Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012

Jennifer E Miller; David Korn; Joseph S Ross

doi:10.1136/bmjopen-2015-009758

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Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012

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Re: Miller J et al, November 12th Publication
Norbert W Bischofberger
Published on: 25 May 2016
Transparency grade reflects only one aspect of transparency
Erick H. Turner
Published on: 25 May 2016
Response to Miller et al on clinical trial transparency
Bryan R Deane
Published on: 15 March 2016

Published on: 25 May 2016
Re: Miller J et al, November 12th Publication
- Norbert W Bischofberger, Chief Scientific Officer
In the November 12th issue the BMJ published a paper (Miller, J., et al) on "Clinical Trial Registration, Reporting, Publication and Food and Drug Administration Amendments Act (FDAAA) Compliance of Drugs Approved by FDA in 2012".
In the paper the authors conclude that for Stribild, a drug for the treatment of HIV infection developed and marketed by Gilead Sciences, Inc., only 9% of clinical trials submitted to...
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In the November 12th issue the BMJ published a paper (Miller, J., et al) on "Clinical Trial Registration, Reporting, Publication and Food and Drug Administration Amendments Act (FDAAA) Compliance of Drugs Approved by FDA in 2012".
In the paper the authors conclude that for Stribild, a drug for the treatment of HIV infection developed and marketed by Gilead Sciences, Inc., only 9% of clinical trials submitted to FDA as part of the New Drug Application were publicly reported and only 21% of the trials were published.
Miller's article was widely quoted in mainstream media with a negative reporting bias toward the industry (e.g., "Drug Makers Kept One- Third of Trial Results Secret" (Bloomberg); "How Pharma Keeps A Trove of Drug Trials out of Public View" (The Washington Post); "Study Finds Big Pharma Skirts Laws" (Boston Business Journal); "Clinical Trial Results Disclosure by Large Biopharmaceutical Companies Falls Below Legal and Ethical Standards" (BioEthics Int. Press Release).
We wish to point out, however, clinical trial results reporting of Stribild has been 100% compliant with all legal requirements and 100% of the clinically important results have been disclosed in either presentations or peer-reviewed publications. As a matter of fact, 26 of the 32 studies (88%) contained in the Stribild NDA were presented at scientific meetings and/or published in peer-reviewed publications.
According to FDA guidance only "Applicable Clinical Trials (ACTs)" are required to be disclosed, which excludes phase 1 and observational studies. Stribild is a fixed-dose combination of 4 pharmaceutically active compounds and the development necessitated 28 phase 1 studies. Twenty two of these 28 studies (79%) were presented and/or were published. The only studies that have not been disclosed include 2 studies designed for selection of a suitable formulation, a drug-drug interaction study with an experimental compound which is no longer in development and 3 safety studies with no identified safety signals (2 of which are mentioned in the U.S. prescribing information).
Gilead supports full disclosure and transparency of clinically relevant study data that informs the patients who use our products and the providers who prescribe them. At the same time, we believe that assessment of disclosures should be comprehensive and rather than being dogmatic about transparency, we believe it is sensible to consider the relevance of the information to the medical community.
Summary of the phase 1 studies and disclosure reference available upon request.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 25 May 2016
Transparency grade reflects only one aspect of transparency
- Erick H. Turner, associate professor
Imagine a drug company conducting 10 trials, 5 of which turn out positive and 5 negative. The 5 positive trials are, unsurprisingly, published. The 5 negative trials are subjected to outcome reporting bias, aka statistical alchemy and HARKing (hypothesizing after the results are known), so that they appear to be positive in the final publications. The downstream reader (or even systematic reviewer) is misled into believi...
