CBER Director on COVID-19 and Vaccine Development

On July 8, the Alliance for a Stronger FDA was pleased to host a webinar with Peter Marks, MD, PhD, Director of FDA’s Center for Biologics Evaluation and Research. He joined the FDA in 2012 as CBER’s Deputy Director before becoming Director in 2016.Dr. Marks greeted the participants and thanked the Alliance for organizing the event. During his opening remarks, Dr. Marks highlighted FDA’s critical role in protecting public health, promoting research and development, working with industry stakeholders, and ensuring the safety and efficacy of medical products.He then turned to the main topic: vaccine development. He pointed out that there are at least eight different approach to constructing vaccines (e.g., DNA, RNA, inactivated viruses, and protein subunits). Across these broad range of starting points, FDA has three primary responsibilities: ensuring manufacturing consistency, especially as production scales up; evaluation of safety; and evaluation of efficacy.Vaccine developers should have data from non-clinical animal model studies that help identify safety risks and inform selection of dose, dosing regimen, and route of administration before first-in-human clinical trials.Clinical development programs for COVID-19 vaccines should pursue traditional approval based on direct evidence of vaccine efficacy in protecting humans from the disease. Development may be expedited through adaptive or seamless clinical trial designs.Late phase trials should be randomized, blinded, and placebo-controlled and enroll thousands of participants, including those with co-morbidities. Clinical trials should include diverse populations in all stages, including older people, pregnant women, women seeking to become pregnant, and children.The primary efficacy endpoint for a placebo-controlled, late-phase trial should be at least 50%, with an adjusted lower bound of > 30%. Interim analyses should be planned so that results can be evaluated for safety and futility. Safety evaluations (including the size of the safety database) should be similar to other preventive vaccines. The follow-up period needed to evaluate safety, duration of immune response, and risk of disease enhancement will take months. Preparing a program of post-licensure pharmacovigilance in advance is recommended.Applicants that can establish surrogate endpoints that are likely to predict clinical benefits may be eligible for expedited approval. FDA may issue Emergency Use Authorizations for vaccines with adequate manufacturing information before the manufacturer submits its product for formal review (or before FDA has completed its formal review of the Biologics License Application) if studies demonstrate the safety and efficacy of the vaccine.In his presentation and during the Q&A, Dr. Marks stressed that public confidence in vaccines is critical to success in eliminating diseases. While COVID-19 presents a challenge that requires a speedy process, FDA must be able to assure the public that standards have been maintained and that any marketed vaccine is safe and effective and has consistent quality manufacturing.During the Q&A, Dr. Marks was asked for more detail on the 50% efficacy threshold. He explained that going lower than 50% allows for the possibility of a vaccine that isn’t sufficiently useful, while a 70 to 80% threshold may deny approval to a vaccine that could protect a significant population until more effective vaccines become available. Eventually, a vaccine will be needed that is “probably in the order of 70% effective and 70%, at least, of the population is going to need to take it.” He anticipates that more than one vaccine will be needed because of likely differences in effectiveness and safety in different populations.Dr. Marks was also asked about the potential use of challenge trials that involve intentionally infecting someone with a disease to study a vaccine’s effect. While Dr. Marks did not rule out the option of a challenge trial, he expressed ethical concerns, especially if such trials were planned before COVID-19 treatments are available that could serve as rescue medicine.Editorial note: The Analysis and Commentary section is written by Steven Grossman, Deputy Executive Director of the Alliance for a Stronger FDA. Special thanks to Reed Diskey for sharing his meeting notes.