By Melinda Young

The United States is at a challenging and possibly dangerous crossroad as the desire for speedy development of a COVID-19 vaccine might be pushing political concerns ahead of safety, efficacy, and the regulatory process, bioethicists and researchers say.

In May, President Trump launched Operation Warp Speed, including agreements with pharmaceutical companies and a $12 billion federal investment in six vaccine candidates with the intention of shaving years off the typical decade-plus vaccine development process.1

In early August, President Trump said he expected a coronavirus vaccine to be ready by the Nov. 3 general election. In the first week of September, the Centers for Disease Prevention and Control (CDC) asked state governors to be ready for vaccine distribution by early November, before the general election.2

These signified the election was possibly affecting the regulatory process and scientific research. Several national research organizations raised objections and concerns.

“The idea is that perhaps one of these COVID-19 vaccines in development might be prematurely released for use — via an emergency use authorization [EUA] order — on political grounds,” says Alison Bateman-House, MPH, PhD, assistant professor in the division of medical ethics at NYU Grossman School of Medicine in New York City.

The Food and Drug Administration (FDA) should decide whether to approve a vaccine for public use based on the apolitical grounds of science, as it has historically, Bateman-House says.

“That accounts for the anger and revulsion that has been evinced toward the idea of partisan politics influencing FDA decision-making,” she adds.

On Sept. 8, nine chief executive officers of biopharma companies signed a pledge stating they are committed to developing and testing potential vaccines in accordance with high ethical standards and sound scientific principles. They pledged to only submit their investigational vaccine for approval or for emergency use authorization after a Phase III clinical study demonstrated safety and efficacy.3

The research community, FDA, and IRBs should make decisions about vaccine trials based on the four ethical principles of autonomy, beneficence, nonmaleficence, and justice, Bateman-House says. (See story on following ethical principles in vaccine study decision-making in this issue.)

In August, the Infectious Diseases Society of America and the HIV Medicine Association asked the FDA to allow vaccine trials to go through the full licensure process and not be made available through an EUA, which allows for far less scrutiny of trial data. “Cutting corners with respect to the evaluation of safety and effectiveness must not be done,” the organizations wrote.4

Regulatory Ambiguity

COVID-19 research has proliferated and received a lot of public and governmental attention. This has led to some ambiguity in how regulatory agencies are handling it.

“This is a unique pathway of activities with COVID. Rarely do we get that amount of [research attention], and rarely do we get lot of ambiguity,” says Chris Weir, CIP, IRB operations manager at Fred Hutchinson Cancer Research Center in Seattle.

For instance, IRBs and research organizations might view risks and benefits of a clinical trial differently when it involves a therapeutic or vaccine needed for a public health emergency and/or pandemic.

“If you put COVID on it, you could argue that any activities are in the public health realm,” Weir says.

This does not mean IRBs should make decisions that bow to political or other pressure because the studies might be labeled as for the public good.

There would be no reason not to issue a vaccine EUA if all clear conditions were met, says Herschel Nachlis, PhD, research assistant professor of government and policy fellow in the Rockefeller Center for Public Policy and Social Sciences at Dartmouth College in Hanover, NH.

“It’s true that prior EUAs, like for hydroxychloroquine, were probably not great for the agency or for public health,” Nachlis says. “But there is no reason to not issue EUA for a vaccine if conditions are met.”

These conditions include trials enrolling quickly, providing successive doses of vaccine fast enough, and enrolling sufficient numbers of people in the treatment control arm. “If the average treatment effect is very large, efficacy is clear in data, and safety is clear in the data, then that’s what we should all be praying for,” Nachlis says. “If everyone agrees on data, that would be wonderful.”

But if a vaccine receives an EUA from the FDA, there should be robust, rigorous, and detailed post-marketing surveillance. “This is not something the agency has historically put at the top of its agenda,” he adds. “If we get an EUA before a Phase III trial is done, it will be done based on less data than a full trial. Because of low probability and high-impact safety concerns, there has to be really robust post-marketing surveillance.”

Evidence from ongoing SARS-CoV-2 vaccines could be discussed at the Oct. 22 meeting of the Vaccines and Related Biological Products Advisory Committee. (More information is available at: https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-october-22-2020-meeting-announcement.)

“Having the meeting 13 days before the presidential election is less than ideal,” Nachlis notes. “The committee can make a recommendation to the agency and commissioner, and that is nonbinding. But they’re typically followed 80% of the time, and that meeting will be public and, possibly, livestreamed, so we’ll see that discussion and the evidence.”

The decision ultimately rests with the FDA commissioner. No one knows what the current FDA commissioner will decide, but some say politics could play a big role in this decision because of the president’s repeated claims that a vaccine will be released before the election.