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Imagine a drug company conducting 10 trials, 5 of which turn out positive and 5 negative. The 5 positive trials are, unsurprisingly, published. The 5 negative trials are subjected to outcome reporting bias, aka statistical alchemy and HARKing (hypothesizing after the results are known), so that they appear to be positive in the final publications. The downstream reader (or even systematic reviewer) is misled into believing that 10 of the 10 trials were positive. In my opinion, this hypothetical drug would deserve a transparency score of 50%, but according to the methods employed in this study, simply because all 10 were published, the drug would receive a score of 100%. To more fully assess for transparency, one must go beyond the fact of publication and verify the published results by checking for consistency with results reported in ClinicalTrials.gov and/or FDA Drug Approval Packages.
Conflict of Interest:
None declared
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Conflict of Interest:
None declared.
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Published on: 15 March 2016
Response to Miller et al on clinical trial transparency
- Bryan R Deane, Independent Consultant in Pharmaceuticals
The article by Miller et al. published on 12th November (1) took a similar approach to previous studies by Rawal and Deane (2, 3) that also set out to examine the clinical trial evidence related to recently approved medicines. The article therefore requires some qualification; while the study examines some of the industry-sponsored clinical trials related to 15 selected new medicines approved by the FDA in 2012, their st...
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The article by Miller et al. published on 12th November (1) took a similar approach to previous studies by Rawal and Deane (2, 3) that also set out to examine the clinical trial evidence related to recently approved medicines. The article therefore requires some qualification; while the study examines some of the industry-sponsored clinical trials related to 15 selected new medicines approved by the FDA in 2012, their study methodology is not 'unique' or 'novel', but was preceded by two publications (the earliest in November 2013) which together assessed all the industry-sponsored trials in patients related to all 76 new medicines approved by the EMA during 2009, 2010, 2011 and 2012 (2, 3).
The Miller et al. report focused on trials related to the FDA approvals, and it includes the early phase I trials, which are not 'applicable trials' under the FDAAA reporting requirements. Conversely, our studies assessed all completed clinical trials in patients, (in line with industry commitments since 2005), covering a wider range of clinically important trials available at the time - not just those completed and submitted to regulatory bodies such as the EMA or FDA.
The variance in reported numbers are a direct consequence of these differences in methodology, and the cut-off dates for data collection. For example, Eliquis (apixaban) was approved by the EMA in May 2011 and by the FDA in December 2012; data collected by Rawal and Deane up to 31st January 2013 included 12 trials in patients completed by the end of January 2012 (allowing 12 months for reporting) and excluding trials in healthy subjects, while data collected by Miller et al. up to April 2014 included 39 trials submitted to the FDA of which at least 29 were phase I trials in healthy subjects.
Miller et al. reported an overall disclosure rate for Eliquis of 17/39 (44%, including phase I trials not required under the FDAAA), while Rawal and Deane reported 12/12 (100%, excluding trials in volunteers). In addition, a quick search of ClinicalTrials.gov on 12th December 2015 revealed 21 completed, industry sponsored phase II, III or IV trials (twice as many as covered by Miller et al.) - and it is immediately obvious (without exploring other data sources) that results of at least 18 of these (86%) have been disclosed.
This is another reminder of the complexity of this topic (which is inextricably linked to the complicated global process of new drug development), and the difficulty of comparing disclosure figures from study to study, especially when the timing of data collection varies.
References
1. Jennifer E Miller, David Korn, Joseph S Ross. Clinical trial registration, reporting, publication and FDAAA compliance: a cross- sectional analysis and ranking of new drugs approved by the FDA in 2012. BMJ Open 2015;5:11 e009758 doi:10.1136/bmjopen-2015-009758
2. Rawal B, Deane BR. Clinical trial transparency: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved recently in Europe. Curr Med Res Opin; 2014 Mar; 30(3):395-405. Epub 2013 Nov 11
3. Rawal B, Deane BR. Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012. Curr Med Res Opin; 2015 Jul; 31(7):1431-1435. Epub 2015 Jun 9
Conflict of Interest:
As a consultant, I undertake a variety of projects for pharmaceutical companies and for agencies providing services to the industry
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Conflict of Interest:
None declared.
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