Why emergency authorization of COVID-19 therapies could pose regulatory questions

Few of the COVID-19 therapies in use in the U.S. have won full FDA approval. The widespread use of emergency use authorization may accelerate the distribution of disease-modifying agents and vaccines to patients, but it also could cause regulatory complications.

“I’m nervous about the prospect of there never being a COVID vaccine that meets the FDA’s approval standard,” said Peter Doshi, an assistant professor of pharmaceutical health services research at the University of Maryland.

The FDA’s decision to grant emergency use authorization to investigational vaccines could lead to the development of a “marketplace” where vaccines are deemed “good enough to be authorized, but never approved,” Doshi opined in the public comment period of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting on Johnson & Johnson’s vaccine.

FDA could approve the Pfizer-BioNTech and Moderna vaccines as early as next month, according to The New York Times, which could facilitate employee mandates for those vaccines.

One factor influencing the U.S. regulatory landscape at large is “the fact that the original declaration of a public health emergency by the prior Secretary of Health and Human Services in the past administration is still in place,” said Reed Stephens, a partner at the global law firm Winston & Strawn. “Many long-established regulatory and statutory obligations have been put on pause in response to the ongoing public health emergency,” Stephens said.

But the Biden administration is charting a new course in terms of pandemic response, swiftly invoking the Defense Production Act to facilitate vaccine production, for instance. “Once the public health emergency declaration lapses, we are likely to see the new administration’s FDA and HHS leaders, with active oversight from Congress, take a thoughtful approach to pandemic response planning that looks closely at the framework of a proactive vaccine research and development program under a private-public partnership that will inspire public confidence and is not saddled with the label of ’emergency’ response,” Stephens said.

Another factor complicating matters is the decision from pharmaceutical companies to administer vaccines to placebo recipients in clinical trials, according to Diana Zuckerman, president of the National Center for Health Research. “As soon as the vaccine is authorized, we start losing the placebo group,” Zuckerman said in the VRBPAC meeting on the J&J vaccine.

When faced with the quandary of whether to maintain double-blinding of clinical trials or to offer vaccines to participants who received a placebo, Pfizer, Moderna and Johnson & Johnson opted for the latter — at least for some placebo recipients.

“As we move forward, the controls in these studies will be offered vaccination, we hope, or they may well be exposed to COVID,” said Dr. Susanne Hodgson, a clinical researcher at Oxford University, in a BMJ webinar. “And either way, we’ll be losing the controls for these studies.” And as a result, it won’t be easy to make conclusions about the duration of protection from vaccines or their efficacy against variants.

While FDA requires two months of follow-up data post-vaccination, the agency had issued a non-binding recommendation to follow study participants for “as long as feasible, ideally at least one to two years,” according to a guidance document.

“FDA has been lowering its expectations about followup and at the most recent VRBPAC [meeting] was saying six months,” wrote Doshi over email.

Similarly, the International Coalition of Medicines Regulatory Authorities, to which FDA belongs, has also stressed the importance of “gathering data about [COVID-19] vaccine safety and efficacy in the longer-term after the interim or final analysis is completed.”

The quick speed of COVID-19 vaccine commercialization “throws a wrench into ongoing and future placebo-controlled vaccine trials,” wrote Dr. Rita Rubin in JAMA. “Why would anyone want to remain or enroll in such studies when they could get vaccinated outside of them?” she asked.

But unblinding trials after vaccines win emergency use authorization is “a huge loss for public health and a huge loss of information about how we can stay safe,” Zuckerman said.

Given the difficulty of maintaining large-scale randomized, controlled trials (RCTs), regulatory agencies may be forced to rely more on non-randomized observational studies and in vitro surrogates for efficacy.

Regarding how non-randomized observational studies might affect our understanding of COVID-19 vaccines, Doshi pointed to flu vaccines in a BMJ webinar. Decades after influenza vaccines have become widely available, “we still lack definitive randomized evidence that any influenza vaccines lowers mortality because the placebo-controlled RCT with that endpoint has never been done.”