questions. What was the urgency to get
this information to Galson?
Mr. Seligman. I have no--I don't know the answer to that
question.
Mr. Deutsch. And what about the propriety to initiating an
investigation? Whom did you talk to in CDER and what were their
opinions about your proposed actions?
Mr. Seligman. I took these actions independently. I
informed Dr. Galson, who is indeed my supervisor, that I was
considering such action, but received no direction from him,
one way or the other, as to whether I should take it. He was
the only person with whom I discussed these matters.
Mr. Deutsch. Who did you keep informed regarding the
progress of the investigation?
Mr. Seligman. The only time I received any information
about the progress of the investigation was at the conclusion
of the investigation on May 10 when I met with Agent Coleman
and Kurisky who provided me the report and debriefed me on the
investigation.
Mr. Deutsch. One final question. This summary report, also
Dr. Hammad's reanalysis and its comparison to Dr. Mosholder's
original work was widely reported in the press before FDA
released any of the information publicly.
My understanding is you did not initiate an investigation
into these leaks and, if not, why not?
Mr. Seligman. I did not report those allegations to the--I
did not--that is correct. I didn't mention that to the Office
of Internal Affairs.
Mr. Deutsch. Why was that different than the earlier
release?
Mr. Seligman. Probably no different than the earlier
release.
Mr. Deutsch. I mean, there is no basis for the difference?
The original investigation is technically considered a criminal
investigation. I mean, is it just by whim that we start
criminal investigations? I mean, is there some basis of
differentiating?
Mr. Seligman. This is not treated as a whim. I take, and I
imagine everyone at the agency takes the protection of
proprietary information and trade secret information very
seriously. When allegations of such are brought to my
attention, I----
Mr. Deutsch. Let's be very specific, though. The Mosholder
thing didn't involve proprietary information.
Mr. Seligman. As it turned out, that is correct.
Mr. Deutsch. Right, but even the allegation, even the
report wasn't proprietary.
Mr. Seligman. The allegation had to do with inappropriate
disclosure of----
Mr. Deutsch. Yes, but not proprietary.
Mr. Seligman. That is correct. Inappropriate disclosure of
confidential information. That is correct.
Mr. Deutsch. I mean, I am just going to ask one more time
and give you a chance to maybe try to be clearer or think
again. But why were these two leaks treated differently?
Mr. Seligman. I can't explain why they were treated
differently.
Mr. Deutsch. And it was your decision to treat them
differently.
Mr. Seligman. It was probably my oversight in the latter
circumstance to treat it differently, yes.
Mr. Deutsch. Thank you.
Mr. Walden. Dr. Seligman, can we go to this affidavit
again.
Mr. Seligman. Certainly. What tab was that?
Mr. Walden. This is troubling just in--this is the one that
I think is Tab 57, I believe, sir. Now walk me through again.
What was the reason for, and who would have suggested that Mr.
Mosholder modify this?
Mr. Seligman. I wasn't involved in that at all.
Mr. Walden. Who was?
Mr. Seligman. I would have to turn to Dr. Mosholder for
that. I wasn't involved in the discussion or consideration of
this affidavit.
Mr. Walden. Okay, but this is an affidavit that was
provided to you. Right? The original affidavit?
Mr. Seligman. The affidavit did appear in the May 10
report. That is the first time that I saw it.
Mr. Walden. All right. So it was an official affidavit. It
comes to your--it is part of your investigation. Right?
Mr. Seligman. It was part of the Office of Internal Affairs
investigation Mr. Walden. I'm sorry. All right, part of the
Office of Internal Affairs.
Mr. Seligman. I did not conduct any such investigation.
Mr. Walden. All right. So I guess what I am trying to
figure out with this affidavit is what was the need to--who can
answer why this affidavit would need to be altered to be
presented to somebody else?
Mr. Temple. I don't think anyone at the table can. It was
my understanding that a letter or something like that has been
sent to the committee explaining all that. Am I mistaken?
Mr. Walden. All right. If there is nobody here that can
address that, I believe we do have a letter. I just remain
concerned about it is all. I was hoping to dive in a little
deeper on it, because it is sort of----
Mr. Temple. I am sure, if after looking at our response the
committee has more questions, we will be glad to answer them.
Mr. Walden. I appreciate that, Dr. Temple. Dr. Hammad,
would you agree that, with only 400 or so person years of
exposure that FDA cannot rule out that there is a risk of
suicidal behavior of one out of 100? I'll make you a deal. You
turn your mike on, and I will repeat the question. There we go.
