Transparency practices at the FDA: A barrier to global health
View the article online: https://www.science.org/doi/10.1126/science.abq4981
By Murray M. Lumpkin, Margaret A. Hamburg, William B. Schultz, Joshua M. Sharfstein
During the COVID-19 pandemic, scientists at the US Food and Drug Administration (FDA) have reviewed large numbers of pandemic-related tests, medications, and vaccines. However, long-standing confidentiality practices have kept FDA from sharing many of these analyses and the data behind them with the regulatory agencies of other nations, especially those in low- and middle-income countries (LMICs). With FDA not sharing key information, the primary source of dependable COVID-19 product regulatory documentation and information for resource-constrained countries has been the World Health Organization (WHO) in coordination with leading European regulators. These efforts are commendable, but in many cases FDA’s assessments will be some of the most sought after and scientifically robust in the world—and should be shared with the widest possible regulatory audience. FDA must demonstrate similar leadership and commitment to global health by reforming its outdated, restrictive practices on information sharing.
Even absent a pandemic, most agencies find the challenge of medical product regulation daunting. Thousands of medical products come onto the global market annually, but few agencies have the capability to assess these products thoroughly. The WHO has estimated that only one-quarter of its member states have agencies with at least a “stable, well-functioning, and integrated regulatory system” (1). In most countries, underfunded and understaffed agencies struggle to meet basic regulatory tasks. Even mature agencies find that they sometimes lack the resources they need to meet expectations.
In 2020, a US National Academies of Sciences, Engineering, and Medicine committee highlighted one solution to this challenge: strengthening reliance-based regulatory pathways in which agencies use the extensive reviews and inspections conducted by trusted counterparts to better inform their own regulatory decision-making (2). For such an approach to work, timely sharing of complete critical information and relevant documents between agencies is essential. Such access allows a relying agency not only to trust but to understand what a reference agency has decided, and then to use that information to help inform the appropriate decision for its population. Such reliance-based regulatory decision-making is now a 21st-century “best regulatory practice,” enshrined in WHO guidelines (3).
Unfortunately, FDA entered the current pandemic ill equipped to serve in the role of reference agency to LMICs because of its decades-old confidentiality practices, dating back to a world in which most US pharmaceutical product development, manufacturing, and sales were of US or European manufactured products. In that era, other regulators’ actions had negligible impact on product development, authorization, or access in the United States. Yet FDA’s strict prohibitions on data sharing have remained in place even as the global pharmaceutical ecosystem has been transformed. Today, products may be manufactured in part or in whole in various countries and shipped widely before distribution. During that journey, the product will often be under the authority of a variety of agencies of varying capabilities. Sharing of critical information garnered along this global manufacturing and transit train is needed for effective oversight of the global supply chain of all products, including those bound for the United States.
Yet until 1993, FDA regulations did not even distinguish between release of information to the general public and document sharing with other regulators (4); as a result, no information considered confidential was shared. Then in 1993, FDA took a step toward greater international cooperation. The agency adopted a regulation permitting the agency to share some nonpublic information with foreign regulators, provided that the foreign country makes certain commitments to protect the information from disclosure (5). In practice, however, FDA created an extensive process to validate the ability of countries to maintain confidentiality.
Nearly 30 years later, the agency has established confidentiality arrangements with only a few counterpart agencies (6), focusing on a small number of countries perceived to be able to provide the most helpful information in return—not on agencies in LMICs. Moreover, in all but one of these arrangements, FDA does not share data classified as “trade secret,” a term that the agency has applied more broadly than necessary to include large amounts of manufacturing and biopharmaceutical data (7).
The one agreement permitting the sharing of trade secret information, with the European Medicines Agency (EMA), took 25 years and several legislative interventions to operationalize (8, 9). It was made possible by 2012 legislation that permitted the sharing of unredacted reports after FDA verified the “demonstrated ability” of foreign regulators to protect trade secret information (10). FDA extended this approach to the United Kingdom’s regulatory agency after it left the European Union because it was part of the EMA agreement. FDA has made no other such agreements regarding full inspection reports.
Separately, FDA has established a limited data sharing relationship with WHO, which exemplifies the challenges of current FDA practices with LMICs. FDA sends certain redacted documents to WHO, which then, using its own scarce resources, further distills information into a WHO document, which WHO can share (11). But the heavily redacted documents FDA can share make it difficult or impossible for resource-constrained agencies to rely on FDA regulatory activities when making their own regulatory decisions.
During the current pandemic, FDA has issued emergency use authorizations (EUAs) for multiple products. The only public documents related to these actions are the authorization letters to the companies and the “fact sheets” for health care providers and for patients and caregivers. The full (unredacted) assessment and inspection reports, were they available, would have been enormously valuable to agencies in resource-constrained countries. These agencies are highly interested in what the FDA EUA decision means, what data support it, what dataset was submitted to FDA, where and how the product was manufactured, and why FDA made the decision it made. In some cases, FDA may have been the first or only global regulator inspecting a clinical trials site or manufacturing facility or authorizing a product. Without this critical information, agencies cannot even assure that shipments they receive are the same version as those authorized by FDA (and not, for example, from a manufacturing facility not assessed by FDA).
In contrast to FDA, WHO and the European agencies initiated special procedures to include assessors from several countries, including LMICs, in their deliberations before product authorization (12). Such reliance-based pathways reduced the need for every country to conduct time-consuming, redundant, and often poorly informed assessments and inspections. It also created an extra benefit of faster access to markets in LMICs for companies seeking authorization in Europe, compared with the United States.
