Could the SARS CoV2 Vaccines Take a Short Cut?
The U.S. has an organized way of approving new vaccines and drugs for use and regulating them once they’re approved. However, during public health emergencies, the FDA is allowed to provide for short cuts. This week we explore the normal approval process, investigational new drugs, and the Emergency Use Authorization process which can be used in public health emergencies.
Normal Approval Processes
A key player in the process of approving new drugs is within the FDA’s Center for Drug Evaluation and Research. The center’s job is to evaluate new drugs before they can be sold. Their core mission is to ensure that drugs work and that their health benefits outweigh their known risks.
The first step in getting a new drug or vaccine approved is testing it in clinical trials. Drug companies do that testing and send their evidence to the Center. Next, a series of tests (clinical trials) determines whether the vaccine or drug is safe when used to treat a disease and whether it provides a real health benefit. Basically, do the benefits of the vaccine exceed the risks?
That’s where the independent review comes in. The FDA Center for Drug Evaluation and Research has a team of physicians, statisticians, chemists, pharmacologists, and other scientists that review the company’s data and proposed labeling. This is an independent review to make sure that a vaccine’s health benefits outweigh its known risks. If a drug or vaccine is considered safe and effective, then it can proceed through the approval process.
Part of the approval process includes developing a Package Insert that describes how the drug or vaccine should be used. The Package Insert has 2 main parts, the “highlights of prescribing information” and the “full prescribing information”. Together this information provides clinicians with access to the information they’ll need to responsibly prescribe the medication.
Clinicians that prescribe drugs are encouraged (but not required) to follow the instructions in the package insert. Clinicians can use professional judgment as they prescribe the drug and can decide to use a drug in a way that’s different from what is described in the Package Insert. When clinicians do this, it’s called prescribing off-label.
Prescribing off-label also has its risks. One obvious one is that since the clinician is prescribing in a way that may not be well-researched, he or she may be taking a risk with their patient. Also, if a patient has a bad outcome, the prescriber’s actions will be measured against the standard of care… and one tool considered by the courts in damages lawsuits is whether the clinician was prescribing according to the package insert.
Investigational New Drugs
The Investigational New Drug program allows drug makers to get permission to start human clinical trials before a drug or vaccine is approved. Drug makers or researchers file an application with the FDA that discloses the pre-clinical testing, manufacturing information, investigator information, the clinical trial protocols, and commitments to get informed consent.
If an investigational new drug application is approved, then the researchers can begin using the drug, but they’re supposed to stay within the boundaries of their application and be diligent and measure and report their findings.
An example of an investigational new drug for COVID-19 is convalescent plasma (plasma donated by folks that have recovered from COVID-19). Applications for using convalescent plasma were authorized in early April to fill an urgent need to provide patient access to a medical product when FDA was working with researchers to facilitate randomized clinical trials to study convalescent plasma.
Emergency Use Authorization
Another process by which new drugs or vaccines which aren’t yet approved is called an Emergency Use Authorization (EUA). An EUA doesn’t constitute approval of a drug, but facilitates availability of an unapproved drug (or an expressly unapproved use of an approved drug). EUAs can only be used during a state of emergency (as is the case right now with the COVID-19 pandemic).
The standard for approval of an EUA is lower than a regular approval of a drug. All the applicant needs to show is that it’s “reasonable to believe” that the drug (or vaccine) “may be effective to prevent, diagnose, or treat serious or life-threatening diseases”.
Over the course of the pandemic, the FDA has approved scores of drugs, tests and medical devices under EUA protocols including Drug and Biological Products, In Vitro Diagnostic Products, High Complexity Molecular-Based Laboratory Developed Tests, SARS-CoV-2 Antibody Tests. Personal Protective Equipment and Related Medical Devices, and Ventilators and Other Medical Devices.
For example, last week the FDA approved convalescent plasma under an EUA. The FDA cited what was learned about the efficacy and safety of convalescent plasma in the authorized Investigational New Drug studies.
