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Thank you for the opportunity to respond to Lassman et al.’s re-analysis of our study titled, “Clinical trial registration, reporting, publication and FDAAA Compliance: A cross-sectional analysis and ranking of new drugs approved by the FDA in 2012”.1 Our original study assessed the clinical trial transparency of novel drugs approved by the FDA in 2012 that were sponsored by large drug companies. We assessed the drugs by two sets of transparency standards: U.S. legal requirements and an ethical standard that all human subjects research should be publicly accessible to contribute to generalizable knowledge.
Our original analysis included a review of 15 drugs, sponsored by 10 large companies, involving 342 trials. Lassman and colleagues’ reassessment examined 69 of these 342 trials and focused on only the U.S. legal requirements standard. Lassman et al did not elaborate on why they limited their assessment to this subset of trials and on compliance with legal requirements. As a reminder, US clinical trial disclosure requirements are defined by the Food and Drug Administration Amendments Act (FDAAA), passed in 2007.2
We applaud efforts to replicate studies. We are glad that our policy of publicly sharing data through the Dryad Digital Repository enabled replication and re-analysis.3 Additionally, we generally agree with the Lassman and colleagues re-assessment of our study using today’s new and updated knowledge base and world-view....
We applaud efforts to replicate studies. We are glad that our policy of publicly sharing data through the Dryad Digital Repository enabled replication and re-analysis.3 Additionally, we generally agree with the Lassman and colleagues re-assessment of our study using today’s new and updated knowledge base and world-view. However, we do not agree with their implications that our study was lacking in some way. Our work reflected prevailing standards at the time.
It is important to note, that, when we conducted our analysis (starting around 2013), implementation and interpretation of FDAAA were very different than today. Our study used the leading interpretation of the law at the time of our study. Our interpretation was shared by many drug companies, researchers, and reflected in top academic publications, including the banner NEJM publication on the subject by Anderson et. al. titled, “Compliance with Results Reporting at ClinicalTrials.gov.”4
As such, Lassman et al paper isn’t so much a re-analysis of our work, but rather a reflection and update on our work given the learning and evolution of practices that have emerged since the time our original study was conducted. Updated interpretations of FDAAA were generally catalyzed by the NIH issuance of a Final Rule, on September 21, 2016, clarifying key ambiguous language in FDAAA.5 In particular, thanks in large part to the Final Rule, there is now general consensus that under FDAAA, there was no requirement to report trial results for unapproved drugs (for trials studying initial use indications).
Prior interpretations involved results reporting by one year after a trial’s primary completion date, unless a certificate of delay was filed asking for an extension of time to report. In the case of a certificate being filed, results reporting could be delayed until 30 days after FDA approval of the indication. Under the Final Rule, this will change. Results will be required to be reported for both approved and unapproved drugs.
Lassman et al acknowledge that interpretations of FDAAA have been varied and evolved over time. They state: “FDAAA is complex, and after its passage “a spectrum of interpretations” emerged, particularly with respect to the deadlines for results reporting and the necessity of “certificates of delay” (CODs)….The COD provisions… are ambiguous in some cases.”
Below is a table showing our original 2012 analysis, along with a re-analysis of our 2012 sample of drugs using today’s interpretation of FDAAA. Lassman and colleagues 2017 reanalysis is included in the table as well (Table 1). Our analyses are in general agreement.
Our aim as investigators on the Good Pharma Scorecard project is to ensure that we employ an iterative, open and adaptive learning system when establishing standards and reporting on clinical trial transparency. We strive to continuously improve and refine our methods as appropriate. We also continuously reach out to and convene stakeholders, soliciting feedback to ensure the accuracy and timeliness of our work and that the project is advancing the needs of patients and public health broadly.
We recently published an assessment of clinical trial transparency for novel drugs approved by the FDA in 2014 that were sponsored by large companies.6 It uses the updated and current interpretations of FDAAA catalyzed by the passing of the Final Rule. They are similar to those of Lassman and colleagues. There is less debate at this point about how to interpret most sections of FDAAA reporting requirements. Experts should generally be in agreement on requirements and be better positioned to advance a more open and transparent healthcare innovation and drug development enterprise that strives towards trustworthiness and patient-centricity.
Table 1 (found here: http://blogs.bmj.com/bmjopen/files/2017/09/Miller-1.png): Table showing our (Miller et al) original analysis, along with our re-analysis of our 2012 drugs using current FDAAA interpretations and Lassman and colleagues’ analysis.
The Good Pharma Scorecard is funded by a grant from the Laura and John Arnold Foundation to Bioethics International. In the past 36 months, Dr. Ross has received support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from Medtronic, Inc. and the Food and Drug Administration (FDA) to develop methods for post-market surveillance of medical devices, from the Food and Drug Administration (FDA) to establish the Yale-Mayo Center for Excellence in Regulatory Science and Innovation (CERSI), from the Blue Cross Blue Shield Association to better understand medical technology evaluation, from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting, from the Agency for Healthcare Research and Quality, and from the Laura and John Arnold Foundation to support the Collaboration on Research Integrity and Transparency (CRIT) at Yale.
Miller JE, Korn D, Ross JS. 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: e009758. doi: 10.1136/bmjopen-2015-009758
2 Food and Drug Administration Amendments Act of 2007 (FDAAA), Public Law No. 110-85, § 801, 121 Stat. 904 (2007) (codified at 42 U.S.C. § 282).
3 Miller JE, Korn D, Ross JS (2015) Data from: Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012. Dryad Digital Repository. http://dx.doi.org/10.5061/dryad.t8n07.
4 Anderson ML, Chiswell K, Peterson ED, et al. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med2015;372:1031–9. doi:10.1056/NEJMsa1409364
5 Clinical Trials Registration and Results Information Submission; Final Rule (NIH Final Rule), 81 Fed. Reg. 64982 (Sept. 21, 2016) (codified at 42 C.F.R. Part 11).
6 Miller JE, Wilenzick M, Ritcey N, Ross JS, Mello MM. Measuring clinical trial transparency: An empirical analysis of newly approved drugs and large pharmaceutical companies. BMJ Open (in press).