Far more transparency is needed for Covid-19 vaccine trials

With vaccines against SARS-CoV-2, the virus that causes Covid-19, on the near-term horizon, U.S. policymakers are focusing on how to ensure that Americans get vaccinated. This challenge has been compounded by reports that White House officials are exerting undue influence over the agencies that would ordinarily lead such efforts, the Food and Drug Administration and the Centers for Disease Control and Prevention.

Public trust in these storied public health institutions is now deeply compromised: 62% of Americans worry the FDA will rush to approve vaccines without adequately assuring safety and effectiveness because of political pressure; only 25% have “a great deal” of trust in the CDC; and only 21% definitely plan to get vaccinated while 49% probably or definitely will not.

Although rehabilitating public trust will take time, one step can and should be taken now: enhance research transparency. It is essential to widen public access to information about vaccine clinical trial design, conduct, and data. Research indicates that a majority of Americans may trust scientific research findings more if data and information were publicly shared. Yet vaccine manufacturers’ current legal obligations and voluntary commitments often fall short of full transparency.

Particularly in light of criticisms that Pfizer failed to swiftly share its amended trial protocol and AstraZeneca delayed releasing details about serious safety concerns in its vaccine trials, it is vital that all vaccine developers concretely commit to complete transparency.

Some pharmaceutical companies have already made important public assurances. For instance, nine company CEOs have pledged to develop their SARS-CoV-2 vaccines “in accordance with high ethical standards and sound scientific principles.” They promised to prioritize vaccine safety, adhere to “high scientific and ethical standards” in the conduct of clinical trials and in manufacturing processes, seek FDA approval or emergency use authorization only after demonstrating vaccine efficacy and safety in a Phase 3 trial, and work to ensure an adequate vaccine supply.

Moreover, a larger group of CEOs, along with the Bill and Melinda Gates Foundation, pledged to help develop timely, affordable, and equitably distributed SARS-CoV-2 vaccines for patients worldwide, which included commitments to expanding trials to account for diverse representation in lower-income settings, scaling up manufacturing faster and earlier than usual, and maintaining public confidence in innovations.

Further steps need to be taken. The CEO pledges notably do not commit the signers to publicly share clinical trial protocols, results, or participant-level data. So far, only Johnson & Johnson has committed to sharing participant-level data, results, protocols, and other trial documents. Just three other companies — Moderna, AstraZeneca, and Pfizer — have made their vaccine trial protocols public. These steps were taken only recently, long after trials began enrolling patients, as vaccine developers came under intense public scrutiny.

Gaps in transparency commitments clearly remain and legal requirements do not bridge them. The Food and Drug Administration Amendments Act of 2007 (FDAAA) requires sponsors of interventional clinical trials of FDA-regulated products, including SARS-CoV-2 vaccines, to register basic details in a publicly accessible registry and report a summary of results there, generally within one year after a trial is completed or 30 days after FDA approval.

These requirements explicitly apply to trials conducted at a U.S. site, conducted pursuant to an investigational new drug application filed with the FDA, or testing a product manufactured in the U.S., with exceptions for Phase 1 studies. These details matter for SARS-CoV-2 vaccine research because several developers are based outside the U.S. and many trials are safety studies, not interventional.

Ensuring that all SARS-CoV-2 vaccine trials register basic details in a public registry and report a summary of results would be important steps toward transparency. Publishing results in peer-reviewed journals and publicly sharing participant-level trial data, along with trial protocols and other documents necessary to understand these data, are also vital.

These four elements of research transparency — registration, public results reporting, publication, and data and protocol sharing for all vaccine trials — would permit intermediaries who still maintain public trust, such as academic scientists, independent committees of experts, individual physicians, and community-based organizations, to understand and communicate the evidence base regarding vaccine safety and efficacy.

Releasing study protocols is particularly important in light of concerns that some SARS-CoV-2 vaccine trials may have design flaws or restrictive enrollment criteria. Moreover, publication and data sharing are particularly important for conducting high-quality meta-analyses on vaccine safety and reproducing trial results to verify them. Research transparency also honors the contributions of trial participants, who have volunteered to shoulder risk to help end the pandemic.

Although it would be desirable for the FDA to make public all data and other information considered in both approval and emergency use authorization decisions, the agency has not moved in that direction despite years of pressure. Doing so risks legal challenges from companies alleging disclosure of “confidential commercial information,” which could result in years of delay as courts seal the documents in dispute. Consequently, the optimal path is for companies themselves to make these disclosures.

How likely a scenario is this? For the past five years, we have published evaluations of pharmaceutical companies’ transparency practices for clinical trials supporting newly approved products. This initiative is called the Good Pharma Scorecard. Drawing on recommendations from several expert bodies, we developed research transparency standards focusing on four metrics:

• timely registration of the trial’s protocol registration
• timely public reporting and publication of the trial’s results
• FDAAA compliance
• corporate commitments to provide public access to participant-level data and the clinical study report (containing the trial protocol, dataset codebook, case record, and statistical analysis plan) within six months of FDA approval or 18 months of trial completion.

This work has generated some insights relevant to ongoing Covid-19 vaccine research.

Of the 12 frontrunner companies currently involved in SARS-CoV-2 vaccine clinical trials, six have been in one or more rounds of our Good Pharma Scorecard. Three of these six have above-average transparency track records in the scorecard: Johnson & Johnson, Sanofi, and GlaxoSmithKline (see the chart); Merck has an average transparency score for a large company; and Pfizer and AstraZeneca — the same companies for which concerns about SARS-CoV-2 vaccine trial conduct and transparency have surfaced — have below-average scorecard records.

We know little about the other companies developing vaccines, as most are newer, smaller companies with no FDA-approved products. Some are also based outside the U.S.

These scores suggest that company culture and support of transparency initiatives vary. To address this unevenness and ensure public trust at this critical time, all companies engaged in vaccine development should make or reaffirm an explicit commitment to the suite of transparency practices we have described. And even though public results reporting and data sharing are not typically done until the FDA approves a product, given the urgency of the pandemic and the public trust at stake, companies should take steps toward complete research transparency at the time of emergency use approval or full approval — or even before.

The usual worries about competitors taking advantage of the information are less salient because the global demand for vaccines will likely outstrip supply, many purchasing commitments are already in place, and much of the investment in vaccine development has come from government rather than companies.

The U.S. public has already endured repeated missteps in the pandemic response, so the stakes involved in bringing safe, effective vaccines to market and ensuring their uptake have never been higher. Transparency will help ensure this achievement is trusted.

Jennifer E. Miller is an assistant professor at Yale School of Medicine and founder of Bioethics International. Joseph S. Ross is a professor of medicine and public health at the Yale School of Medicine. Michelle M. Mello is a professor of medicine and law at Stanford University. All authors receive support through their respective institutions from Arnold Ventures to support the Good Pharma Scorecard at Bioethics International.