Linda Mobula MD, MPH Johns Hopkins School of Medicine April 25, 2017

THE ETHICS OF CONDUCTING MEDICAL RESEARCH DURING A HUMANITARIAN CRISIS

Disclosure

• No disclosures to report

Overview of Ebola Virus Disease

• Ebola virus was identified after a Belgium nun died in Zaire (DRC) in 1976

• Simultaneous outbreak in Sudan in 1976

• Viral hemorrhagic fever with high case fatality rate and severe morbidity

• Emerging zoonotic disease, likely from consumption of bushmeat or contact with fruit bats

In September 1976, alarming news started oozing from Yambuku

“An increasing number of patients are coming to the hospital with malaria-like symptoms that do not respond to the usual drugs… and with diffuse bleeding”

Discovering the agent of the outbreak

(Alexander, 2015)

West Africa Ebola Outbreak • The 2014 West Africa Ebola outbreak was unprecedented

• Geographic scope • Duration (December 2013-June 2016) • Number of people affected • Required a humanitarian response

• Second order impact

• Socio-economic loss • Mortality

WHO, 2016

Public Health Emergency of International Concern (PHEIC)

• The first meeting of the World Health Organization Emergency Committee was convened in August by the Director-General under the International Health Regulations (2005)

• In view of the virulence of the disease, potential for additional international spread, risk for global health security, limited and grossly inadequate response capacity, the World Health Organization declared this outbreak to be a Public Health Emergency of International Concern.

Case Study: Compassionate Use of Zmapp

• On August 31,2014, KB and NW were first humans to receive Zmapp,

an experimental treatment for the treatment of Ebola Virus Disease

• Zmapp is a cocktail of 3 monoclonal antibodies against the glycoprotein surface of EBOV

• Trials in non human primates found that Zmapp conferred a survival

benefit in infected nonhuman primates when administered 24 to 48 hours after infection, also if started 4-5 days after infection

• Limitations: never been used in humans a the time of its

administration

Evacuation of US EVD patients to US

WHO Ethics panel

• On August 11, the WHO convened a panel in response to use of Zmapp in Monrovia

• “It is ethically acceptable to offer unproven interventions that

have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention”

• After this meeting, within months, under the oversight of

national, international and academic ethics committees, a number of clinical trials were allowed to be conducted, testing novel or repurposed therapeutic agents, vaccines and convalescent plasma.

EVD Clinical Management

• MSF Guidelines were only existing guidelines at the onset of the outbreak

• No scientifically proven treatment at the time of the outbreak

• Treatment is mostly supportive • Fluid administration (PO and IVF) • Treatment of co-infection (malaria, bacterial

infections, etc.) • Electrolyte repletion • Symptomatic treatment

PREVAIL II trial • PREVAIL II (Partnership for Research on Ebola Virus in Liberia II) is a

randomized controlled trial of ZMapp in patients with a diagnosis of acute Zaire ebolavirus (EBOV) infection

• Enrollment: March 2015-November 2015

• Ebola treatment units capable of providing the current standard of care were selected as trial sites by regional partners

• Objective: determine if a combination of ZMapp plus the current standard of care was both safe and superior to the current standard of care alone in managing EVD

PREVAIL II Results- Comparison of 28 Day Mortality

Case Study II: WHO Ebola Ring Vaccination Trial

WHO Ring Vaccination Trial ● Trial was led by the World Health Organization and the

Government of Guinea ● VSV-ZEBOV is a recombinant, replication competent vesicular

stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus.

● Open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!)

● Among the 5837 people who received the vaccine, no Ebola cases were recorded 10 days or more after vaccination

WHO Vaccine became part of response, Guinea 2016

Public Health Crisis and Research • The West African Ebola accelerated the launch of clinical trials of

potentially lifesaving interventions, which were tested in the course of a major public health crisis.

• Severe acute respiratory syndrome (SARS) coronavirus and H1N1 influenza pandemic led to similar discussions

• H1N1 influenza pandemic was projected to precipitate the need for increased critical care resources for many patients worldwide, as 10-25% of these patients were expected to die.

• Need to understand epidemiology, but also to conduct high-quality diagnostic, therapeutic, and health services research that maximizes the chance of improving outcomes.

Do No Harm • Both an ethical principle and a humanitarian principle

• Abuse of vulnerable persons under the auspices of research has

been documented throughout history • When mortality rates are extremely high and there is no proven

treatment for a disease, this principle can be considered for the following Can act as a trigger to accelerate research when case fatality rates are high Protective: Limits the use of untested investigational drugs due to uncertainty

about safety or efficacy

• Dealing with uncertainty

Informed Consent • Should there be alternate models for informed consent during an

emergency (for critically ill patients) Deferred Waived A priori

• Conditions have been proposed under which informed consent

could be waived. When all treatments offered in the trial do not involve more than minimal

additional risk in comparison with alternatives When treatments offered in the trial could be offered outside the trial without

informed consent

Clinical Trial Design during a PH emergency • Clinical research is essentially justified by a public health imperative

that outweighs the medical obligation to provide optimal medical care (Calain, MSF)

• The magnitude of risk (50-90% death) would probably be felt as

high enough for most of us to rationally accept the uncertain risk/benefit of receiving an unproven intervention, provided that scientific and ethics oversight are guaranteed (Calain, MSF)

• Should individuals be randomized to “standard of care” when it is known there are high case fatality rates associated with standard of care and there is no scientifically proven treatment?

Randomized Controlled Trials • The primacy of RCT versus the understanding of ‘compassionate’

use continues to be debated

• National Academy of Science concluded that RCTs are ethical and most reliable way to identify the relative benefits and risks of investigational products, and except in rare circumstances, every effort should be made to implement them during epidemics.

• RCTs may be the most ethical trial design, because they offer the fastest route to identifying beneficial treatments while minimizing the risks of exposure to potentially harmful investigational agents.

Challenges with Research during a Humanitarian Emergency • IRB processes are lengthy

• Individual versus collective benefit

• Scarcity of resources during a humanitarian emergency

• Trial design

• Community perception (fear, distrust, etc.)

• Feasibility, acceptability and design of proposed interventions

Lessons Learned • Research and development of therapeutics and vaccines is a long,

complex, and expensive process • Community mistrust, feasibility of a standard-of-care-only arm, the

high and variable mortality rate, limited product availability, and the potential conflicts between research and care -- are likely to recur in future epidemics.

• Clinical research program needs to be mobilized rapidly • Engage communities and establish mutual trust

• Consider compassionate use of investigational drugs

References • 1. WHO. Ethical considerations for use of unregistered interventions for Ebola viral

disease. Report of an advisory panel to WHO. • 2. Cook D, Burns K, Finfer S, et al. Clinical research ethics for critically ill patients: a

pandemic proposal. Crit Care Med 2010;38(Suppl 4):e138–42 • 3. Calain P The Ebola clinical trials: a precedent for research ethics in disasters

Journal of Medical Ethics Published Online First: 29 August 2016. • 4. The PREVAIL II Writing Group, for the Multi-National PREVAIL II Study Team. A

Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med 2016; 375:1448-1456. October 13, 2016

• 5. Alexander KA, Sanderson CE, Marathe M, Lewis BL, Rivers CM, Shaman J, Drake JM, Lofgren E, Dato VM, Eisenberg MC, Eubank S. What factors might have led to the emergence of Ebola in West Africa? PLoS Negl Trop Dis. 2015 Jun 4;9(6).