Clinical Researcher—April 2020 (Volume 34, Issue 4)

ETHICS IN ACTION

Lindsay McNair, MD, MPH, MSB

As I write this column, COVID-19, the illness cause by the SARS-CoV-2 virus, is wreaking havoc on societies and healthcare systems across the globe. COVID-19, which was officially declared a pandemic by the World Health Organization (WHO) on March 11, 2020, is an infection that attacks the lungs, causing significant damage from both the infection and the resulting immune response. Any numbers will be completely out of date at the time this column is published, so I will say only that the United States and the majority of countries affected are still on the uphill side of the incidence peak, with various forms of social engineering being used to try to “flatten the curve” and reduce or spread out the total number of cases so that healthcare systems are not overwhelmed.

Of course, the very reasonable questions being asked in this situation are about what else we can do. Is there a vaccine that can reduce the size of the population at risk? Are there therapies that can minimize the chance of significant disease once infected, or that can support those who have severe lung complications to increase the survival rate? (Actually, we know there are not, because how could we have developed ways to treat a virus that we’d never encountered before?)

We’ve Been (Close to) Here Before

Which brings us to our current position of doing research in the midst of a pandemic. It’s not the first time that the international research community has encountered this kind of situation.

In September 2014, an Ebola outbreak in West Africa brought this issue to everyone’s attention. The world prepared for the possible spread of the infection, and the research community directed resources toward potentially effective therapies. However, with no research infrastructure ready to come into place quickly, and difficult ethical questions being continually debated, it was six months before one of the most promising agents was first dosed in a clinical trial in March 2015. That seems like a fairly speedy start up process for most clinical trials, but in an epidemic, it is an eternity.

The Ebola trial was able to dose only 72 participants between March and November 2015, and closed enrollment in January 2016, far below the intended sample size of 200 participants, due to the decreased incidence of new cases in West Africa. While the end of the outbreak was good news, it also meant that the question of the efficacy of the study drug could not be definitely answered from the resulting underpowered study, leaving us unprepared for the next outbreak.

Where to Now?

So how can we prepare in advance for research in epidemic settings, in a way that will let us prioritize experimental agents, launch trials quickly, collect data cleanly, and get rigorous answers? The following are some of the things that the international clinical research community can think about, and ideally decide, in order to prepare.

First, and most basically, we can create the skeleton of a clinical trial design that allows rapid adaptation to the specifics of the clinical characteristics of the epidemic, and a quick launch into place once potentially promising agents are identified. Platform studies, which allow the assessment of multiple potential agents, either in parallel or sequentially (first with one agent, then when that one reaches an efficacy or futility determination, moving on to the next agent in the same trial), may be ideally suited for this.

In the COVID-19 outbreak, the WHO has already announced the initiation of a platform study called SOLIDARITY, designed to assess four different study drug regimens.{1} The study, which does not have a control arm, will accept online registration of potential participants by the treating physician, with consent e-mailed to the site and returned electronically. Randomization assignment will then be given based on which of the agents are already available at the local institution.

The SOLIDARITY trial is designed to minimize burden on caregivers with regard to administration and data collection, given the stress they are under to provide clinical care. This is a significant consideration; in these settings, the investigators may very likely be research-naïve, and trial sponsors will have to think about which data are absolutely essential to collect rather than interesting to have.

Thinking Things Through

Second, the global clinical research community and research ethics community can also discuss and try to come to consensus on some of the ethical questions and priorities—or to at least narrow the discussions so there are fewer real-time decisions to be made. For example, should clinical trials in epidemics include a standard therapy control group if we know the response to standard therapy is poor, or should everyone enrolled get an experimental agent? Giving everyone access to (unproven) study drugs feels more like “doing something,” but it could also mean doing something even more harmful than nothing.

Along those lines, what should be the role of expanded access/named patient/compassionate use programs, which provide experimental therapies in a way that collects little or no data to be able to assess outcomes? Should there be a minimum level of data that indicates a favorable balance of efficacy and safety before making a product widely available? This question becomes even more important when the therapy is already marketed for a different purpose, and the only thing limiting its use is the behavior of prescribers.

We are seeing this in the COVID-19 setting, where a very small, poorly controlled, self-published study touting the antiviral effects of a certain medication has set off worldwide prescribing and even hoarding of the medication, with the well-designed clinical trials barely begun. If preexisting “miracle” drugs can be accessed anyway and patients, families, and the media are convinced that they will work, it may be very difficult to conduct controlled trials on any of them now.

Who should get first priority for clinical trial enrollment—healthcare providers who are most at risk? Should children be enrolled in early studies, or should enrollment of children wait until data are collected in adults?

In any epidemic setting, the specific characteristics of the epidemiology and clinical picture will certainly impact decisions. For example, since COVID-19 seems to largely (although not completely) spare the very young, considerations about enrolling children are not being widely debated, although they might in a different epidemic where young people were more at risk.

Similarly, the design of the intervention and intended use will also guide some of these questions; in a study of post-exposure prophylaxis, healthcare workers who are being frequently exposed to the pathogen may be the best population in which to conduct the study most efficiently. Control arms may be considered widely acceptable if the study only includes patients with mild disease.

So, we can’t answer every question in advance, but we can list the questions that we will need to think about and form a group that can be prepared to come together and resolve them on short notice.

The Risk of Losing Focus

Third, perhaps the biggest challenge to planning for research in a future epidemic may be driving both interest and resources to prepare for a crisis that has not yet, and perhaps may never, actually happen. Dr. Peter Hotez started working on a vaccine against coronaviruses in 2003, after the initial SARS outbreak, and he and his team had a candidate ready to go into human trials in 2016.{2}

However, with no apparent risk from coronavirus at the time, Hotez was unable to get funding to move his project forward and clinical trials were never started. Flash forward to today, and it will take months for his team to get back to where they were when the project was put on hold. Similarly, discussions of potential trial designs and ethical quandaries will need a strong and impartial body to organize and drive discussions forward, when it can always seem like immediate issues need to take precedence over hypothetical future ones.

Hopefully, as some of the lessons from the Ebola outbreak provided us with information to help us better prepare for COVID-19, some of the lessons we learn from COVID-19 will also help us plan for the future.