New England Journal of Medicine
September 10, 2015 Vol. 373 No. 11
http://www.nejm.org/toc/nejm/medical-journal

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Perspective
Combating Emerging Threats — Accelerating the Availability of Medical Therapies
Luciana Borio, M.D., Edward Cox, M.D., M.P.H., and Nicole Lurie, M.D., M.S.P.H.
N Engl J Med 2015; 373:993-995 September 10, 2015 DOI: 10.1056/NEJMp1508708

Life-threatening emerging or reemerging infectious diseases increasingly inspire demands for access to novel, often untested therapies. Recent concern about transmission of the Middle East respiratory syndrome coronavirus (MERS-CoV) in Asia underscores the need to rapidly evaluate investigational therapies during outbreaks, identify those that actually benefit patients, and protect against those that cause harm. Although a traditional sequence of studies in animals followed by phased clinical trials works well for many therapeutics, that process may be too slow during public health emergencies. We propose establishing a new paradigm for accelerating evaluation of investigational therapies during public health emergencies so that therapies shown to be safe and effective can reach patients as soon as possible.

The primary approach to containing outbreaks of emerging infectious diseases involves standard public health measures, such as identifying and isolating infected persons, tracing their contacts to detect secondary infections, and protecting contacts and health care workers from exposure. General supportive medical care for anyone who becomes infected is essential, in addition to use of any proven specific treatments. When such treatments are lacking, clinicians commonly try therapies on the basis of experience with other diseases (usually on the basis of a postulated mechanism of action) in the hope of improving outcomes. For example, during the 2003 epidemic of the severe acute respiratory syndrome (SARS), several small observational studies examined the use of interferon, ribavirin, steroids, and convalescent plasma.1 Unfortunately, the inability to implement properly designed trials precluded any clear demonstration of benefit, and some evaluations suggested possible harm.

During the 2009 H1N1 influenza pandemic, it was considered infeasible to establish a multisite clinical study for an investigational therapy during a public health emergency. Peramivir, an intravenously administered influenza antiviral drug under clinical development, was made available in the United States under Emergency Use Authorization (EUA) to treat certain hospitalized patients. Demand was brisk — nearly 1300 seriously ill patients received the drug.2 Unfortunately, no reliable data on effectiveness were derived from this use. Some analyses suggested that mortality was increased among patients receiving peramivir, although that finding could have represented channeling bias (if patients receiving peramivir were already “sicker” in ways that could not be readily measured). A subsequent randomized clinical trial did not demonstrate either benefit or increased mortality associated with peramivir in patients hospitalized with influenza.3 Demand for this investigational drug drove its use under EUA, but any imperative to get demonstrably effective products to people in need as quickly as possible was not fulfilled. This experience showed that a reasonable expectation of benefit doesn’t always pan out, data derived from uncontrolled use may not be interpretable, and use outside a properly designed clinical trial can delay product assessment.

In early August 2014, two Americans who became infected with Ebola virus in West Africa were evacuated to the United States for medical care. They received various interventions, including ZMapp, an investigational monoclonal antibody cocktail in early development, not previously tested in humans. Their survival from what had been considered a highly fatal disease was followed by widespread demand for access to early-stage investigational therapies for Ebola. A World Health Organization ethics panel opined that although it was ethical to offer interventions with as-yet-unknown efficacy and adverse effects as potential treatment or prevention, there was a moral imperative to determine as quickly as possible which therapies worked.4
The international medical research community rushed to conduct clinical trials of several investigational products, but trial infrastructure took some time to establish. Meanwhile, initial doses of investigational drugs, some of which existed in very limited quantities, were administered to a few patients outside a clinical trial through so-called compassionate use. In some countries, such use continued even after clinical trials were established, despite the knowledge that it could delay the gathering of high-quality evidence to identify beneficial drugs or prolong the use of harmful ones.

Moreover, substantial disagreement emerged about the types of clinical trial designs that were appropriate for rapidly evaluating unproven therapies. Some investigators argued that randomized, controlled studies comparing an investigational therapy with available supportive medical care would be unethical,5 even when a drug’s limited supply meant that some patients would receive it while others couldn’t; others argued that early randomized trials should take priority both ethically and scientifically. Several uncontrolled studies were implemented, but their design makes them unlikely to provide reliable efficacy data or adequately protect patients by detecting serious adverse effects.

In early 2015, the National Institutes of Health, in partnership with U.S. and West African academic institutions and health authorities in Liberia, Sierra Leone, and later, Guinea, implemented a common protocol in which multiple therapies, even those at very early stages of development, could be simultaneously evaluated against a shared control group in an adaptive randomized trial. In this design, the shared control group is initially given the best available supportive care until a drug is identified that improves outcomes. Once a drug is proven effective, it’s incorporated into the supportive care that all trial patients receive, and the study may continue in order to evaluate the added benefit of other investigational drugs.

The first drug being evaluated under this protocol, ZMapp, advanced more rapidly than usual to a clinical trial designed to assess both safety and efficacy (typically, efficacy trials occur much later in development). The study is very efficient because it includes frequent prespecified interim evaluations of the accruing data, employing Bayesian analytic techniques, to identify a winner or a harmful drug as early as possible. If proven effective, ZMapp will be incorporated in the control group against which other therapies are tested. This protocol is being used in both high- and low-resource settings, providing equity of access to the study drug.

The critical need for rapid availability of effective new therapies coupled with advances in product development, manufacturing, and clinical trial design create new opportunities for efficient, scientifically sound evaluation of investigational therapies during public health emergencies. The serious impact of these emergencies and the lack of effective therapies warrant moving forward with clinical testing as soon as possible. The Ebola experience indicates that the usual phased development approach can be accelerated and abridged on the basis of what’s known about the candidate product, the severity and acuteness of the disease, and the limited window of opportunity for study. In such emergency settings, it may be appropriate to accept greater-than-usual degrees of uncertainty and risk in order to move rapidly to clinical trials, with the goal of getting safe, effective therapies to patients sooner.

The common protocol launched during the Ebola epidemic could serve as a model for rapidly evaluating promising but unproven therapies in the current MERS-CoV outbreak and future epidemics. Such an approach would allow earlier clinical testing of investigational drugs to accelerate identification of safe, effective therapies and thereby make them available to patients sooner. To succeed, this model requires close cooperation among clinical researchers, product developers, and public health and regulatory authorities globally.

Public health leaders need to take action before the next new threatening infectious disease emerges. One high-priority action will be the development and prepositioning of scientifically sound and widely accepted protocols by global public health authorities, to have them ready for use at the onset of a deadly outbreak wherever it strikes. In addition, work is needed to augment global clinical trial infrastructure, streamline processes for careful ethical review of multisite international studies, and establish model agreements for managing data and addressing intellectual property issues. If we are to act on lessons learned, there is no time to waste in getting this work done.