Bioethics Forum Essay
Ethics and Evidence in the Search for a Vaccine and Treatments for Covid-19
During public heath emergencies like the Covid-19 pandemic, when no known preventive or effective treatment exists, researchers understandably want to start conducting studies with humans as soon as possible to find a vaccine and therapeutic treatments that are safe and effective. This was true during the 2013-2016 outbreak of the deadly Ebola virus in three west African countries (Guinea, Liberia, and Sierra Leone) and during the 2015-2016 Zika epidemic in Brazil and other parts of South and North America. Yet in the rush to find a Covid-19 vaccine and one or more drugs to treat the deadly disease, concerns are being raised that ethical standards for conducting human clinical trials, and the evidentiary standards for determining whether interventions are safe and effective, might be loosened.
One issue of concern is that the U.S. Food and Drug Administration (FDA) gave the National Institutes of Allergy and Infectious Diseases permission to test the experimental vaccine mRNA-1273 in healthy research participants even though there is no safety data about the vaccine from preclinical animal studies. Vaccine trials typically are initiated in human studies only after data from animal studies provide evidence that the vaccinated animals did not experience serious side effects and that they developed immunity to the disease in question. The FDA is requiring animal studies with the mRNA-1273 vaccine to be conducted at the same time as the phase I human trials with healthy volunteers, but there is no publicly available information about what parallel animal vaccine trials are in progress or about who is conducting those studies. Moreover, since the consent form for the phase I vaccine trial is not publicly available, it is unclear what healthy individuals were told about the potential risks of receiving doses of the mRNA-1273 vaccine and from what sources such risk information was obtained. Did they know, for example, that any information about risks did not come from testing the vaccine in animals?
At the same time that scientists are racing to test vaccines in humans, they are also testing the safety and efficacy of Covid-19 drugs in humans. Yet there is growing pressure—including from President Trump—for physicians to treat patients with some drugs that have not been tested in humans or approved by the FDA to treat Covid-19 in the clinical setting. For example, the president and others have claimed that chloroquine and hydroxychloroquine, both of which are approved by the FDA to treat malaria and certain autoimmune diseases, might be effective treatments for COVID-19, even though there is no valid evidence of effectiveness from human clinical trials. In the few studies that have been conducted, there were a small number of participants and they were not randomized into a treatment group and a placebo group. The results about therapeutic effectiveness are not promising.
Despite the lack of safety and efficacy evidence from randomized controlled trials, on March 28, the FDA issued an Emergency Use Authorization (EUA) that permits physicians to use hydroxychloroquine obtained from the Strategic National Stockpile to treat certain adults and adolescents with the drug: those who are hospitalized with COVID-19, weigh 110 pounds or more, and for whom a clinical trial testing the drug is not available or participation is not feasible. By granting some patients “off-trial access” to these drugs using the FDA’s EUA, it will be difficult to track the outcomes of those patients. It will also be difficult to make reliable claims about the drug’s effectiveness in the absence of outcomes from a control group that does not receive the drug, a concern raised about a doctor at a Texas nursing home who is giving hydroxychloroquine to residents with Covid-19 and observing their outcomes. There is also the real danger of a drug shortage for patients with lupus and other autoimmune diseases who have for years been using the drug approved for these diseases.
We know from recent history that the rush to use medical interventions without adequate evidence of their safety or effectiveness has harmed patients, including breast cancer patients treated with unapproved autologous bone marrow transplants; patients with metastatic breast cancer treated with Avastin, and patients with various illnesses who went blind after receiving unapproved stem cell interventions. An important lesson about Avastin is that the FDA later revoked approval for using the drug to treat metastatic breast cancer because post-approval data established that the harms to patients outweighed the benefits. And there are scores of other examples of medical interventions that public and private insurers have paid for even after studies have shown that although they are safe, they are either ineffective or no more effective than other interventions. Of note, one prominent scientist leading a study of a drug to treat COVID-19 admits he is haunted by the Ebola outbreak and the rush to find treatments. “Then, too, doctors said they could not wait for scientific evidence, and untested drugs were given to suffering Ebola patients by optimistic physicians with noble intentions. In the long run, none of the drugs was ever approved in the United States for treatment of the disease,” he told the New York Times.
We are not eager to see Covid-19 interventions join the list of others that entered the clinic on the basis of limited or contested evidence of effectiveness and then harmed patients or proved to be ineffective. Strategies can be developed to minimize this from happening, but they will only work with commitment from scientists, physicians, policymakers, patients, and the general public.
All animal testing protocols for Covid-19 vaccines–including any parallel studies conducted while human trials are taking place–should be available from a publicly accessible research registry. And if data from parallel vaccine animal studies reveal safety concerns or show that the vaccine is not working, then the human clinical trials should be stopped.
There should also be greater transparency about the vaccine and treatment trials being conducted with human participants and about the use of interventions under the FDA’s off-trial pathways. Protocols and informed consent forms for both treatment and vaccine studies should be publicly available once they are approved by the relevant institutional review board. For example, both the protocol and the consent form (in English, Spanish, and Arabic) for the FDA’s off-trial pathway for treating certain Covid-19 patients with plasma obtained from individuals who recovered from the diseases (convalescent plasma) are available from the program’s website. This approach is a model for providing greater transparency about the use of experimental interventions with humans.
The Avastin episode highlights the potential harms to patients from interventions approved through one of the FDA’s accelerated approval pathways. It’s possible the FDA might approve a Covid-19 vaccine or treatment on the basis of efficacy data from phase II clinical trials rather than from phase III trials that test the interventions in more participants, and/or from studies other than randomized clinical trials, which establish a high bar for obtaining valid and reliable evidence of safety and efficacy. Yet the positive lesson from the Avastin case is that the FDA not only continued to monitor the drug’s safety after granting market approval, it withdrew approval even in the face of opposition from many physicians and patients when there was compelling post-approval evidence that the drug was seriously harming patients. If the FDA eventually approves a vaccine or treatments for Covid-19 through one of its accelerated drug approval pathways, the agency should mandate post-approval testing and withdraw interventions that are found to have serious side effects or to be ineffective in preventing or treating the disease. And the agency should require standardized outcomes reporting for the off-trial use of Covid-19 interventions similar to what is being done through its national convalescent treatment program. Without outcomes data from the seriously ill patients receiving off-trial access through one of the FDA’s pathways, it will be difficult to make any claims about the effectiveness of interventions in these patient populations.
Both the negative and positive lessons of the Avastin case are worth remembering while pushing as fast as possible Covid-19 candidate vaccines and potential treatments through the preclinical, human trials, and regulatory review processes.
Karen J. Maschke is a research scholar at The Hastings Center, and editor of The Hastings Center journal Ethics & Human Research (E&HR). Michael K. Gusmano is an associate professor in the Department of Health Behavior, Society, and Policy, at the Rutgers University School of Public Health and a research scholar at The Hastings Center. Twitter: @gusmano_mk. Their most recent book is Debating Modern Medical Technologies: The Politics of Safety, Effectiveness, and Patient Access (Praeger, 2018).
For more information, see The Hastings Center’s Ethics Resources for Conducting Research in Public Health Emergencies.
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