Would you agree that, with only 400 or so--we are talking
about the pediatric clinical trials. Would you agree with only
400 or so person years of exposure that FDA cannot rule out the
possibility there is a risk of suicidal behavior of one out of
100?
Mr. Hammad. Actually, I did not deal with the person years.
I used the individuals as the unit of analysis. So I can't
answer the question, because I did not analyze it.
Mr. Walden. Dr. Mosholder, would you mind returning, and
perhaps you could help us on this question. I appreciate your
long day here, sir.
Here's the deal. You have 10 million prescriptions for
anti-depressants written on an annual basis for children in the
United States, and so how many person years of exposure would
you estimate this prescription volume represents?
Mr. Mosholder. Well, 10 million prescriptions, just a very
rough rule of thumb, one would figure a month per prescription
is usual practice. So that would be 10 million months divided
by 12. So I guess that is something like 800,000 person years,
if my arithmetic is correct.
I think you may be referring to a calculation that was in
my March consult report, if I may. If that is in this binder,
perhaps I can refer to it.
Mr. Walden. Yes, sure. I think it was in your presentation,
too, the PowerPoint presentation that is dated September 13,
2004. It is one of the slides there. Reference is 406.9 patient
years.
Mr. Mosholder. Oh, yes, that is correct. Having observed no
actual suicides in that amount of person time, there is a way
to calculate sort of the upper limit of what a true number of
suicides might be expected, which I did in my March consult. If
it is in the binder, I can probably find that.
Mr. Walden. We are going to see if we can't find it in the
binder. It looks like there are 74 sponsored defined suicide
related events, 54 serious, it says on your slide. But again we
are trying to find the right tab in our binder of documents.
Tab 53, I am told.
Mr. Mosholder. Oh, yes. These are my slides from last week.
The calculation I was referring to, I think I can find in the
March consult document, which I think may address your
question.
Mr. Walden. Well, I'll tell you. Why don't we go to this
question, the one that is more recent, dealing with the 400. I
guess the question is: Would you agree that with only 400 or so
person years of exposure that FDA cannot rule out there is a
risk of suicidal behavior of 1 out of 100?
Mr. Mosholder. I am not sure I----
Mr. Temple. You don't mean suicidal behavior. You mean
suicide.
Mr. Mosholder. Do you mean--yes, that was my question.
Mr. Temple. Suicidal behavior, we know, occurs at 2 percent
in the control group and about 4 percent in the treated group.
So as Dr. Hammad showed, there is a 2 to 3 percent frequency of
that. I think you must be referring to how sure can you be that
there are no suicides, and the answer is, with that exposure,
you don't have much information on that.
Mr. Mosholder. Yes. If I can refer to my March consult,
which is Tab 29, page 20 at the top paragraph, this is a
calculation I did based on some statistical assumptions. The
upper one-sided 95 percent confidence limit for the actual rate
given in observation----
Mr. Walden. Dr. Mosholder, can I interrupt you a second,
sir. What page in that document are you referring to?
Mr. Mosholder. Page 20.
Mr. Walden. Page 20. Thank you. Okay, and where are you on
that page?
Mr. Mosholder. The top paragraph on that page, I think, is
maybe pertinent to your question.
Mr. Walden. Okay. Go ahead and read that for us, would you.
Mr. Mosholder. Yes. What it says is that the upper 95
percent confidence limit, as we say, for an actual rate in the
population given an observation of zero suicides out of 407
patient years of exposure is 1 in approximately 136 patient
years, the point being not the numbers so much, but just to
illustrate that 407 patient years, as we reckon these things,
doesn't--it only goes so far in reassuring about whether or not
there is a risk of actual suicide as opposed to suicidal
behavior, which we have already established is increased.
Mr. Walden. So, basically, 400 patient years is not a very
long time for the kind of research you need or the data you
need?
Mr. Mosholder. Well, the real question here, one of the
limitations of all this is that the real issue is whether there
is an impact on suicide, not just suicidal behaviors, and we
don't have enough information to really address that as
adequately as one would like.
Mr. Walden. But there could be a risk of death?
Mr. Mosholder. There could be----
Mr. Walden. You can't rule that out either.
Mr. Mosholder. There could be. The clinical trials aren't
long enough in exposure to give us a precise risk estimate.
Mr. Walden. But you do know from the data we have that
there is a higher risk of suicidality. Correct?
Mr. Mosholder. That is true.
