“The desire for safety stands against every great and noble enterprise.” Publius Cornelius Tacitus, Roman historian and politician
“Keeping the public committed to the important and ongoing measures necessary to ensure that prevention/control efforts are effective and that as few lives as possible are lost will require strengthening the widespread and deep trust in the science and practice of public health.” Marianne Udow-Phillips, MHSA and Paula Lantz, PhD
After learning that a participant experienced a serious neurological condition, AstraZeneca suspended its late-stage coronavirus vaccine trials in early September and initiated a safety review. Scientists, ethicists and champions of the integrity of medical research welcomed AstraZeneca’s decision. Their consensus: “This is the way science is supposed to work.” In this Germ Gem post, I’ll support this opinion and provide a brief update on the status of the “race for a vaccine”—a race that, as of this writing, AstraZeneca has rejoined.
The scientific method: a brief refresher. If you are in a field unrelated to science, you may nonetheless remember (albeit vaguely) that you once learned about the scientific method in a science course that you were probably required to take. Let’s refresh your memory.
The scientific method applies to both clinical trials research (for example, of medicines or vaccines) and laboratory-based investigations (for example, with cell cultures or animals). Generally, it proceeds from a hypothesis (derived from observations) to testing (experimentation), and analysis (i.e. do the findings support the hypothesis or not.) The goal in clinical research is to find a drug or vaccine that is not only effective, but more importantly, safe. In fact, safety is the first and foremost concern of any clinical trial.
Randomized clinical trials (RCTs): first an anecdote. Before discussing the details of the AstraZeneca situation, I’d like to provide some perspective by relating briefly my first experience as a Principal Investigator of a RCT. It was in 1989, several years before RCTs became the gold standard of evidence-based medicine. Several research colleagues and I were trying to discover the mechanism behind, and more importantly an effective treatment for, chronic fatigue syndrome (CFS), a disabling idiopathic illness, that is now called myalgic encephalomyelitis ((ME)/CFS).
Based on the clinical histories of CFS patients and some preliminary laboratory findings, we hypothesized that one or more infectious agents triggered a dysregulated immune response resulting in CFS. In our RCT, we tested the hypothesis that intravenous immunoglobulin (IVIG), a solution containing antibodies to a large number of different viruses, would neutralize these viruses and/or modulate the patients’ immune systems. It was a placebo-controlled trial; for the placebo we chose human serum albumin, a totally safe protein found in everyone’s blood.
Much to our shock, the very first patient enrolled in the study developed a serious reaction to the infusion. My research colleagues and I agreed we would end the trial because although CFS is disabling, it’s not life-threatening. As the study was double-blinded (that is, neither the patients nor the research staff knew what the patients were getting), we broke the code on this patient. Lo and behold she was receiving the placebo (albumin). We concluded she had experienced a “nocebo” effect—an adverse response to a placebo—and we went on to complete the trial. When we broke the code and analyzed the data, we disappointedly found, however, that the IVIG was of no benefit. We then revealed the results to each of the participants. One patient who had improved remarkably on the albumin infusions pleaded to continue receiving it (she was experiencing a robust placebo effect). We considered that this would be unethical and weren’t able to abide her wishes.
This is an anecdotal example of the scientific method underlying clinical trials: first, coming up with a reasonable hypothesis; second, testing it (carrying out an experiment); and third, analyzing the data. And it is basically what’s happening in the RCTs of vaccines to prevent COVID-19. But, of course with the COVID-19 vaccine trials, the stakes are enormously higher. And for the first time, as far as I know, a new challenge has arisen—politicization of the process.