The EUA was issued despite the fact that COVID-19 Treatment Guidelines Panel concluded that there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19 and that plasma should not be considered the standard of care for the treatment of patients with COVID-19. For more information, please read the full statement on the COVID-19 Treatment Guidelines website.
Another example is hydroxychloroquine. A couple of months ago the FDA authorized the use of hydroxychloroquine as a treatment for COVID-19 under an EUA. However, the FDA later removed the EUA after evidence was discovered that the harms of using hydroxychloroquine for treating COVID-19 exceeded the benefits.
Which Path will COVID-19 Vaccines Take?
Every vaccine in use so far has gone through the traditional FDA approval process. Phase I, Phase II and Phase III followed by the traditional data review process. Vaccines have needed to establish that they are safe and effective and publish that data publicly. If the review is successful it is approved. Sometimes the vaccine is approved for just certain populations.
For example, the first time the HPV vaccine was approved it was licensed just for females because they only tested the vaccine in women. That has since been expanded to males after additional clinical trials and a modified approval process.
The COVID-19 vaccines in development might take an alternative route. Because of the public health emergency status, the FDA has the authority to authorize vaccines for use among the general public before it’s formally approved under an EUA.
Making that choice would be unprecedented. It would mean that the vaccine becomes available for general use without the rigorous review process. Additionally, the FDA could even elect to not publish the data that they considered for their EUA review.
Fortunately, in a joint letter signed this morning, the manufacturers of the vaccines currently under development have agreed to complete Phase III trials before applying to the FDA. However, the statement doesn’t commit to seeking full approval of the vaccine leaving emergency use authorization on that table. Such a move would short-circuit the FDAs data review and approval vetting process.
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Always make the safety and well-being of vaccinated individuals our top priority.
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Continue to adhere to high scientific and ethical standards regarding the conduct of clinical trials and the rigor of manufacturing processes.
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Only submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA.
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Work to ensure a sufficient supply and range of vaccine options, including those suitable for global access.
Editorial Note I: Waiting for the normal review process and official approval before distributing the vaccine to the general public would take an additional 6 to 8 weeks. During that time, the review team would have time to analyze the data and determine whether the vaccine is safe and effective and in what doses and to determine whether there are any sub-populations who may have adverse effects.
However, there will be intense pressure in some circles for the FDA to issue an EUA rather than the full licensing review. That may work out in the end, bit it might not. And with several vaccines in the pipeline, even if the first one doesn’t work or had adverse effect there will be several others right behind it.
If a vaccine is distributed under an EUA and it doesn’t work out and there are bad adverse effects or if it’s ineffective but distributed anyway, it could do serious and lasting damage the overall confidence that vaccines are safe and effective- and that could have longer-lasting deleterious effects to public health. Something to think about as we approach the end of the Phase III trials.
Editorial Note II: The Association for State and Territorial Health Officials (ASTHO) put out a clear statement urging the FDA to complete Phase III trials before making a decision either through an EUA or via Approval to release COVID-19 vaccine to the public. Here is an excerpt from their statement last week:
“Our nation’s health officials are concerned by recent statements from FDA Commissioner Hahn and NIAID Director Fauci indicating they would consider authorizing the use of a COVID-19 vaccine prior to the completion of phase 3 clinical trials. The safety and efficacy of vaccines is paramount to protecting the health of the American public and to building confidence in our state and territorial immunization programs.
“The nation’s health officials strongly encourage FDA to require the completion of phase 3 trials—or an equally rigorous evaluation—prior to approving a COVID-19 vaccine. Leadership must use the best available science to guide vaccine distribution decisions and timelines.”
“We must also address concerning racial and ethnic inequities in vaccination rates and speak to the mistrust that many Americans have of governmental immunization efforts. Vaccinations are a monumental public health accomplishment built on decades of research and transparency by the world’s scientists. We must work together to ensure the COVID-19 vaccine builds upon this legacy.”
