Normally, it takes about eight years to move a drug through clinical trials and approval by the US Food and Drug Administration. In the current pandemic, patients don’t have this time to wait for COVID-19 therapies. How can we responsibly speed innovation, access to experimental medicines, and FDA approvals during this public health emergency?
There is no shortage of calls to act more quickly in response to this pandemic. Mike Ryan, the executive director of the health emergencies program at the World Health Organization (WHO), for example, urged everyone at a press conference this week: “Be fast. Have no regrets. . . . The virus will always get you if you don’t move quickly. . . . If you need to be right before you move, you will never win. . . . Everyone is afraid of the consequence of error. But the greatest error is not to move. The greatest error is to be paralyzed by the fear of failure.”
Putting aside the ethics of acting without due caution or data, it’s worth noting that the US has been accelerating the drug approval process and approving drugs with less evidence for years. FDA drug reviews now take less than one year, and just 53 percent of drugs are approved based on at least two pivotal trials, in contrast to 81 percent in the past. It is also no longer uncommon to see a drug approved largely on Phase 2 data, without a completed Phase 3 trial, particularly in oncology.
See “Picking Up the Pace”
Still, this acceleration isn’t enough in this pandemic. Undertaking clinical trials is usually the best way to advance drug development and get experimental drugs to patients, but their timelines and strict inclusion criteria leave a lot of patients without drug access for many years.
There is a chance that doctors intubate COVID-19 patients earlier than normal to qualify them for the group expanded access program.
A next best option can be expanded access programs, designed to provide experimental medicines to patients with serious conditions who cannot enroll in a trial. They allow for drug safety and efficacy data collection, thus aiming to support both drug development and access. Ultimately, each drug’s manufacturer must agree to provide drug access and have sufficient supply to meet requests. The question is: What is the likelihood that expanded access programs can work in the face of this pandemic?
Take Gilead’s remdesivir, a promising COVID-19 drug according to the WHO, as an example. Aside from severely ill children, pregnant women, and Department of Defense workers, patients seeking access to remdesivir for COVID-19 must enroll in a clinical trial or Gilead’s expanded access program. The expanded access program is for severe acute respiratory syndrome coronavirus patients who are hospitalized and require mechanical ventilation. Typically, doctors can also request expanded access to experimental drugs for individual patients outside of group programs. However, Gilead suspended individual requests in late March.
The ethics of suspending individual expanded access requests are challenging. On the positive side, group programs save time. Individual requests require time-consuming reviews by several parties—a taxing prospect when thousands of requests flood a system within a short period of time during a pandemic. However, there is a chance that doctors intubate COVID-19 patients earlier than normal to qualify them for the group expanded access program. There is anecdotal evidence of this happening. In these cases, doctors likely determine that the risks of early intubation are offset by the potential benefits of gaining access to remdesivir, despite the lack of final clinical trial data. Access then can become a function of how well and willing a doctor is to work around the expanded access system for their patient, yielding an inherently unequal system.
In mass critical-care events, such as the current pandemic, bioethics generally gives way to public health ethics. Whereas bioethics traditionally focuses on the health and interests of individual patients and the private doctor-patient interaction, public health ethics focuses on groups and decisions by authorities responsible for large numbers of people. Bioethics tends to be guided by principles such as respect for an individual’s autonomy, while public health ethics on social justice and the just distribution of social resources.
This shift in ethics orientation is seen as critical to saving the most lives. In pandemic triage, for example, we usually prioritize those most in need and most likely to benefit. Additionally, we see who will benefit the fastest, with the least resources. If you can save two people in the time that it would take to save one, the choice is clear. This isn’t good news for the one patient.
Today, physicians at the front lines of this pandemic face challenging issues. Should they remain patient centered, working around systems to get their COVID-19 patients access to experimental drugs and other interventions? If so, they aren’t necessarily thinking about other patients or the big picture, but they are thinking about the health of their patient right in front of them. In this scenario, a doctor remains a patient advocate while a company, such as Gilead, focuses on population health outcomes. This may not maximize lives saved and it may exacerbate inequalities. And it could very well influence doctors’ decisions, such as intubating sooner to give their patients access to an experimental treatment. But it may also protect doctors from feeling like they abandoned their patients. These are hard choices. Hospital ethics committees and the US Centers for Disease Control and Prevention should provide guidelines—ideally with stakeholder input, including the patient voice—to help make these ethical decisions.
The FDA is working closely with innovators to expedite their efforts, leveraging scientific information about the virus and about ongoing clinical trials around the world. We are confident that these efforts will have a major positive effect on this pandemic.
John D. Loike is a professor of biology at Touro College and University Systems and writes a regular column on bioethics for The Scientist. Jennifer E. Miller is an assistant professor at Yale School of Medicine and is the founder of Bioethics International and the Good Pharma Scorecard. Follow her on Twitter @millerbioethics.