Mr. Walden. Okay. All right. Dr. Temple, on page 4 of your
testimony you state, the pediatric suicide rate, ``has fallen
about 25 percent over the last decade, the period in which the
use of anti-depressants has grown steadily. This association
does not prove that the increasing use of anti-depressants is
the cause of the decline in suicide, but it at least is
suggestive.'' However, according to the slide presentation by
Dr. Diane Wiskausky of FDA's Office of Drug Safety before the
September 2004 Advisory Committee meeting, the increasing use
of anti-depressants and decreasing suicide may simply co-exist
and may not relate at all to each other. Her slide states that
correlation does necessarily imply causality, and that numerous
factors may be coincidental, not causal.
Dr. Temple, did you ever have a discussion on ecological
association with Dr. Wiskausky?
Mr. Temple. Well, we talked a little at meetings about
this. I don't think I had a particular discussion, and I don't
disagree with the assertion that these kind of data are hard to
interpret. There could be other factors. But these were
presented to us at an Advisory Committee by people who thought
that there weren't any obvious other explanations, and it is
something to be considered.
I would never allege that that is proof. It is not a
controlled trial. You can't do controlled trials of that, but
it is what you got. And it also doesn't seem to be going up,
which is not a trivial matter either, because the drug use has
been going through the roof, as people have pointed out.
Mr. Walden. If that is all the case then, why would the
Europeans suddenly find there are problems?
Mr. Temple. Well, I don't think the Europeans found
anything that we didn't find also. In fact, they used our data.
The question is what to do about it. What they decided to do
about it was tell everybody to start with Prozac and, if that
doesn't work, only experts should use the other drugs.
You know, it depends on the arrangements you have, whether
experts are available, and a lot of other things. That
determines what you do.
One of the major concerns of our advisors was that people
who aren't really knowledgeable about these drugs are using
them, and that is one of the reasons, you know, all these
warnings go in there. One of the hopes--there is sort of pro
and con here. One of the hopes is that it will scare people who
aren't very qualified into sending people to doctors who are.
Nonetheless, the same figures, I understand, are seen in
Europe, too, that the rate is declining.
Mr. Walden. But they prescribe a far lower percentage, do
they not, among this class?
Mr. Temple. Yes, they do. That is correct.
Mr. Walden. Do you know the difference?
Mr. Temple. No, I wouldn't have those figures.
Mr. Walden. I thought I had heard it was like 1/6 of what
we do in young people.
Mr. Temple. That could certainly be.
Mr. Walden. That would tend to lend some credence to Dr.
Wiskausky, her comment that it may not be causal.
Mr. Temple. Well, or it could mean they are better at
picking the people who really can benefit.
Mr. Walden. I see.
Mr. Temple. One of the concerns that was expressed. There
isn't any doubt that people--almost everybody thinks the drugs
are used casually for people who really probably don't need it,
and if there is a risk of making people worse, there may be no
compensating benefit in those people. So that is a legitimate
worry.
Mr. Walden. Just seems like, when these concerns have been
raised, again it seems like effort by the FDA hasn't been to
put that word out. You've really erred on the side of caution
in terms of putting any word out there that there may increased
rates of suicidality, and yet when the studies are there that
show these may be no more effective than sugar pills, that
doesn't seem to be something that gets put out there much. I
just--I don't get it.
The Chair recognizes the gentleman from Michigan, Mr.
Stupak.
Mr. Stupak. Thank you, Mr. Chairman. On the last document
you just showed from Diane Wiskausky--this was shown at last
week's Advisory Committee hearing--underneath there it mentions
a patient level controlled observation study, the Jick, et al.,
study. Is that Dr. Jick from Saskatchewan, Canada? Do you know?
Mr. Temple. No. I think he operates out of Seattle.
Mr. Stupak. Okay. I was interested in your conversation
when you were going back and forth with the Chair on, you call
it, suicidality scores or signals, and you were saying, not
that Dr. Mosholder was wrong, but you were looking at different
signals, and there's different signals to look at, and you
mentioned the Hamilton-D scale, Hamilton depression scale, Ham-
D you called it. Okay? Remember that?
Mr. Temple. Yes.
Mr. Stupak. Earlier today when Dr. Mosholder was
testifying, I had a couple of exhibits there. One was
pharmacology/toxicology consultation from September 2001, and
that was on Accutane, but they related to an SSRI. Remember
that discussion?
Mr. Temple. Yes.
Mr. Stupak. Then I had the PET scan which, again with
Accutane at 4 months, showed a decrease in the brain in the
frontal orbital lobe. You remember that?
Mr. Temple. I remember that. Not that I know how to read
those.
