Everyone awaiting a vaccine against Covid-19 must understand this fact: Bad outcomes may happen in vaccine trials. The good news is the U.S. Food and Drug Administration evaluates these outcomes before approving a vaccine. The purpose of clinical trials is to discover what can go wrong with a vaccine, before it is administered to millions of healthy people. During my 20 years at the FDA, including as director of the Office of Vaccines Research and Review, I was directly involved in the assessment of these outcomes.
AstraZeneca reported on Sept. 9 that a single unexplained safety event occurred in the U.K. Phase 3 randomized, controlled clinical trial of the Oxford coronavirus vaccine, AZD1222. The event resulted in the voluntary pause of vaccination across all the Oxford-AstraZeneca trials to allow an independent committee to review the safety data. Subsequent reports, not confirmed by AstraZeneca, stated that the patient was afflicted with transverse myelitis, which involves inflammation along the spinal cord. The trial remains paused in the U.S.
Safety is one of the most important considerations when evaluating new vaccines, especially those being administered to healthy individuals. The initial responsibility for determining vaccine safety begins with clinical investigators and vaccine manufacturers. The FDA, as the U.S. national regulatory authority, is responsible for assuring that clinical trials adhere to the ethical and regulatory standards known as Good Clinical Practices. Further, the sponsors of investigational new drugs, such as the Oxford-AstraZeneca vaccine, are required to notify the FDA in a written safety report of any adverse experience associated with the use of the drug or vaccine that is both serious and unexpected.
With several human trials for Covid-19 vaccines and drugs occurring across many countries, there is the possibility that serious adverse events may be observed. Side effects such as pain at the injection site, fatigue, and fever occur frequently in vaccine clinical trials. These kinds of side effects are not normally reason to pause a trial. Rare serious adverse events may be observed as well in clinical trials. In fact, large clinical studies are done in part to detect potential unexplained adverse events that may or may not be associated with the vaccine.
There have been several serious adverse events reported in vaccine clinical trials over the years; not all were caused by the vaccines. In some cases, vaccine candidates have made the condition they are trying to treat worse, an outcome known as vaccine-induced enhanced disease. Examples of enhanced disease were reported in vaccine clinical trials for respiratory syncytial virus in the 1960s. More recently a dengue vaccine was observed to trigger more severe disease when given to children who had never had a dengue virus infection. The serious adverse event of enhanced disease precluded the development of RSV vaccines for decades, and although there are new generation RSV vaccines under development, none to date have been licensed by the FDA. Dengue vaccine was eventually licensed with a limited indication. It should be noted that enhanced disease has not been reported in any of the Covid-19 vaccines being tested.
We should not be totally surprised when an unexplained adverse event is observed in a clinical study. The Covid-19 vaccine trials overseen by the FDA are enrolling 30,000 or more people. In trials this size, the intent is, in addition to determining efficacy, to identify individuals who may have an unexplained adverse event that could possibly be associated with the vaccine. An independent review is required to determine whether the event is the result of a vaccine candidate or just a random unrelated illness.
When a serious adverse event is observed, it is routine for the event to be reported to the FDA. The study is either voluntarily paused by the sponsor or in some cases placed on clinical hold by the FDA. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend a continuing investigation. The clinical hold order may apply to one or more of the investigations covered by an investigational drug. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug, and no new subjects may be recruited to the study. Not all adverse events warrant a clinical hold or pause in a clinical study. This action is generally focused on rare serious adverse events. A pause in a clinical study is a routine action that occurs whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring the integrity of the trials are maintained. A serious adverse event is not necessarily a death knell for the vaccine.
Any decision to stop a clinical trial is not taken lightly by regulatory authorities. They must be allowed the time to access the cause of the rare event and weigh the risk of the serious event against the benefit of a vaccine that has the potential to save millions of lives. The adverse event needs to be investigated to determine whether it was caused by or only temporally associated with the vaccine.
The FDA will seek answers to a series of questions about the event. They will attempt to determine causality: Can the vaccine cause the adverse event, at least in certain people under certain circumstances? Was the adverse event caused by the vaccine? Will the next person who receives the vaccine experience the adverse event because of the vaccine? How frequently will vaccine recipients experience the adverse event? They will assess the strength of association: What is the relative risk? They will investigate whether the vaccine adverse event is plausible and coherent with current knowledge about the biology of the vaccine and the adverse event. They will review the characteristics of the adverse event: Are there any available laboratory tests or biomarkers that either support of undermine the hypothesis of vaccine causation?
The FDA cannot publicly comment on an active submission; however, one can rest assured that FDA scientists are combing through the data, reaching out to their counterparts in other regulatory authorities in other countries and external expert advisors if necessary to reach a conclusion as to whether clinical trials should proceed and ultimately whether the vaccine warrants licensure. Sponsors must also be transparent and forthcoming without jeopardizing the integrity of the clinical trials.
Regulators must be allowed to thoroughly review all the data prior to deciding whether they support the safety and effectiveness of the vaccine. They must maintain the public trust. The only way to do this is to make science-based decisions without external pressure from politicians and special interest groups. The FDA regulatory review process has stood the test of time. It must be science-based, and deliberate. The SARS-CoV2 pandemic is serious, and the worst in a lifetime. However, the FDA has been through this drill before with other pandemics, although other than the 1918 influenza pandemic, they were not as serious and fatal as this one.
The FDA in collaboration with its partners at the National Institutes of Health and the Centers for Disease Control and Prevention know how to do this. They must be allowed to get us through this. The FDA understands the urgency of health emergencies. If the FDA’s credibility is challenged, it will exacerbate the pandemic.
This article was originally published on Barron’s.
Barron’s. 2020. AstraZeneca’s Trial Is on Hold. It’s a Sign that the Science Is Working. Retrieved from source.