By Invitation . Clinical Trials during an infectious outbreaks: More questions than answers

The world is facing a pandemic of COVID-19, for which there is no effective therapy. And any new therapy can be used in medical practice only if its efficacy is proved in clinical trials.

But the experience of previous outbreaks such as Ebola show that there are scientific and ethical challenges in planning clinical trials in patients with serious infections.

The first challenge is the choice of therapy. As there is no time for research and development of new drugs in a pandemic, so therapies already approved by health authorities, with known safety profile, are investigated. These could be tried, provided there is scientific evidence about their potential efficacy, based on biological mechanisms studied in laboratory or animal studies. However, approved standard doses of therapy may not be considered effective. If higher doses are to be investigated, there should be robust justification based on lab, animal, and human studies. But the risk of side effects would also be higher. And since there is a need for rapid action, health authorities and ethics committees expedite the approval process, with limited information available to evaluate the risk-benefit ratio of the investigational therapy.

The second challenge involves the selection of patients. In epidemics, clinical trials usually include adult serious patients who are hospitalized. The therapy has less of a chance of working in patients admitted late and suffering from serious irreversible organ damage. So, the physician should try to include patients suffering from a mild infection of short duration of illness. This would be practically demanding considering the delay in appearance of symptoms.

The third challenge is to do with the design of the clinical trial. For assessment of a new therapy, the best evidence comes from a Double Blind Randomized Controlled trial. Double blinding means that the participants and the physicians are not aware of which group of participants have been assigned to the active treatment or the inactive placebo. This reduces the risk of intentional or unintentional bias of patients and physicians, who are aware of which participants are getting which therapy.

High expectations from a new therapy could influence a patient’s reporting of clinical symptoms or the physician’s judgement in assessing subjective effects of the therapy. During an outbreak there is no time to manufacture good quality placebo. Hence, these would be open clinical trials, without blinding, comparing two groups: one that is given a combination of investigational therapy + standard care, and the other that group that’s given only standard care.

Randomization is a powerful method to reduce risk of bias in open trials. It means, each participant has an equal chance of being in any of the 2 groups. For the patients and family, randomization means accepting choice of receiving only standard care, when a potentially beneficial new therapy is available. For the physician, it would be unethical and impractical to ask the patients to consent to a randomized trial.

Informed consent, which is a patient’s voluntary agreement to participate in a clinical trial, requires an understanding of the relevant information. Seriously ill patients, who are vulnerable with impaired decision-making capacity, would not be able to make an informed decision. In addition to the challenges of language of consent and literacy level, the physician wearing full personal protective equipment would find communication with the patient difficult. Even the consent from family members may not be possible as they may be quarantined or hospitalized.

Due to such ethical challenges, most clinical trials in epidemics are open non-randomized single arm trials, where all patients receive the investigational therapy and standard care. Results of such trials provide early indication of activity but cannot be considered evidence of efficacy of the treatment. Additional well designed randomized blinded clinical trials would be necessary to establish efficacy of the investigational therapy for wider usage in population. As the severity of epidemic may diminish in few months, and number of patients decrease, planning another trial would be virtually impossible.

But the media’s interpretation of outcomes of an open clinical trial, and high societal pressure may influence health policy makers to support wide use of a still to be fully proved therapy. Which explains why planning a clinical trial during an infectious disease outbreak raises more questions, even as it offers few answers.

The writer is a consultant on clinical research and therapy development. Views are personal

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