Mr. Stupak. I'm not asking you to read it. But that study
showed that the 17-year-old was noted by her family and
clinician to have behavioral disturbances and dropped out of
school. She did not, however, have a clinically significant
increase in depression as measured by the Hamilton depression
scale. Even though we can see a physical change in the brain,
the Hamilton-D scale did not pick it up, but the PET scan
picked up.
Are we maybe looking at the signals?
Mr. Temple. Maybe Tom knows the answer to this. I don't
know how well any particular brain lesion or finding has been
correlated with depression. The world is full of people who are
trying to do that, to try to pick out who is going to be a
responder and things like that. But I don't know that
literature. So I don't know whether there is a credible PET
scan that indicates depression or anything like that.
Mr. Laughren. I am not an expert in that area, but from
what I know, most experts agree that we don't understand--we
really don't understand the pathophysiology of depression or
any other psychiatric illness. But what I wanted to come back
to is this issue of whether or not the Ham-D, as it is
currently used, or any other depression rating scale, is an
adequate instrument for assessing suicidality.
I think that is one of the things that we have learned
here, and one future direction in which we are moving and
trying to greatly improve our ability to do ascertain it for
suicidality. This is one of the things that we hope to come out
of this collaboration with Columbia University.
The one thing that they have done is help us in classifying
more appropriately and rationally events, but the other thing
that was apparent in these trials is that it appeared patients
were not asked all the right questions.
Mr. Stupak. Well, isn't the questions on the Hamilton-D
scale the same?
Mr. Laughren. No, no. Again, there is no clear instruction
on these instruments as to what sort of follow-up questions
should be asked if a patient responds positively. That is
something that Columbia is working on, developing an instrument
that gives clinicians very clear instructions about how to
follow up if there----
Mr. Stupak. Sure, but the point here is the patient,
whether you want to believe the PET scan or not, had social
behavior, like dropping out of school and behavioral
disturbances, but one of the scales you used, the Hamilton-D
scale, to judge depression didn't pick it up, which would
indicate--which would indicate either the person didn't tell
the truth when they did the testing on the Hamilton-D scale and
is good enough to fool the clinician and everything, or does it
really beg to another question that maybe there really is
something going on here in the brain with these SSRIs that we
are not picking up and we never thought of before.
That's the only question. I am putting forth another
possibility here, because the jury is still out, as you keep
saying, and if the jury is still out, I think you ought to
start looking at other factors, because obviously you guys are
missing something.
I think Dr. Mosholder, more or less, said that. You didn't
want to believe his stuff. So you went to a different set of
signals, and those set of signals, at least according to the
little bit I have seen from this one study, can be fooled.
Have you ever thought about bringing in outside experts
other than just the FDA, like a workshop to bring in other
experts and see what is happening with the orbital frontal
cortex, which is an area we know mediates depression, or the
hippocampus with retinoids and all these other things, and the
SSRIs. Have you thought about bringing in outside experts,
outside the FDA, to take a look at this data and ask them their
suggestions on how do we get to this problem, which we don't
seem to have a good answer for?
Mr. Laughren. It is undoubtedly true that our understanding
of depression and other psychiatric illnesses is in its
infancy. We really do not understand them at a biological
level. There is a lot of work going on. You know, it is
something that we would hope in the future to have a better
understanding of.
There is a lot of work going on, trying to identify various
genetic markers and other things that might help us make
distinctions among people who clinically all look the same.
I mean, that is one of the problems, is that you have a
number of people who all have the same--roughly the same
clinical state, but they may have different underlying
pathophysiologies, and that may explain why some respond to
drugs differently than others, both in a positive sense and in
a negative sense. We just don't understand this.
Mr. Stupak. Absolutely. So that is why I am asking, have
you brought in different people for a workshop or a study to
look at this anti-depressant, this SSRI, to see what are we
missing here? Do we have different ideas on how best to explore
it, to measure it, test it, to do some studies?
Mr. Temple. Tom is going to know this better. There are
just constant workshops on these very questions, some of them
devoted to----
Mr. Stupak. Okay. But I am asking about SSRIs. Have you
done that, like you have done for Accutane and some of these
others? Have you done that? That's what I am asking.
Mr. Temple. You mean to see if there is something about the
effects on the brain of SSRIs that would tell you something? Is
that the specific question?
Mr. Stupak. No. The question was: On SSRIs have you brought
in to do a workshop to try to figure out maybe what else--are
we just missing something, just kick it around with the
experts, whether it is the talk about SSRIs, the effect on
hippocampus where we know there is depression, the frontal
orbital cortex where we know it mediates depression, different
ideas other than--you know, we all, even Members of Congress,
believe it or not, get rigid in our thinking, and sometimes we
don't think outside the area and bring i n other experts to
help us out.