There is much “nonsense” about coronavirus vaccines, said Arthur Caplan, PhD, professor of bioethics at NYU Grossman School of Medicine and founding director of the division of medical ethics. Caplan is on the World Health Organization’s emergency use investigation committee and has advised two companies with vaccine candidates — work for which he is unpaid and has no equity or stock. Caplan spoke at the Aug. 5 WIRB-Copernicus Group webinar on vaccine development.

“The White House says they’ll expect to see a vaccine in a few months, and now we hear we may get a vaccine by the fall,” Caplan said. “I think there has been a lot of nonsense about vaccine availability. I don’t believe we’ll see a vaccine this year.”

Starting with animal studies, it takes many years to get to Phase III trials. The mumps vaccine was produced in four years, but most vaccines take at least 10 years, Caplan explained.

There is no guarantee a vaccine will come to fruition. For instance, decades of work on potential vaccines for HIV and hepatitis C have come up empty, he added.

“As a historian of medicine, I share some of the concerns about Operation Warp Speed because in the past, speed has been associated with mishaps,” says Susan E. Lederer, PhD, professor of medical history and bioethics at the University of Wisconsin-Madison. “We live in a period of vaccine hesitancy. There has been vaccine resistance since the smallpox vaccine.”

It took decades for the United States to develop the current research standards and FDA evaluation process for the marketing of safe and effective vaccines. “Now, we’re just going to ignore that to beat Election Day?” Lederer asks. “I think the same thing is going on with convalescent plasma that the FDA gave an emergency use authorization when it’s not proven. I thought it would be subjected to rigorous clinical trials, but we haven’t finished that, and people are deviating from accepted standards.”

In addition to vaccine reluctance among many Americans, there is the potential for a coronavirus vaccine mishap to set back all vaccine acceptance, Lederer adds.

“I think the term ‘Operation Warp Speed,’ is one that I, as a health communication person, would not have used as a slogan,” says Aisha Langford, MPH, PhD, assistant professor in the department of population health at NYU Grossman School of Medicine, and co-director of the Clinical and Translational Science Institute at NYU Langone Health. “On the one hand — and this is a good thing about COVID-19 trials, in general — is these vaccine trials have aspects of the research process that are being done quicker than usual. There is a lot more collaboration than usual because we’re in the middle of a pandemic.”

Research organizations are learning to be more collaborative and to cut out some of the nonessential steps that make clinical trials take longer than needed. “A lot of people, including the general public and scientists, want to do well-conducted, very sober, step-by-step science,” Langford says.

Promising a COVID-19 vaccine by a set date, rushing the vaccine through the FDA approval process, or bypassing Phase III clinical trials and making a vaccine available via EUA can lead to public trust issues.

“To make an announcement or overpromise and make things available before they’re actually ready is not a good idea because we don’t want to jeopardize public trust for when a vaccine is available, or erode public trust for other treatments,” Langford explains. “The public needs to know we have ethics review boards, and we need safety and efficacy first.”

Scientists should follow their process and not let politics dictate the process. “All regulatory decisions are a combination of policy and politics,” Nachlis says. How much a decision is based on policy, law, and politics is a continuum, and it depends on where it sits on the continuum, he explains.

“What’s unique about this president is his willingness to mobilize public pressure on expert regulatory agencies in a way that other presidents have been less likely or interested in doing,” Nachlis continues. “President Trump has been comfortable and excited about using the bully pulpit and going public to move the needle on the political side of regulatory policymaking.”

From a bioethical standpoint, coronavirus vaccine research cannot skip Phase III trials, Bateman-House says.

“We might allow some high-risk people to get access to an unapproved vaccine through expanded access, but there is no way to approve this for use on only Phase II data,” Bateman-House says. “That sometimes happens in oncology trials, but only for dying patients who have no other option. Vaccines are for healthy people, and I cannot fathom a situation in the United States where a COVID-19 vaccine is approved on Phase II data. It’s too small and short of a time to have a real gauge of efficacy and safety.”

REFERENCES

  1. The White House. President Donald J. Trump is using every available resource to deliver a safe and effective vaccine to the American people. Aug. 11, 2020. https://www.whitehouse.gov/briefings-statements/president-donald-j-trump-using-every-available-resource-deliver-safe-effective-vaccine-american-people/
  2. Kaplan S, Wu KJ, Thomas K. CDC tells states how to prepare for COVID-19 vaccine by early November. The New York Times, Sept. 2, 2020. https://www.nytimes.com/2020/09/02/health/covid-19-vaccine-cdc-plans.html
  3. Sanofi. Biopharma leaders unite to stand with science. Sept. 8, 2020. http://www.news.sanofi.us/2020-09-08-Biopharma-leaders-unite-to-stand-with-science
  4. Infectious Diseases Society of America. Infectious diseases specialists to FDA: Don’t cut corners in COVID-19 vaccine approval. Aug. 26, 2020. https://www.idsociety.org/news--publications-new/articles/2020/infectious-diseases-specialists-to-fda-dont-cut-corners-in-covid-19-vaccine-approval/