The Food and Drug Administration has issued a number of contentious decisions during the Covid-19 pandemic related to investigational products. The controversies that continue to swirl around these decisions stem in part from the agency’s lack of transparency, including its limited explanation and disclosure of the evidence on which it based these decisions.
When the FDA issued an emergency use authorization (EUA) for hydroxychloroquine and chloroquine in March, for example, it did not describe the details of the extremely limited evidence supporting its decision. The FDA revoked that EUA in June.
The same issue of inadequate evidence disclosure arose when the FDA issued an EUA for remdesivir in May on the basis of a reported improvement in time of symptom resolution. Details of trial results were initially limited to a press release and were not disclosed for another three weeks.
Public confidence in the FDA during the Covid-19 pandemic would be improved with greater transparency of the data and the reasoning on which it bases these and other complicated decisions. The timely release of this information would promote trust in the agency throughout the process of clinical trials, review, and authorization and approval for Covid-19 therapies.
As a general rule, the agency keeps confidential much of the information relevant to its drug review decision-making. For example, it routinely treats as confidential commercial information details of clinical trial data submitted to the FDA, outcomes of discussions between the FDA and manufacturers testing investigational drugs, and even the registration of the drugs themselves, which is needed to begin human clinical trials. In the past, researchers have submitted Freedom of Information Act requests to obtain some of this information, but these requests can take years to resolve, may require litigation, and may not ultimately yield useful data sets.
When the FDA approves a new prescription drug or vaccine, federal law requires that certain documents generated in the agency’s review be published. Upon approving a new therapy, the FDA traditionally published separate application review documents from internal teams with expertise in areas including clinical pharmacology, toxicology, and biostatistics. But in June 2019, the agency announced it was replacing these separate reviews with an integrated review in a single summary report. This initiative, though consequential, does not advance the disclosure of clinical trial information. In fact, integrated reviews make detailed information about clinical trials less accessible.
The FDA has tried to take some steps toward greater transparency. In 2010, the agency’s Transparency Task Force, which one of us (J.M.S.) led, published a report that recommended things the FDA could do to increase transparency. Noting that the “FDA generally does not disclose any information about the existence, status, or contents of an investigational application submitted to the Agency, until the product has been approved, licensed, or cleared,” the task force proposed 10 policies related to product applications.
In 2015, the Institute of Medicine recommended additional steps, including the publication 30 days after the FDA approves a new drug of full and analyzable datasets, protocols, analytic code, and clinical study reports (CSRs) with redactions where appropriate to protect proprietary information and patient privacy. Since the FDA’s broad definitions of what it considers confidential are based on amendable regulations, FDA leaders can redefine the agency’s policies on disclosure without congressional authorization.
Yet there has been little movement on these transparency initiatives. In 2018, former FDA Commissioner Scott Gottlieb launched a pilot program to partner with manufacturers that volunteered to publish key clinical information contained in the clinical study reports of newly-approved drugs. The agency ended this pilot in March 2020 after only one product sponsor volunteered to participate. The agency simultaneously announced it had identified another way to disclose key information contained in clinical study reports, though this approach has yet to be implemented.
We see four key ways the FDA could recommit to transparency, promote accountability, and safeguard public trust in the agency and its actions responding to the Covid-19 pandemic (summarized in the table below).
First, when the FDA issues or lifts clinical holds related to the safety or effectiveness of Covid-19 therapies in clinical trials, regulators should release a public explanation within 10 days. Particularly in light of the clinical hold attached to AstraZeneca’s Phase 3 vaccine trial in September after reports of a serious adverse event, the FDA should disclose the rationale for clinical holds to help researchers better understand obstacles that may affect the development of Covid-19 therapies.
Second, the FDA should release information about Covid-19 products that do not merit authorization or approval. Specifically, the agency should implement the Transparency Task Force’s proposals about issuing explanations when the FDA does not approve vaccines, devices, and therapeutics, including those that have been withdrawn or abandoned. The agency should also disclose its clinical and statistical reviews of these products. Such disclosures could help accelerate the development of Covid-19 therapies by helping researchers avoid unproductive pathways.
Third, the FDA should amend the guidance informing its power to issue EUAs during public health emergencies to include disclosure of the scientific basis of the authorization when it is issued. This should include a full explanation of the FDA’s reasoning, the release of review memos, and a pathway for qualified researchers to access important datasets.
