On Monday, Pfizer and BioNTech announced that their experimental Covid-19 vaccine candidate prevented more than 90% of infections in healthy volunteers. Based on these encouraging data — potentially among the most effective for any infectious disease — the companies plan to apply for emergency use authorization, which would let the Food and Drug Administration formally authorize an unapproved medical product during a state of emergency. While well-intentioned, this approach is ultimately misguided. The world faces a crisis not an emergency.
An emergency use authorization would potentially open the floodgates to deploy an unapproved and unlicensed vaccine to millions (or tens of millions) of individuals before gathering the proof of safety and efficacy that licensing a new vaccine typically demands.
This was never the intent of emergency use authorization, which was actually designed for counterterrorism measures to address chemical, biological, radiological, and nuclear hazards — not necessarily a pandemic. (The first use of EUA authority was in 2005 through the Project Bioshield Act to authorize military vaccinations against anthrax).
We fear that an emergency use authorization for Covid-19 vaccines at this stage of development would not require careful reporting of adverse events and could potentially undermine ongoing and future clinical trials that are still necessary to determine safety and efficacy.
There is a better way to provide Americans with access to a new vaccine.
If the FDA and its independent review committees decide the early evidence supplied by Pfizer and BioNTech — or other companies down the road — is sufficiently promising, the agency should grant early access to their Covid-19 vaccines through a process known as expanded access. Expanded access is the use of an investigational new drug product outside of clinical trials to treat patients with serious or immediately life-threatening diseases of conditions when there is no comparable or satisfactory alternate treatment options.
Expanded access is fundamentally different from emergency use authorization, and the distinction between the two is vitally important. Expanded access will preserve the integrity of ongoing large-scale clinical trials under the banner of experimentation while ensuring that high-risk individuals have a pathway to access experimental vaccines that could mean the difference between life and death. An emergency use authorization would not.
Through the expanded access pathway, the FDA would not determine if an investigational Covid-19 vaccine actually works. Instead, via expanded access, it would facilitate access for those at greatest risk without opening the floodgates to access in the way that an EUA might do (although the targeted population for a Covid-19 vaccine could be as limited as the FDA thinks the data support, but that would be difficult to enforce). It would be up to a doctor and his or her eligible patient to determine on a case-by-case basis the risks and benefits of trying a still-experimental vaccine.
The FDA’s history of expanding access to investigational products dates back to the 1970s, but the process first received national attention when patient dying with HIV/AIDS fought for access to antiviral drugs that were available only through clinical trials. The public battle led to much-needed reforms and popularized the idea of compassionate use: allowing broader access to experimental drugs while still classifying them as unproven and experimental.
As expanded access has matured — it is now used for all sorts of diseases beyond HIV — the process has been streamlined. Today, it takes less than an hour to complete an expanded access application and the FDA approves 99% of requests. Expanded access is not a formal approval process, just as the EUA is not a formal approval process.
Certain requirements apply for expanded access:
- The patient must have a serious or immediately life-threatening disease or condition and have no comparable or satisfactory alternative therapy.
- The potential benefit must justify the potential risks.
- Providing the treatment must not interfere with or compromise the ongoing vaccine approval process.
Invoking expanded access for a Covid-19 vaccine would be unusual, but not unprecedented. Meningococcal vaccines and non-U.S.-licensed yellow fever vaccines have been made available through this process, and with good results. Expanded access remains controversial, however. It leads some patients and their doctors to pursue products that are neither safe nor effective. Given these competing interests, we believe expanded access is not only appropriate in the midst of a worsening pandemic, but also necessary.
Roughly 40% of reported Covid-19 deaths in the United States have occurred in long-term care facilities such as skilled nursing facilities, assisted living centers, veterans’ homes, and the like, and the virus continues to surge across the United States. While it is important to allow ongoing vaccine trials to finish, we simply cannot wait to inoculate the most vulnerable citizens. Vaccination of high-risk individuals and clinical trials should proceed in concert, with doctors and eligible high-risk patients deciding when benefits of inoculation outweigh risks.
