The analysis revealed that surrogate end points, rather than end points that captured clinical benefit, were particularly common in confirmatory trials. Furthermore, the time between accelerated approval and completion of the confirmatory trial was slow: After a median of 5 years from the time of approval, more than half of indications (58%) still lacked confirmatory trial results. 

“These reports are extremely important to give a detailed and nuanced overview of the evidence base that supports the regulatory decision,” Dr Naci told Cancer Therapy Advisor

In fact, most recently, Dr Naci and colleagues used European regulatory documents to uncover reporting bias in clinical trials that led to cancer drug approvals by the European Medicines Agency. They determined that half of the randomized control trials that led to approvals between 2014 and 2016 had a high risk of bias.5

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Public access to the FDA regulatory documents, however, could be changing soon. On June 26, 2019, the FDA announced a plan to remove these documents from the Drugs@FDA website and replace them with an integrated review of the data. This effort would be part of the FDA’s New Drugs Regulatory Program Modernization.6

Dr McDonagh and dozens of other researchers from countries outside of the United States have come out against this plan, and so have medical editors of journals that publish this type of research — The BMJ and PLoS Medicine, among them — and staff at Cochrane, which is a group that uses these documents to conduct systematic reviews.7,8,9,10 

In formal comment letters, these groups urged the FDA to continue making the FDA documents publically available and proposed using the integrated review as an additional document to supplement, rather than replace, current documents.

Meanwhile, Pharmaceutical Research and Manufacturers of America (PhRMA) commended the FDA for proposing integrated reviews.11

The concern among researchers, Dr McDonagh explained, is when the FDA summarizes the data in an integrated review, they will have done “a lot of cleaning up” and researchers thereby lose the ability to find the nuances. “That’s going to really chop us off at the knees,” she said. 

The comment period supposedly closed on August 26, 2019 (although many of the comments that were included in this piece were received a few days after this final comment due date). At publication, no date had yet been set for a final decision from the FDA. 

References

  1. McDonagh MS, Peterson K, Balshem H, and Helfand M. US Food and Drug Administration documents can provide unpublished evidence relevant to systematic reviews. J Clin Epidemiol. 2013;66(10):1071-1081.
  2. Floyd JS, Serebruany VL. Prasugrel as a potential cancer promoter: review of the unpublished data. Arch Intern Med. 2010;170(12):1078-1080.
  3. Rising K, Bacchetti P, and Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med. 2008;5(11):e217.
  4. Naci H, Smalley KR, and Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.
  5. Naci H, Davis C, Savović J, et al. Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis. BMJ. 2019;366:l5221.
  6. US Food and Drug Administration. FDA In Brief: FDA seeks public feedback on new drug approval transparency efforts [press release]. Published June 26, 2019. Accessed September 20, 2019. 
  7. Comment from Peter Doshi et al. on the Food and Drug Administration (FDA) Notice: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication. Regulations.gov. https://www.regulations.gov/document?D=FDA-2019-N-2012-0010. Posted August 27, 2019. Accessed September 20, 2019.
  8. Comment from Emily Karanges et al. on the Food and Drug Administration (FDA) Notice: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication. Regulations.gov. https://www.regulations.gov/document?D=FDA-2019-N-2012-0011. Posted August 27, 2019. Accessed September 20, 2019.
  9. Comment from The BMJ and PLoS on the Food and Drug Administration (FDA) Notice: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication. Regulations.gov. https://www.regulations.gov/document?D=FDA-2019-N-2012-0018. Posted August 28, 2019. Accessed September 20, 2019.
  10. Comment from Cochrane on the Food and Drug Administration (FDA) Notice: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication. Regulations.gov. https://www.regulations.gov/document?D=FDA-2019-N-2012-0009. Posted August 27, 2019. Accessed September 20, 2019. 
  11. Comment from Pharmaceutical Research and Manufacturers of America (PhRMA) on the Food and Drug Administration (FDA) Notice: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication. Regulations.gov. https://www.regulations.gov/document?D=FDA-2019-N-2012-0022. Posted August 28, 2019. Accessed September 20, 2019.