The FDA could partner with established organizations involved in mediating data sharing, such as the Yale Open Data Access Project, to make available de-identified participant-level clinical data, protocols, analytic code, and the full and analyzable data sets of all studies supporting EUAs. Johnson & Johnson’s recent announcement that it would share this information and the clinical study report from the company’s Phase 3 Covid-19 vaccine trial demonstrates that such disclosures are viable and may even be viewed favorably by manufacturers.
Disclosing de-identified participant-level clinical data to qualified researchers would have several advantages, including allaying fears that political influence may be corroding the FDA’s conclusions and helping curb actual political intimidation. The likelihood that others will be able to directly review the data makes the FDA as an institution more resistant to outside interference.
Fourth, the FDA should make available pooled datasets pertaining to the development of Covid therapies in masked and de-identified formats to qualified researchers through existing organizations involved in clinical data sharing. For example, the agency could combine the placebo arms of multiple trials to create a dataset to inform scientists’ understanding of the natural history of Covid-19. The FDA itself has noted that these types of pooled datasets “have a tremendous potential to help address critical challenges and provide new opportunities for innovation in medical product development.” FDA scientists’ use of masked and de-identified pooled datasets made it possible for hepatitis C virus treatments to be available to patients more rapidly. In the context of a global pandemic that has already taken hundreds of thousands of lives, the possibility that pooled data sets could reduce the burden of disease is very real.
One potential objection to these reforms is that they may involve disclosing what the FDA has long considered to be confidential commercial information, and increased disclosures could be characterized as undermining firms’ competitive advantages. Agency officials can address manufacturers’ concerns by redacting details of memos relating to manufacturing practices or other business decisions, while still increasing disclosure of scientific insights that will advance researchers’ understanding of Covid-19.
The standard for what constitutes confidential commercial information should also be applied more flexibly in the context of responding to an international pandemic in which traditional competitive markets are not the norm and in which substantial government funds are supporting manufacturing work and being committed to advance product purchases. As a first step, the FDA should also simply ask companies for permission to share this important information with the public.
At this critical juncture, the FDA should look to increase transparency and maximize public trust in its integrity. Sunlight may yet prove to be a disinfectant that helps us fight this pandemic.
Liam Bendicksen is a researcher at the Program On Regulation, Therapeutics, And Law (PORTAL) and an undergraduate at Brown University. Joshua M. Sharfstein is professor of the practice in the Department of Health Policy and Management at the Johns Hopkins Bloomberg School of Public Health, was principal deputy commissioner of the Food and Drug Administration from 2009 to 2011, and is the author of the “Public Health Crisis Survival Guide: Leadership and Management in Trying Times” (Oxford University Press, 2018). Aaron S. Kesselheim is a professor of medicine at Harvard Medical School and directs PORTAL in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. His work is supported by grants from Arnold Ventures and the Harvard-MIT Center for Regulatory Science.
Table: Recommendations for increasing transparency at the FDA
|Policy Proposal||Potential Benefits||Potential Drawbacks|
|Issue public explanations for clinical holds related to the safety and effectiveness of Covid-19 therapies within 10 days of the action||May help speed the development of Covid-19 therapies by helping scientists better understand potential obstacles||May paradoxically intensify the public’s lack of confidence in the safety of future Covid therapies|
|Amend regulations to require disclosure of clinical and statistical reviews and a published explanation when the FDA does not approve a product||May help researchers better understand and learn from the mistakes of would-be innovators||Data from clinical reviews may be considered confidential commercial information|
|Amend emergency use authorization guidance to require disclosure of the detailed scientific basis* for authorization to qualified researchers within 30 days of issuance**||May promote confidence in FDA and would allow experts to independently evaluate the evidence supporting authorized products||The rules that researchers must follow to gain access to study data may cause delays that jeopardize the value of disclosure|
|Disclose masked and de-identified pooled datasets relevant to Covid-19 vaccines and therapeutics to qualified researchers**||May accelerate the development of pandemic-related drugs by improving scientists’ understanding of Covid-19 and SARS-CoV-2||Source data may be viewed as confidential commercial information|
* The agency should disclose the protocols, analytic code, and full and analyzable datasets of all studies supporting the emergency use authorization, redacted to protect confidential commercial information and patient privacy.
** In the time-limited context of the novel coronavirus pandemic, the FDA should partner with established organizations like the Yale Open Data Access Project to achieve these disclosures.
let’s face the real truth whether it is the FDA , FBI , IRS OR DOJ almost all Americans now believe that none of the Federal agencies are transparent at all ; that is why that area is now called the SWAMP by it’s citizens
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