Why does this matter? A recent poll indicates that just over half of all Americans (58%) would get inoculated as soon as a vaccine was available, down from 69% who said the same thing in August. The FDA has used emergency use authorizations to facilitate the use of ineffective treatments such as hydroxychloroquine and fraudulent diagnostics such as point-of-care serology tests that have shaken public trust. The agency should not further jeopardize its credibility by authorizing a Covid-19 vaccine for emergency use before Phase 3 clinical trials have been completed. Without public support of a vaccine, it will be difficult to protect everyone from the virus, and the pandemic will persist. A vaccine that few will take is of little value.
The FDA cannot require Pfizer or any other manufacturer to provide a vaccine through expanded access. Given the robust support of the unfortunately titled Operation Warp Speed, however, expanded access will not impair ongoing clinical trials or sap a limited supply chain. But expanded access can work only if drug companies agree to provide Covid-19 vaccines through the expanded access pathway and the FDA agrees to their doing that.
Americans will soon have access to Covid-19 vaccines, but the manner in which these potentially lifesaving inoculations are authorized and distributed must be carefully thought through in order to ensure public trust in the rollout. Key stakeholders must make the commitment to expanded access.
Matthew W. McCarthy is an associate professor of medicine at Weill Cornell Medicine in New York City. David Oshinsky is director of the Division of Medical Humanities at NYU Langone Health and professor of history at NYU. Arthur Caplan is the founding director of the Division of Medical Ethics at NYU Langone Health School of Medicine. They write on behalf of the Vaccine Working Group on Ethics and Policy.
(Seriously? No edit or delete functions for comments? How old is this platform?)
My primary concern isn’t getting the vaccine out there, but protecting the rights of human subjects. An EUA product is inherently investigation, since it has not been approved by FDA. While expanded access might be a solution for patients ina clinical trial, it is not a solution for the many authorized COVID-19 products for which there is no trial.
Disagree. There are ways to carry on randomized trials while distributing large quantities of vaccine, using lottery methods. The FDA and its apologists are simply too hidebound to adopt different methods for trials from the ones they’ve used before, even when those methods are equally effective and would permit life-saving vaccines to actually be administered in time to help head off a looming second wave of cases and deaths.
I suppose if the FDA is willing to provide “expanded access” for everyone over 70 or 75, I’d be OK with that, but an hour-long application for millions of elderly Americans, who need this vaccine more than they need to be protected from the remote possibility that it might have serious side effects, seems like a big waste of time. (There are strong reasons to believe mRNA vaccines will be safer than vaccines produced with previous techniques. Because most public health professionals don’t tend to approach questions like this in a Bayesian way, they will maintain there is “no evidence” of safety until the trial data come in, but that’s simply false. Our biochemical understanding of how these vaccines work is already strong evidence of their safety.)
What hour-long application are you talking about?
Vaccinating the elderly might not be the best way to protect them. Unless large numbers of elderly were included in the clinical trials, the trials will not have evaluated either safety or efficacy in the elderly, so that would essentially be vaccinating them with what is, as far as they are concerned, an untested vaccine. In addition, the elderly are not just at greater risk of COVID-19. They are at greater risk of many health related risks, including risks from any side effects of a vaccine. For this reason, the best way to protect the elderly is to vaccinate the rest of the population, even though they are at lower risk from COVID-19. They are more likely to be able to tolerate any side effects, and, if they are vaccinated then they can’t spread the virus, including to the elderly.
The authors make an interesting case for use of expanded access [compassionate use] for providing pre-licensure access to emerging COVID-19 vaccines instead of EUA [Emergency Use Authorization]. They thoughtfully argue that using expanded access would be a means to protect the integrity of on-going clinical trials, both for any vaccines that might be involved, but also for other vaccine trials underway.