Have you done that in this problem which has confronted you
on these anti-depressants? That's all the question is. No
trick, just a simple question.
Mr. Temple. I'm sure Tom would know better. There are
constant workshops on every neurologic disease and every
psychiatric disease you can name on these very subjects. They
must, by definition, deal with the question of whether the
drugs work differently and things like that.
I mean, I don't go to those workshops, but the people in
the Division regularly would. The interest in those things is
partly because people, as Tom said, hope to find out who is a
responder and who is not, who gets toxic and who doesn't, and
it is partly because people hope to be able to choose drugs to
develop better on the basis of the effects on some of these
markers.
So there is a tremendous amount of interest in it. But I
can't speak to SSRIs particularly.
Mr. Stupak. Okay. Let me ask you this, Dr. Temple, just a
couple of quick questions here. My time is almost up. I want to
ask a couple of series of questions on the pediatric
exclusivity.
As I understand it, there's 293 written requests that have
been written by the FDA for products to be studied in children.
Of these 393, studies have been submitted on over 110 products.
How many of these studies were efficacy studies?
Mr. Temple. I am just not going to know the answer to that.
In neurology----
Mr. Stupak. Do you require efficacy studies on all drugs?
Do you require efficacy study? No?
Mr. Temple. Not necessarily.
Mr. Stupak. Why not?
Mr. Temple. There are some kinds of drugs where the
pediatric request is based on what you call a pharmacologic
effect. For example, if you wanted to see whether a beta
blocker works in children, you might look at heart rate, if
that was thought to be relevant, for example, for protection
against arrhythmias. That is a judgment call.
In psychiatric disease, there is no marker like that. So I
am quite positive that everyone of them called for efficacy
studies.
It is worth noting that the written requests in depression
always called for at least two studies, because we know it is
so hard to do. The written request in other things, like
obsessive compulsive disease, sometimes have only called for a
single study.
Mr. Stupak. So you don't know how many efficacy studies
were done of these 293 studies. Right?
Mr. Temple. I don't. I may have some notes on it. I will
keep looking.
Mr. Stupak. We will put it in writing to you, because we
would really like to know that.
Mr. Temple. Okay, that's fine.
Mr. Stupak. Of those for which efficacy studies were done,
how many showed they were not effective, that there was no
efficacy?
Mr. Temple. Yes. I'm not going to know that either, but we
can get you the answer.
Mr. Stupak. It would be interesting, because we are working
on some legislation on pediatric exclusivity.
If efficacy is shown, is this then added to the label of
the drug in pediatrics?
Mr. Temple. At least usually, and we can get you numbers on
how many have had----
Mr. Stupak. And if efficacy is not shown in a pediatric
study, is that added to the label?
Mr. Temple. Well, we are in the process of changing our
view on that. Historically----
Mr. Stupak. Up until today, before you change you mind, was
efficacy--if efficacy was not established, was that put on the
label?
Mr. Temple. Usually not.
Mr. Stupak. So we give them the good news but not the bad
news.
Mr. Temple. Well, the reason, which you have heard me say
before, is that failing to show something in a trial doesn't
mean that it doesn't work. This is not related to the pediatric
setting particularly.
Mr. Stupak. Sure.
Mr. Temple. However, in reconsidering this, what we have
come to think is that, really, the whole point of the Best
Pharmaceuticals for Children Act is to find out if what you
know--mostly--mostly--is to find out if what you think you know
about--what you know about adults is applicable to children,
and it is more relevant than usual to say, hmm, I didn't see
anything in children. We are intending to put----
Mr. Stupak. When you are talking about adults and children,
dosage has a lot to do with that, too, does it not?
Have you done any dosage studies on the SSRIs ?
Mr. Temple. No. The substitute for dosage studies--and it
is not an adequate substitute--is to look at the
pharmacokinetics and at least try to get close on the blood
levels. Dose response information in a disease that is hard to
study at all is murderously difficult to get.
Mr. Laughren. Actually, I have one comment on the question
of SSRIs and dose and exposure. Actually, the written request
for the Luvox application was specifically focused on looking
at pharmacokinetics, because what we found--the company had
already done the efficacy trial even in advance of the written
request. They had done the one study that we actually talked
about earlier.
What they had shown is that the drug appeared to work in
children, but there were also adolescents in that trial. It did
not work. So we asked them as part of the written request to go
back and look at exposure, and that helped us to understand
possibly why that trial had failed to show efficacy in
adolescents.