The success of this WHO and Europe-led system of critical information sharing is exemplified by the rapidity of African COVID-19 vaccine authorizations. As of March 2022, in the 54 African countries, there were 277 initial authorizations of COVID-19 vaccines, which had received emergency use listing by WHO. In 52 countries, multiple such vaccines have been authorized (13). These COVID-19 vaccine authorizations were facilitated by using a reliance-based pathway endorsed by the African Union and WHO (14). The vast majority are based on EMA’s authorization decisions because EMA and WHO worked closely together on the products’ assessments and because both EMA and WHO shared—in real time—helpful critical scientific assessment and inspections documents with the African agencies.
Meanwhile, because of its confidentiality practices, FDA was only minimally involved in helpful information sharing with resource-constrained agencies. Had FDA data and analysis been more widely available, many countries could have used them to make rapid, informed decisions for their populations.
Successful US leadership in the modern global pharmaceutical ecosystem, as well as global health and safety, depends on the ability of regulators to trust each other and work together. Greater FDA global data-sharing engagement starts with three steps (below). Progress will require more resources, capacity building, and will. In the 21st century, sharing data and critical documents among regulators cannot be an afterthought: It must be “business as usual,” including for FDA.
Three steps FDA should take for greater global data-sharing
- Share copies of assessment and inspections reports for all pandemic-related products. As a short-term measure during this declared state of emergency, FDA should waive its current practices so that it can share, upon request, with WHO and all other counterpart agencies, whether products have been authorized or not. For the many countries without a confidentiality agreement, FDA should move quickly to accept their statements of authority and commitment for confidentiality. The agency should limit redactions to personally identifiable information and trade secrets as narrowly defined in the statute, which would permit the sharing of much helpful biopharmaceutical and manufacturing data.
This step can still help with the COVID-19 pandemic response. There are new products and new versions of older products to be assessed; there are pressing questions concerning childhood vaccination, boosters, and variants to be answered; there are changes in manufacturing procedures to be validated to enable greater and more cost-effective product production; and there are new efficacy and safety data to be analyzed.
- Develop new practices on data-sharing with WHO and counterpart agencies outside public health emergencies. This should include a rapid path to accepting assurances from foreign counterparts regarding commercial confidential and trade secret information. These new practices should facilitate reliance-based pathways by counterpart agencies and recognize that these agencies should not be considered part of the “general public” for purposes of confidentiality. FDA should also consider additional reforms to make sharing of fully unredacted reports, especially inspection reports, less onerous.
- Publish annual reports of its data-sharing activities with counterpart regulators. This should include both numbers of requests received and from whom and numbers of requests fulfilled and with whom. These reports should document the consequences both for global health and for oversight of products headed to the US market. They should also assess emerging challenges to data sharing, along with potential solutions.
REFERENCES AND NOTES
1. WHO, “List of National Regulatory Authorities (NRAs) operating at maturity level 3 (ML3) and maturity level 4 (ML4)” (WHO, 2022); https://www.who.int/initiatives/who-listed-authority-reg-authorities/maturity-level.
2. US National Academies of Science, Engineering, and Medicine, “Mutual recognition agreements in the regulation of medicines” (2019); https://www.nationalacademies.org/our-work/mutual-recognition-agreementsin-the-regulation-of-medicines.
3. WHO, “TRS 1033 - 55th report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations” (WHO, 2021); https://www.who.int/publications/i/item/55th-report-of-the-who-expertcommittee-on-specifications-for-pharmaceuticalpreparations.
4. Public information; Communications with Foreign Government Officials. Fed. Regist. 58 (223), 61598 ff (19 November 1993).
5. 21 Code of Federal Regulations 20.89.
6. FDA, Confidentiality commitments; https://www.fda.gov/internationalprograms/international-arrangements/confidentiality-commitments.
7. Trade secret is defined as “any commercially valuable plan, formula [that has] a direct relationship to the production process,” with examples including “the type or brand of equipment used in manufacturing, product formulas, product components or ingredients not on the label, specifications that are unique (i. e., not in the US Pharmacopeia), and technical designs” (8).
8. FDA, FDA Staff Manual Guide (SMG 2830.3).
9. FDA, Mutual Recognition Agreement (MRA); https://www.fda.gov/internationalprograms/international-arrangements/mutual-recognition-agreement-mra.
10. The Food and Drug Administration Safety and Innovation Act of 2012, Pub. L. No. 112-144.
11. FDA, “FDA In Brief: FDA announces pilot program with World Health Organization to expedite review of HIV drug applications” (FDA, 2018); https://www.fda.gov/news-events/fda-brief/fda-brief-fda-announces-pilotprogram-world-health-organization-expedite-reviewhiv-drug.
12. EMA, Questions and answers on the pilot project ‘OPEN’. Opening our Procedures at EMA to Non-EU authorities (EMA, 2021); https://www.ema.europa.eu/en/documents/other/questions-answers-pilot-project-open_en.pdf.
13. WHO, AVAREF COVID-19 Africa vaccine dashboard; https://www.afro.who.int/health-topics/immunization/avaref/covid-19-africa-vaccine-dashboard.
14. Africa Centers for Disease Control and Prevention (Africa CDC), “Guidance on emergency expedited regulatory authorisation and access to COVID-19 vaccines in Africa” (Africa CDC, 2021); https://africacdc.org/download/guidance-on-emergency-expeditedregulatory-authorisation-and-access-to-covid-19-vaccines-in-africa.
M.M.L. is a former deputy commissioner for international and special programs of FDA. M.A.H. is a former commissioner of FDA. W.B.S. is a former deputy commissioner for policy of FDA and former general counsel of the US Department of Health and Human Services. J.M.S. is a former principal deputy commissioner of FDA.
This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science , (2022-08-05), doi: 10.1126/science.abq4981
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