Safety first: the AstraZeneca RCT. In the AstraZeneca RCT, an adenovirus-vectored vaccine (ChAdOx1 nCoV-19), developed by researchers at the University of Oxford, was being tested in a Phase 2/3 placebo-controlled trial to assess both its safety and efficacy. The trial was well underway when the decision to hit the pause button was made on September 6. (There already was promising evidence of its safety and efficacy, assessed by immune responses, from an earlier trial, at the time this larger Phase 2/3 trial commenced.) The decision to suspend the current trial across all global trial sites was based on a patient who developed neurological symptoms, subsequently disclosed to be a rare disease called transverse myelitis. (A previous pause of this vaccine trial had occurred in July, when “an undiagnosed case of multiple sclerosis” surfaced that an independent review panel concluded was unrelated to the vaccine.)
Following the most recent assessment of the safety data by independent committees and international regulators, the reviewers recommended on September 12 to Britain’s Medicines Health Regulatory Authority that it was safe to resume the British trials. AstraZeneca announced, “The Company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the vaccine broadly, equitably and at no profit during this pandemic.”
The politicization of clinical trials. As has been mentioned in previous Germ Gem posts, trust in the U.S. Federal Drug Administration (FDA) was tarnished when it issued two Emergency Use Authorizations (EUA) for the treatment of COVID-19 patients. The first, on March 28, was for hydroxychloroquine, and the second, on August 23, for convalescent plasma. In both cases, highly regarded experts in the scientific and clinical research communities were outraged by the FDA’s decisions. Given the evidence, they thought the EUAs were premature and that the FDA’s decisions were being influenced by president Trump whose enthusiasm for the EAUs wasn’t based on scientific merit but rather on political considerations.
Sadly, mistrust of the FDA has seeped over to concern about the integrity of the COVID-19 vaccine trials. The flames of mistrust have been fanned by the designation of the U.S. government’s Operation Warp Speed (OWS) to develop one or more vaccines within six months. OWS’s goal is to deliver 300 million doses of a COVID-19 vaccine by January 2021 by compressing what is normally a 73-month process of creating a safe and effective vaccine into 14 months. It is a public-private partnership in which the US government has invested at least $10 billion. While it is, of course, encouraging to see our government prioritize development of a vaccine for COVID-19, the worry is that the general public may perceive that in the effort to develop a vaccine in such a short time period, safety may be sacrificed.
Allaying safety concerns about a COVID-19 vaccine. Recently, nine pharmaceutical manufacturers that are in the process of developing vaccines issued a joint declaration stating that they would not put forward a vaccine candidate for approval unless it was safe and effective. In other words, science would not be sacrificed for speed (or, for that matter, politics). Dr. Francis Collins, director of the National Institutes of Health (NIH), was pleased by this statement—as am I.
Moreover, at a U.S. Senate Health, Education, Labor & Pensions Committee hearing on September 9, Surgeon General Jerome Adams, MD, MPH stated, “There will be no shortcuts. This vaccine will be safe, will be effective, or it won’t be moved along. And when a vaccine is approved or authorized by the FDA, I and my family will be in line to get it.” Dr. Collins agreed. “I can’t say strongly enough that decisions about how this vaccine is going to be evaluated and assessed are going to be based on science. That can be the only basis on which this decision is made—otherwise the public cannot be expected to trust us.”
Francis Collins then went on to state: “The best antidote is to say exactly what we’re doing.” This statement hits the nail on its head. Both Dr. Collins and his NIH colleague, Dr. Anthony Fauci, recognize that the trust of the medical community, as well as the American public, must be built on transparency. It is this recognition by two of our nation’s top scientists that has allayed my worries about the safety of a COVID-19 vaccine that may be developed within the next six months.
Are we in the home stretch? On a very positive note, on September 12, Pfizer Inc. and BioNTech SE proposed to the FDA to expand their Phase 3 COVID-19 vaccine trial to about 44,000 participants in order to increase the diversity of the trial population. The initial target figure for the trial was 30,000 participants, which they expect to reach by next week. But, according to their Chief Business Officer John Young, “Diversity in clinical trials is a priority for Pfizer and is critical given that COVID-19 disproportionately impacts communities of color.” If the study is successful, the companies could submit the vaccine for regulatory approval as early as October, putting them on track to supply 100 million doses by the end of this year and 1.3 billion doses by the end of 2021.
