By Kurt R. Karst & David B. Clissold –
Three House lawmakers (Reps. Henry Waxman(D-CA), Ed Markey (D-MA), and Diana DeGette (D-CO)) sent letters (here and here) to FDA Commissioner Dr. Margaret Hamburg and NIH Director Francis Collins earlier this week expressing their concern over a recent report published in the British Medical Journal (“BMJ”) documenting the underreporting of results of clinical studies on ClinicalTrials.gov. According to the article published in the January 2012 issue of the BMJ, titled “Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study,” a database search of trials registered on ClinicalTrials.gov which completed in 2009 and that are covered by the 2007 FDA Amendments Act (“FDAAA”) showed that “[o]f the 738 trials that were classified as subject to mandatory reporting, 163 (22%) had reported results. In comparison, 76/727 (10%) trials covered by the FDAAA but not subject to mandatory reporting had reported results . . . . ”
Section 801 of FDAAA amended PHS Act § 402 to expand the clinical trial registry data bank created by Section 113 of the Food and Drug Administration Modernization Act of 1997. FDAAA § 801 expanded the clinical trial data bank (i.e., ClinicalTrials.gov) in two ways. First, a broader range of “applicable” clinical trials must now be registered at ClinicalTrials.gov. Second, certain results information from applicable clinical trials must now be submitted to the clinical trial registry data bank.
An “applicable drug clinical trial” is defined in PHS Act § 402(j)(1)(A)(iii) to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” An “applicable device clinical trial” is defined in PHS Act § 402(j)(1)(A)(ii) to mean “a prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the [FDC Act] against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and a pediatric postmarket surveillance as required under [FDC Act § 522].” In March 2009, NIH posted a revised draft document on its website concerning FDAAA and clinical trial registration. The document provides more detailed information on applicable clinical trials, including defining such trials to include certain in vivo bioequivalence studies used to support the approval of a generic drug under an ANDA (see our previous post here).
Under PHS Act § 402(j)(2)(C), the responsible party of an applicable clinical trial that is initiated after September 27, 2007, or that is ongoing on December 26, 2007, must submit to NIH certain required information for inclusion in the clinical trial data bank by December 26, 2007, or 21 days after the first patient is enrolled in the clinical trial, whichever is later. The only exception to this rule is that if the clinical trial was ongoing on September 27, 2007 and was not for a serious or life-threatening disease or condition, the information must have been submitted by September 27, 2008.
PHS Act § 402 also requires the submission of certain results information of applicable clinical trials to the clinical trial registry bank. FDA, NIH, and the responsible parties for applicable clinical trials all have responsibilities under the law. Among other things, NIH is responsible for maintaining the public database of trial results on ClinicalTrials.gov, and FDA is responsible for enforcing the statutory requirements. (FDA and NIH were supposed to have, by September 27, 2010, expanded the results database by rulemaking to possibly include a summary of the clinical trial and its results, the full protocol, and other information. That rulemaking has not yet been issued, but it might happen soon, according to the Fall 2011 DHHS Unified Agenda.) Responsible parties for applicable clinical trials are responsible for, among other things, submitting certain results information to the basic results section of ClinicalTrials.gov.
Subject to specified exceptions, the general rule is that as of September 27, 2008, the responsible party for an applicable clinical trial must submit the basic results information no later than 1 year “after the earlier of the estimated complete date of the trial . . . or the actual date of completion” (PHS Act § 402(j)(3)(E)). One important exception is that if the trial is completed before the drug is approved or the device is cleared, the responsible party can delay submitting the results information until no later than 30 days after the drug or device is approved (PHS Act § 402(j)(3)(E)(iv)). If the manufacturer of a drug or device or sponsor of an applicable clinical trial is seeking approval for a new use of the drug or device, the same information must be submitted on the earliest of 30 days after approval, 30 days after FDA issues a not approval letter or a not substantially equivalent letter, or 30 days after the application is withdrawn without resubmission for no less than 210 days (PHS Act § 402(j)(3)(E)(v)).
The failure of a responsible party to submit the required clinical trial information under PHS Act § 402(j) is a prohibited act (FDC Act § 301(jj)) that could result in significant penalties of up to $10,000 per day (FDC Act § 303(f)(3)). FDA has not, to our knowledge, taken any enforcement action with respect to PHS Act § 402(j).
The February 14th letters from the trio of lawmakers to FDA and NIH raise both common concerns (e.g., “publication delays may allow ineffective or dangerous drugs to remain on the market, resulting in significant harm to patients and waste in the health care system”) and agency-specific concerns, such as “whether FDA is adequately enforcing the law requiring such reporting” and “whether NIH is adequately implementing the law requiring such reporting” (emphasis added). The letters also contain requests specific to FDA and NIH to help the lawmakers better understand the issue. FDA is asked to provide answers to the following questions:
1) Do the findings of the [study reported in the BMJ] correspond with FDA‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA? Please summarize FDA‘s internal compliance data.
2) Has FDA issued any warning letters, imposed any fines, or otherwise initiated any enforcement actions related to these reporting requirements?
3) Does FDA have adequate resources and authority to enforce these reporting requirements?
4) Does FDA believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?
NIH is asked to provide answers to the following questions:
1) Do the findings of the [study reported in the BMJ] correspond with NIH‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA? Please summarize NIH‘s internal compliance data.
2) Does NIH have adequate resources and authority to implement these reporting requirements?
3) Does NIH believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?
Depending on how FDA and NIH respond to the inquiries – particularly the queries regarding whether additional statutory changes are necessary – it is possible that we could see even more proposed legislation that might be taken up this year alongside the various user fee bills.
An interesting finding of the BMJ paper was that the source of funding for the clinical trials greatly influenced the reporting of results. Industry-funded studies were far more likely to report results (40%) than were studies “not solely industry funded“ (9%). Of note, the latter category included studies funded solely by NIH and other government agencies. This suggests that even NIH and FDA are not in compliance with their own reporting requirements, which would surely complicate enforcement and any attempted legislative correction. Further, the “source of funding“ used by the BMJ authors does not necessarily reflect the “responsible party.” As permitted under the statute (PHS Act § 402(j)(1)(A)(ix)), even industry-funded studies can designate “the principal investigator” as the party responsible for the submission of clinical trial information. Before rushing to portray these findings as another example of “industry“ not in compliance with the law, it would seem prudent to know how many NIH employees designated as either the “sponsor“ or the “responsible party“ have failed to meet these reporting obligations.
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