Mr. Stupak. Well, our concern is, being the policymakers
and writing the Best Pharmaceuticals--I didn't write it, thank
God. But in 1997 when we did it, and again in 2001, the Best
Pharmaceutical Act, we were told efficacy would be labeled. Now
you are telling us, up until today, it has not been labeled.
That was one of the big contentions on this committee. If
you are going to give people the good news, you also have to
give them the bad news.
Mr. Temple. Just let me be sure I understand. You were told
that, if the studies were negative, that would go in?
Mr. Stupak. That would go in?
Mr. Temple. That would go into the labeling.
Mr. Stupak. Of course, you shouldn't label before you give
the patent extension, so people know what the heck is going on.
But we don't do that either.
Mr. Temple. We have pretty much decided to do that. So it
is a little late, but we are going to do that.
Mr. Stupak. We are not a little late. FDA is a little late,
since 1997.
Mr. Temple. That is what I said. We are a little late.
Mr. Stupak. Okay. I thought you said it is a little late
now. All right. Probably got time to vote.
Chairman Barton. Is the gentleman through? Okay. The Chair
would recognize himself for what he hopes to be the last 10
minutes. I'm sure you all are glad to hear that.
We want to thank you all for being here this afternoon. It
has been a long day, and I appreciate your patience. I have
just 2 or 3 questions, and then a wrap-up.
I am going to direct some of these questions to Dr.
Knudsen--Is it Knudsen or K-nudsen? Knudsen? Sure. Okay. You've
got to push that little button there.
Now I know that some of this ground has been plowed before,
but I wasn't here when it was plowed. So I apologize if we have
gone over this.
You are aware that your letter of March 19, 1996, was not
in the FDA file. I think you are also aware now that there are
two versions of the letter that wasn't in the file, one
apparently a typographically incorrect that was sent at 10:18
on March 19, 1996. The other was sent at 12:10.
I believe you told the staff that you have no recollection
of these letters. Is that correct or incorrect?
Mr. Knudsen. That is correct.
Chairman Barton. So once you saw the letters, did that
revive any memories of them?
Mr. Knudsen. No.
Chairman Barton. What were you involved in, in March 1996,
that would have caused you send these letters to the Pfizer
Corporation?
Mr. Knudsen. I was involved in the review of the OCD NDA
Supplement for Certraline.
Chairman Barton. Which is an anti-depressant?
Mr. Knudsen. That is correct.
Chairman Barton. And they were attempting to have it
approved for use in adults or in adolescents?
Mr. Knudsen. Treatment of OCD in adults, I believe.
Chairman Barton. And you--were you the reviewer of that
application or were just asked to comment on it by somebody
that was reviewing the application?
Mr. Knudsen. I was the reviewer of the supplement or the
OCD supplement submitted by Pfizer--for Certraline by Pfizer.
Chairman Barton. Taking aside the point that the letter
wasn't in the file, and apparently you didn't have a copy in
your personal files, the substance of the letter is that it
appears--and I will read the last paragraph: ``We note''--These
are your words: ``We note that there appears to be an increased
frequency of reports of suicidality in the pediatric/adolescent
patients exposed to Certraline compared to either placebo or
Certraline treated with adult OCD patients. If this in fact the
case, what would be a plausible explanation?''
So even though you have no recollection, you apparently
were looking at some data that caused you to think that, if
this particular drug was used, it would increase suicidality in
the pediatric population, which is a serious concern. Would you
agree with that?
Mr. Knudsen. Yes.
Chairman Barton. Now once you sent the letter, apparently
you and everybody at FDA forgot about it. Is that true or not
true?
Mr. Knudsen. I want to back up a second. I commented upon
the fact that I did not recall at the time--since it was 1996
this letter was generated, I personally do not recall
information back that length of time. Even with looking at the
letter, you asked if I generated the letter or if I recall
generating the letter. In fact, as I said, I do not recall
writing the letter.
It does not mean that I did not. I simply do not recall. I
understand. But 1996, for me--even yesterday is a little
difficult to remember sometimes. But 1996, quite frankly, as I
told the subcommittee folks who called me in Maine, much to my
chagrin, I simply do not recall writing that letter. I may
have.
Chairman Barton. You do recall that you were involved in
the review of an application for the drug.
Mr. Knudsen. That is correct, although that is a bit
different than generating and writing a letter and not--I
just----
Chairman Barton. Well, but this isn't a run of the mill
application. Your last paragraph is pretty important. ``There
appears to be an increased frequency of reports of suicidality
in the pediatric/adolescent patient exposed to Certraline
compared to either the placebo or the Certraline treated with
adult OCD patients.''