Indeed, the question about using an expanded access channel was raised briefly at the recent FDA Vaccines and Related Biological Products Advisory Committee, and in follow-up media coverage.
What the authors do not mention is that using expanded access for this purpose would also trigger very important patient safeguards built into this access channel — specifically that patients give their informed consent to receiving the vaccine and that ethics review boards [IRBs] review and approve such use.
While we [Center for Vaccine Ethics& Policy; http://www.ge2p2.org] feel strongly that consent must play a critical role in any ethically-responsible COVID-19 vaccine deployment before licensure, we recognize that the logistics of accomplishing this are probably more challenging than the logistics of maintaining a -180-degree cold chain in getting many of the COVID-19 vaccine candidates successfully to, and into, the arms of patients who might benefit.
We urge the authors to complete their analysis and address how these important requirements impact their core argument.
Typo: Cold chain reference should have been -100 degrees [F] or -70 degree [C]!!
Thank you for bringing up this point. You mention that that the logistics of implementing informed consent and IRB review are more challenging than the logistics of -70C cold chain distribution. I am confused about this comparison, since wouldn’t the cold chain challenge be present with both channels (expanded access and EUA)? I must be missing something. Thank you!
If the logistics of getting patient consent were more challenging than those of a 180-degree cold chain, the practice of medicine would have virtually ceased decades ago. Patients are consented all the time, including in the ER before being wheeled into the OR for emergency cardiac surgery.
I’m still confused about the difference between the two.
1. Is one difference that with the EUA route the participants are not placed on a registry (and therefore adverse events are not formally tracked)?
I do think not interfering with ongoing vaccine trials is an important consideration. Can you clarify how expanded access doesn’t interfere but an EUA does interfere?
Finally, could you explain how an EUA “leads some patients and their doctors to pursue products that are neither safe nor effective.”
Actually there are more than two, if you want to make sense of things.
IND/IDE is FDA approval, but not to market a product. It is approval to conduct a clinical investigation of an unapproved medical product. “Expanded access” is sometimes permitted once the original endpoints of the trial have been reached. If the data are looking good, the trial sponsor is permitted to enroll more patients, typically with reduced follow-up and sometimes less stringent enrollment criteria.
Expanded access offers an opportunity to broaden clinical experience with the product beyond the narrow confines of the clinical trial, and also to bring the product to more patients, while working through the premarket approval process. Probably often offers an opportunity to sell the product, or to sell more of it, if it was being sold for use in the trial. (Yes, that can happen.)
“Approved” as it is applied to a product, rather than a clinical trial, means that, after reviewing the data that support its safety and effectiveness, FDA has approved the product for sale in the US.
“Authorized” is FDA saying you can sell your product without its approval, because there is a public health emergency. Without emergency authorization, selling an unapproved product in the US would otherwise be illegal.
The EUA is essentially an end run around FDA. They have tried to put lipstick on it by issuing high-sounding “guidances,” but there is nothing to assure that the guidances are being followed, nor that FDA is even looking at whatever data the manufacturer might collect, per FDA’s guidance or not. One bewildered manufacturer, selling an “authorized” product early in the pandemic, posted on its website a summary of the data they had to support their product, with the caveat “FDA has not reviewed these data.”
It is also an end run around all ethical standards for research involving human subjects. EUA products are experimental. Their use in patients, with or without “authorization,” is human experimentation, without ethical oversight or informed consent.
If a clinical trial is conducted ethically, then it is being conducted with ethical oversight (typically an IRB) and informed consent is required. The same “should” apply if access to the trial is expanded beyond planned enrollment. However, if the trial was never approved by the FDA (IND/IDE), there is no assurance of the protection of subjects in the trial. The “should” also be true if the product is being sold under an EUA, but as far as I can tell, this is not what is happening with the many COVID-19 products that FDA has “authorized” thus far.
IMO, the EUA is a good idea that has been hijacked, and is now not being used for good, but for the other thing.
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