Opinion

VIEWPOINT
Evaluating Novel Therapies
During the Ebola Epidemic
Steven Joffe, MD, The Ebola hemorrhagic fever outbreak in West Africa and efficacy in humans, provided that certain condi-
MPH poses acute and novel challenges for health policy and tions are met.”4
Department of Medical research ethics. Faced with an exceptionally virulent in-
Ethics and Health
Policy, Perelman School
fectious agent, limited resources, and danger to health Avoid Compassionate Use
of Medicine, University workers, local and international authorities struggle to The vernacular term “compassionate use” refers to the
of Pennsylvania, deploy proven public health techniques that can limit the use of an unapproved agent, outside the context of a
Philadelphia. spread of the disease.1 In the midst of the crisis, experi- scientific protocol, with the goal of benefiting an indi-
mental interventions that have never been evaluated in vidual patient with a serious, usually life-threatening
human trials have captured professional and public at- condition. In the face of a disease such as Ebola, with a
tention. The prospect of first-in-human use of these in- case-fatality rate greater than 50%, the inclination to
Viewpoint page 1297
terventions during an uncontrolled epidemic raises at administer promising but unproven new agents in a
least 4 pressing ethical questions. First, is there a role for compassionate-use manner is understandable. Com-
“compassionate use” of agents in the absence of hu- passionate use is theoretically compatible with learn-
man safety, efficacy, or dosing data? Second, given the ing; as the WHO advisory panel noted, “physicians
critical scarcity of these agents, which patients should overseeing [the administration of unproven new
receive priority access? Third, what trial designs should agents] have a moral obligation to collect and share all
be used to study these agents? Fourth, how should ef- scientifically relevant data generated…in order to
forts to evaluate experimental agents coexist with es- establish the safety and efficacy of the interventions.”4
tablished clinical and public health interventions to treat Allowing considerations of rescue rather than sci-
patients and to minimize spread? entific hypotheses to drive use of novel agents, how-
Two fundamental principles should guide re- ever, risks compromising the acquisition of knowledge
sponses to these questions. Decisions must aim to pre- needed to clarify their role in the next epidemic and ul-
vent the maximum number of deaths during the cur- timately to maximize benefits for patients. In addition,
rent outbreak. Equally important, policy makers must particularly in the first-in-human setting, a compassion-
seek to optimize knowledge gained for use in confront- ate use approach will not necessarily prevent more
ing future Ebola epidemics. deaths than would administration of the drug in a well-
designed clinical trial. Moreover, when the novel agent
Experimental Interventions for Ebola is scarce, clinicians and health system authorities will
A small biotechnology company, Mapp Biopharmaceu- need to confront the difficult question of who among the
tical, has conducted preclinical testing of ZMapp, a pas- many deserving patients should receive access regard-
sive immunotherapy that combines 3 humanized mono- less of whether a compassionate use or clinical trial
clonal antibodies produced in Nicotinia plants. A recent framework is adopted. For these reasons, policy mak-
trial of this product, administered up to 5 days after ex- ers should advocate for clinical trials organized around
perimental inoculation of macaque monkeys with a viru- appropriate scientific questions, rather than endorsing
lent Ebola strain, suggests impressive efficacy at pre- compassionate use.
venting lethal disease.2 Based on these data, 6 health
workers and a priest have received doses of ZMapp, and Emphasize Patient Benefit and Scientific Gain
media reports suggest that at least some of these pa- in Decisions About Access
tients benefited from the product. However, the abso- In the short term, production of ZMapp and other novel
lute scarcity of the product—the available supply is de- agents will be insufficient to provide these therapies to
pleted, and scaling production will take months—limits all patients who might benefit. As a result, clinicians
broader access. Other novel agents under develop- and health authorities will inevitably need to ration the
ment may also have a role and may be more amenable available supplies. In the context of clinical trials, deci-
to rapid scale-up of production.3 sions about eligibility criteria should incorporate judg-
Prompted by the controversy surrounding this im- ments about 2 factors: which patient groups are most
munotherapy product and other novel agents, the World likely to benefit from receiving the agent and which are
Health Organization (WHO) convened an expert panel most likely to generate scientific insights that will
Corresponding
Author: Steven Joffe,
on August 11, 2014, to advise on its role. The panel “con- inform its evidence-based use in the next epidemic.
MD, MPH, Department cluded unanimously that it would be acceptable on both The inclination to conduct initial trials among critically
of Medical Ethics and ethical and evidential grounds to use as potential treat- ill Ebola patients, rather than among patients with less
Health Policy, 3401
ments or for prevention unregistered interventions that advanced disease, will be strong. However, in the
Market St, Ste 320,
Philadelphia, PA 19104 have shown promising results in the laboratory and in macaque trials that ought to inform design of the first-
(joffes@upenn.edu). animal models but have not yet been evaluated for safety in-human studies, ZMapp was effective when adminis-