That is a pretty important finding or pretty important
question. Yet once you sent the letter off, which nobody at the
FDA kept any copies of, everybody forgets about it until 8
years later or 6 years later.
Mr. Knudsen. Well, in fact----
Chairman Barton. You can't even remember writing the
letter.
Mr. Knudsen. Well, I mean, how many people in this room, I
would like to ask, can remember writing letters in 1986? This
is purely speculative, and I am not going to speculate. I
cannot recall writing the letter.
The point of fact is it is a very important issue. I may
have written it. For simplicity, I will say I did write it, and
because I was very much concerned about this issue when I
reviewed the OCD----
Chairman Barton. You are missing my point. Nobody is
challenging whether you wrote the letter or not. Now if you
want to--you know, you said it looked like your signature, so
you probably did or you did. You will stipulate. I could care
less.
What I am concerned about, that we have a drug that is
being used in adolescents to treat depression and, according to
whoever wrote this letter, there appears to be an increase in
suicidality. Now that is an important thing, and nobody at the
FDA did anything on it for 6 years. That is pretty important.
Mr. Temple. That is not entirely correct. Dr. Laughren
reviewed----
Chairman Barton. It is more correct than incorrect.
Mr. Temple. Dr. Laughren reviewed the data that was the
basis for that letter, wrote a memo.
Chairman Barton. Well, you all didn't even find a copy, and
now we got two different copies from the drug manufacturer, and
we get--when we asked about document retention policy--you
don't have access to this, because it didn't come in until
today.
It is an e-mail that was sent today to the young lady to my
right, and it says, ``FDA does not have a specific regulation
that governs the record retention of NDA files and drug master
files.''
It is pure serendipity that the manufacturer kept a copy.
Mr. Temple. I think the problem was that the letter never
went into appropriate channels. That is why it was never seen.
Chairman Barton. Well, it is not stamped. There is no stamp
that it was.
Mr. Temple. It didn't go to Dr. Laughren. It didn't get
into the file. That is why nobody knows it was there.
Chairman Barton. Do you think you should have a document
retention policy? Do you think that something like this should
have gone through channels, that somebody at your level or some
level should have checked into it and done something before 6
years later?
Mr. Temple. Of course.
Chairman Barton. Yes or no?
Mr. Temple. Of course, it should have gone through
channels.
Chairman Barton. And you think something should have been
followed up on this?
Mr. Temple. Had anybody known about it and seen the result,
yes, of course. But I do want to point out that the basis for
that letter was reviewed by Dr. Laughren a couple of months
later, and his conclusion was that there was no signal there.
Chairman Barton. Beg your pardon?
Mr. Temple. His conclusion was that there was no signal
there, that the analysis was invalid. I believe the letter
never should have been sent. It doesn't make any sense.
Chairman Barton. In spite of all the studies that have been
done since then--and correct me if I am wrong. We have looked
at 15 studies. Twelve of the 15 have shown no effect, no
efficacy. Some of those have shown an increase in suicidality,
and in spite of that, you say this letter shouldn't have been
sent?
Mr. Temple. This letter reported that there was an
increased risk of suicidality in children compared to adults.
Chairman Barton. Let's be fair. It says there appears to
be.
Mr. Temple. Okay.
Chairman Barton. He is just questioning. Even though he has
developed amnesia, at the time he was doing his job, and he was
saying that somebody needs to check--well, he didn't say that.
He just says what are your comments on it. Now once he wrote
it, he forgot he wrote it. He didn't keep a record of it, and
it was forgotten about.
Mr. Temple. Right. The----
Chairman Barton. Now this gentleman to your right, Dr.
Laughren, says that he reviewed this letter?
Mr. Temple. No, not the letter, the review that led to the
letter.
Mr. Laughren. I would like to clarify.
Chairman Barton. All right. So you reviewed the same data.
Mr. Laughren. No, no. Let me explain. Dr. Knudsen wrote a
review of March 1996 around the same time that he sent the
letter. He raised the concern in his review, and I responded to
that concern in a memo that I wrote to the file later that
year.
It is true--I mean, there is no question. This is a failure
in our document flow. However, the response that Pfizer sent in
response to his letter in May of that same year----
Chairman Barton. The response is in the file. Isn't that
correct?
Mr. Laughren. That response apparently is in our file. I
have since--I agree that it is years later, but I have recently
looked at it. It is completely consistent with the conclusion
that I reached in the memo that I wrote in October of the same
year, in October 1996.
So it is true, you know, this is a document failure. No
question about it.
