Two Harvard-affiliated experts on the pharmaceutical industry and drug approvals raise questions about using antibody titers as a surrogate markers for COVID-19 vaccine efficacy in an opinion piece published today in the New England Journal of Medicine.
The experts, Jerry Avorn, M.D., and Aaron S. Kesselheim, M.D., J.D., M.P.H., of the Program on Regulation, Therapeutics and Law at Harvard-affiliated Brigham and Women’s Hospital in Boston, write that if an antibody titer is used as evidence for early approval “its clinical meaning could be difficult to assess.”
“What antibody level could reliably be predicted to confer immunity? Exactly which antibody? For what duration?” ask Avorn and Kesselheim.
The pair of Harvard experts caution against using antibody levels in recovered patients as the standard by which vaccine-induced antibodies would be measured because “we are still learning about the extent to which such natural immunity confers protection from infection and for how long.”
They also question whether a vaccine that raises antibody levels will have an effect on the contagiousness of a vaccinated person.
Aaron S. Kesselheim, M.D., J.D., M.P.H.
It is not clear whether vaccine develops are planning to use antibody titers to win FDA approval.
But, as Avorn and Kesselheim mention, a guidance for COVID-19 vaccines that the FDA issued in June mentions the possibility of approving a product based on a “surrogate endpoint (e.g., immune response) that is reasonably likely to predict clinical benefit.”
The guidance also discusses a primary efficacy endpoint of at least 50% — with infection with SARS-CoV-2 or a severe case of COVID-19 qualifying as an endpoints.
Jerry Avorn, M.D.
Drug approvals based on surrogate markers — also known as surrogate measures or surrogate endpoints — have become increasingly common. In oncology, for example, drugs are approved based on measures of how the tumor has responded, rather than overall survival. Proponents say surrogate endpoints hasten the availability of helpful medications while critics say approvals based on surrogate endpoints are resulting in medications of dubious value getting on the market. Avorn and Kesselheim chalk up the growing use of surrogate markers to the “combined pressure” of the pharmaceutical industry, patient groups and Congress.
In the accelerated approval process that may use unvalidated markers, there are supposed to be follow-up confirmatory trials, although Avorn and Kesselheim reference problems of timeliness and whether the needed data actually get collected. “This challenge would be even greater if widespread availability of a vaccine makes it harder to enroll patients in a placebo-controlled trial,” they wrote.