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tered within 5 days after experimental inoculation. Extrapolating Some will argue that it is unethical to randomize patients with
from this preclinical experience—and acknowledging that evidence a disease that has a 55% to 60% short-term case fatality rate to a
about the efficacy of this form of immunotherapy when adminis- control group when an intervention that holds any promise for re-
tered late in the course of infection is lacking—both patient-benefit ducing their likelihood of death is available. This objection does not
and scientific rationales suggest limiting eligibility in the initial trials consider that, given the scarcity of the drug, a finite number of pa-
to patients with early rather than advanced disease. Furthermore, tients will receive access regardless of what study design is used. It
in situations of extreme scarcity of therapy, considerations of con- also fails to acknowledge that alternative means for prioritizing ac-
sent, reciprocity, and logistics might justify prioritizing health care cess, such as first-come first-served and sickest first, are them-
workers and others on the front lines of the Ebola epidemic for selves ethically unsatisfactory.5 Especially in the setting of abso-
access to trials. lute scarcity of the novel agent, where nothing ethically is lost by
allocating access through a lottery,6 randomization should begin with
Use Randomization in Study Design the very first trials.7
Given the urgent circumstances, individuals and organizations in-
volved in planning clinical trials may consider administering the ex- Protect Clinical and Public Health Infrastructures
perimental agent to a consecutive series of patients and then at- Perhaps most important in confronting the present epidemic, ef-
tempt to evaluate its safety and efficacy in light of what is known forts to evaluate novel agents risk diverting attention and human and
about the natural history of the disease. This would be a mistake. material assets from proven therapeutic and public health
Investigators should instead move directly to randomized trials that measures.4 Well-motivated initiatives directed at promising new
compare best supportive care plus an experimental agent with best therapies must not jeopardize existing health infrastructures. Rather,
supportive care alone. Without a concurrent randomized control local and international health authorities must ensure that the re-
group, individuals who receive the drug will differ systematically from sources needed to conduct clinical trials represent dedicated addi-
the untreated individuals with whom they are compared. Study par- tional capacity. Without attention to this issue, efforts to study novel
ticipants may be sicker or less ill, younger or older, or identified at agents may ironically increase, not reduce, the death toll from this
an earlier or later stage of disease than those in historical—or even epidemic.
contemporary—comparison groups. These differences will con-
found efforts to reach valid inferences about the safety and effi- Moving Forward
cacy of the drug. Scientifically and ethically justified use of scarce new agents in the
Objections to the use of randomization in the midst of a dev- midst of the Ebola epidemic, or any other epidemic for which novel
astating epidemic will center on ethical and scientific concerns. Sci- agents hold promise, requires reflection on the understandable de-
entific questions will focus on whether dose-finding and feasibility sire to rescue imminently dying patients. Clinicians, investigators, and
considerations require a pilot single-treatment group, uncon- policy makers must deploy novel agents in ways that address press-
trolled trial. Yet even these preliminary questions are best an- ing scientific questions, prioritize research in populations that will be
swered in the context of a randomized control group. Further- most scientifically informative as well as most likely to benefit, en-
more, it is possible that early hints of either efficacy or serious toxicity sure valid answers through the use of supportive care controls, and
in an uncontrolled trial, even if difficult to interpret given inevitable protect critical clinical and public health resources from diversion to
selection biases, will derail the possibility of conducting a subse- longer-term aims. By doing so, they can maximize lives saved in the
quent randomized trial. present epidemic and ensure knowledge gains for the next.

ARTICLE INFORMATION 2. Qiu X, Wong G, Audet J, et al. Reversion of 5. Persad G, Wertheimer A, Emanuel EJ. Principles
Published Online: September 11, 2014. advanced Ebola virus disease in nonhuman for allocation of scarce medical interventions. Lancet.
doi:10.1001/jama.2014.12867. primates with ZMapp [published online August 29, 2009;373(9661):423-431.
2014]. Nature. doi:10.1038/nature13777. 6. STREPTOMYCIN treatment of pulmonary
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for 3. Hampton T. Largest-ever outbreak of Ebola virus tuberculosis. Br Med J. 1948;2(4582):769-782.
Disclosure of Potential Conflicts of Interest. Dr Joffe disease thrusts experimental therapies, vaccines 7. Chalmers TC. Randomization of the first patient.
reports being a paid member of a data monitoring into spotlight [published online August 27, 2014]. Med Clin North Am. 1975;59(4):1035-1038.
committee for Genzyme/Sanofi until November JAMA. doi:10.1001/jama.2014.11170.
2012. 4. Advisory Panel to the World Health
Organization. Ethical considerations for use of
REFERENCES unregistered interventions for Ebola viral disease.
1. Gostin LO, Lucey D, Phelan A. The Ebola http://apps.who.int/iris/bitstream/10665/130997/1
epidemic: a global health emergency. JAMA. 2014; /WHO_HIS_KER_GHE_14.1_eng.pdf?ua=1&ua=1.
312(11):1095-1096. August 11, 2014. Accessed September 1, 2014.

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