Chairman Barton. Well, it is more than document failure.
Mr. Laughren. No, no. There is no signal there. There is
just no signal there. There is no signal in those data.
Mr. Temple. The analysis included three uncontrolled trials
and one controlled trial in excessive compulsive disease. In
the OCD trial there was one suicidality case in the placebo
group and none in the treated group.
The comparisons are entirely invalid. The letter should not
have been sent.
Mr. Laughren. Yesterday I spoke to someone completely
independent, an epidemiologist in our Division, the head of the
safety team, about these data just to get another view on this,
and she completely agreed with me, that looking at those data
that Dr. Knudsen looked at back in 1996, there is no signal for
pediatric suicidality. None.
Chairman Barton. But nobody did that. You all didn't even
look at the data.
Mr. Temple. No, he did.
Mr. Laughren. I did.
Mr. Temple. He looked at the data that Dr. Knudsen had
placed in his review, not the letter. We didn't know about the
letter.
Chairman Barton. Well, let me ask another, because I don't
follow the--I am not a medically trained person.
This particular drug--in 1996 was it being prescribed off-
label for adolescents?
Mr. Laughren. I can't answer that. It probably was.
Chairman Barton. It probably was?
Mr. Laughren. The point of this----
Mr. Temple. But it is not for depression.
Mr. Laughren. Right. This study was for--sorry.
Mr. Temple. This was for a different condition.
Mr. Laughren. This study was for obsessive compulsive
disorder in kids.
Chairman Barton. But it leads to an increase in--it could--
it appears that there could be, ``that there appears to be an
increased frequency of reports of suicidality.''
Mr. Temple. Yes, that is what it says, but----
Chairman Barton. That was in 1996. This is 2004. It is 8
years ago. If it was prescribed to 10,000 children and 100 of
them committed suicide because they took it, I think something
should have been done.
Mr. Temple. That would be a bad thing. This provides no
signal that that is a risk. There is no signal in those data.
In the controlled trial there were more suicidality----
Chairman Barton. What did--apparently, what the FDA--I've
got some other questions, but apparently what the FDA did about
this, this gentleman or others looked at this data and said we
don't see a problem there. And so you did nothing. You did
absolutely nothing.
Mr. Temple. I don't understand. There was no signal.
Chairman Barton. Well, you know what I would have done?
Mr. Temple. What would you have done?
Chairman Barton. I would have gone in and done some more
trials. I might have even told the drug manufacturers not to
let it be--strongly encourage them not to prescribe it off-
label. I might have erred on the side of safety and prudence
and said let's don't take a chance. That's what I would have
done.
Mr. Temple. So in response to a study that showed more
suicidality in the placebo group than in the treatment group,
you would have done more studies? I don't think I understand.
I understand why the words--this looks like it might be a
signal--would be distressing, but that was a wrong
interpretation of the data.
Chairman Barton. Well, even Dr. Laughren said--and again
this is a memorandum. It is Tab 75 dated October 25. This is
apparently after he had reviewed the data. He says, ``I don't
consider these data to represent a signal of risk for
suicidality for either adults or children. Supplements are
planned for both depression and OCD in pediatric patients, and
when we have more complete data, including Ham-D data, we can
look more critically at this issue using the now standard
approach of comparing the proportions of drug in placebo
exposed patients to show worsening on Item 3, which is the
suicidality item, to the Ham-D during the treatment.'' So even
he said that there should be something done.
Mr. Temple. Well, those things were done, but we now have
exquisite evidence that looking at the Ham-D doesn't work.
Chairman Barton. Well, I am going to, unfortunately, have
to run and vote.
Should FDA develop a document retention policy for NDAs and
drug master files? Yes or no? You have none now.
Mr. Temple. Well, I believe we have one, but we will----
Chairman Barton. Well, your e-mail says you don't.
Mr. Temple. We don't have a rule.
Chairman Barton. If you don't, should you?
Mr. Temple. Yes.
Chairman Barton. What did the British see when they pulled
these things off the market that you didn't see, that FDA
didn't see?
Mr. Temple. You mean when they wrote their thing
contraindicating it?
Chairman Barton. Yes, sir.
Mr. Temple. It is a different interpretation of the same
data. I don't know why they reached that conclusion. One reason
might be that they are less inclined to use these drugs in the
first place. Why that is, I can't say.
Chairman Barton. All right. I am going to thank you
gentlemen. There will be further questions for the record, and
we are going to adjourn this hearing.
[Whereupon, at 5:46 p.m., the subcommittee was adjourned.]
[Additional material submitted for the record follows:]
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