In the United States, the Food and Drug Administration (FDA) faces a challenging task—striking a balance between allowing promising new drugs to enter the market as quickly as possible and ensuring that they are safe and effective. Over the last decade, there has been significant pressure on the FDA to expedite their regulatory review and approval process, in particular for therapeutics that treat serious life-threatening conditions.
As these expedited review and approval programs have been increasing adopted, likely in response to the desires and demands expressed by clinicians and patients, there have been concerns that certain drugs are being approved on the basis of shorter, smaller, and fewer trials. As FDA’s regulatory approach continues to shift further towards a lifecycle drug evaluation process, greater emphasis will be placed on the evidence that postmarket studies generate.
Our study published today in The BMJ attempts to characterize a sample of postmarket studies required by FDA (that is, postmarketing requirements) and examines the proportion of all required clinical studies that are fulfilled, the rigor of evidence generated, and the timeliness of results reporting.
FDA’s approval process and postmarketing requirements
In the United States, the FDA generally requires drug manufacturers to submit at least two “adequate and well-controlled” trials that demonstrate independent evidence of safety and efficacy. However, certain drugs, including those that target serious or life-threatening conditions, can be approved on the basis of more flexible standards. For instance, drugs evaluated through the Accelerated Approval pathway, a special expedited FDA review pathway, can be approved on the basis of surrogate markers (that is, intermediate outcomes or biomarkers) that are only “reasonably likely” to predict patient-relevant outcomes, which reflect how patients feel, function, and survive. However, after approval has been granted, drug sponsors are required to perform additional trials to confirm efficacy.
Currently, the FDA can use four separate authorities to require sponsors to conduct various types of studies after approval to answer important unanswered questions about the benefits, harms, and uses of new drugs and biologics (see Table 1). These postmarketing studies have the potential to inform clinical practice and can lead to regulatory actions, such as the addition of new safety information to a drug’s label. However, there have been growing concerns about the fulfilment and public dissemination of required postmarket studies.
Evaluating postmarketing requirements
Using the publicly available Drugs@FDA database, we identified and then categorized all postmarketing requirements outlined in the approval letters for new indications for drugs and biologics first approved between 2009 and 2012. We then determined whether clinical studies were registered, along with their reported results, on ClinicalTrials.gov, and how often study results were published in peer-reviewed journals.
We identified 97 new drugs and biologics approved between 2009 and 2012 with a total of 437 individual postmarketing requirements, of which only 134 (30.7%) were likely of most clinical importance to physicians and patients (prospective cohort studies, registries, and clinical trials).
Overall, we found that postmarket study descriptions were short (median word count of 44) and did not report enough information on study design features, including whether there was randomization or which comparators or outcomes should be used. These are essential features to understand how a trial might inform clinical practice. Furthermore, we were often (30%) unable to locate public information to determine an up to date progress.
As FDA continues to adopt a lifecycle evaluation process, there will be an increasing reliance on data generated by these postmarket studies. However, our findings indicate that there are numerous opportunities to continue to enhance transparency at the FDA. For instance:
- Postmarketing requirement descriptions should clearly outline the study design, trial endpoints, potential comparators, use of randomization, and target sample size.
- When available, ClinicalTrial.gov identification numbers could be added to postmarketing requirement descriptions.
- FDA should consider making certain components of their Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) publicly available, including postmarketing requirement final study reports.
- FDA should ensure that the statuses of all postmarketing requirements, including those that are fulfilled or released, are available online.
Although we found relatively high rates of registration and results reporting or publication (approximately three-quarters) of required prospective cohort studies, registries, and clinical trials, our findings suggest that at least one quarter of these required studies are not being publicly disseminated. Considering that registration and reporting is required by law for ongoing and forthcoming non-interventional applicable clinical trials, the FDA may also need to provide additional clarity to sponsors about registration and reporting guidelines in order to ensure that the results from postmarket studies are publicly disseminated.
After collecting these data, we submitted two FDA Freedom of Information Act (FOIA) requests for some of FDA’s non-publicly available information. In one request, we asked the FDA to provide all archived Postmarketing Requirement and Commitments Database Files since 2008. Although these files outline the statuses of ongoing postmarketing requirements, all “fulfilled” and “released” requirements are only displayed on the website for “not more than 1 year from the date of fulfillment or release.” We believe that the historic data will make it easier to track the completion of postmarketing requirements.
In our second FOIA request, we asked the FDA for the final study reports for all postmarketing requirements issued for new drugs and biologics approved since fiscal year 2008. According the FDA, “protocols and final reports can be requested either directly from the applicant or from FDA under the Freedom of Information Act (5 U.S.C. 552).” These final reports will increase transparency and allow for more accurate characterization of FDA’s postmarketing requirements.
Overall, our study highlights key opportunities to improve FDA’s lifecycle evaluation process. In particular, the need for more detailed postmarketing requirement study descriptions, increased transparency, and more consistent registration and results reporting standards.
Joshua D. Wallach is a research fellow at Yale University, working within the Collaboration of Research Integrity and Transparency (CRIT) and the Center for Outcomes Research Evaluation (CORE)
Joseph S. Ross is an Associate Professor of Medicine (General Medicine) and Public Health (Health Policy and Management) at Yale University.