Letters

Author Affiliations: Division of Infectious Diseases and International Health, Duke University School of Medicine, Durham, North Carolina.

Wales, Sydney, Australia (Haire); Department of Anthropology, University of California, Irvine (Peterson).

Corresponding Author: Vance G. Fowler Jr, MD, MHS, Division of Infectious Diseases and International Health, Department of Medicine, Duke University School of Medicine, PO Box 102359, Durham, NC 27710 ([email protected]).

Corresponding Author: Morenike Oluwatoyin Folayan, MBChD, MBA, FWACS, Obafemi Awolowo University, Ile-Ife, Nigeria ([email protected]).

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Holland reported being a consultant for The Medicines Co, Affinium Pharmaceuticals Inc, and Forest/Cerexa. Dr Fowler reported receiving grants from the National Institutes of Health, MedImmune, Forest/Cerexa, Pfizer, Merck, Advanced Liquid Logics, Theravance, Novartis, and Cubist; serving as chair of the scientific advisory board for V710 Staphylococcus aureus vaccine for Merck; being a consultant for Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, Cerexa, Tetraophase, Trius, MedImmune, Bayer, Theravance, and Cubist; having a patent from NCGR; receiving royalties from UpToDate; and receiving payment for educational presentations from Cubist, Cerexa, Durata, and Theravance. 1. Holden E, Bashir A, Das I, et al. Staphylococcus aureus bacteraemia in a UK tertiary referral centre: a “transoesophageal echocardiogram for all” policy. J Antimicrob Chemother. 2014;69(7):1960-1965.

Ethical Testing of Experimental Ebola Treatments To the Editor In his Viewpoint, Dr Joffe1 sought to justify the need for randomization of experimental drugs used for the management of the Ebola crisis due to the need for scientific information. He explicitly argued against the compassionate use of experimental interventions. Instead, we argue for compassionate use of experimental interventions for Ebola management in ways that do not legitimize inequitable access to resources, especially in countries where human rights violations routinely occur. We prefer access to experimental drugs through a first-come, firstserved approach for allocating scarce resources.2 We reject the notion to conduct randomized clinical trials (RCTs) during the current Ebola epidemic in West Africa on scientific and ethical grounds. First, there is insufficient stock of experimental therapies to conduct RCTs of sufficient power to test the level of efficacy. Second, observational data obtained through compassionate access programs can provide preliminary data that can be useful in designing subsequent RCTs needed for drug approval. The experience with ZMapp so far provides useful data for future trials.3 The current Ebola epidemic requires measures that can increase survival. The decision for compassionate use of experimental drugs by the World Health Organization4 is laudable, especially for countries where inadequate health systems do not provide optimum supportive therapy that could otherwise increase the rate of survival. We do not know whether the current experimental therapies are effective, but having a control group is not ethically justifiable until such time as a trial can be designed with sufficient statistical power to answer that research question. In the meantime, compassionate access can provide some preliminary data as well as give hope to patients. Morenike Oluwatoyin Folayan, MBChD, MBA, FWACS Bridget Haire, PhD Kristin Peterson, PhD Author Affiliations: Obafemi Awolowo University, Ile-Ife, Nigeria (Folayan); School of Public Health and Community Medicine, University of New South jama.com

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Joffe S. Evaluating novel therapies during the Ebola epidemic. JAMA. 2014; 312(13):1299-1300. 2. Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet. 2009;373(9661):423-431. 3. Ross W. Ebola crisis: doctors in Liberia “recovering after taking ZMapp.” http: //www.bbc.com/news/world-africa-28860204. Accessed September 1, 2014. 4. Maurice J. WHO meeting chooses untried interventions to defeat Ebola. Lancet. 2014;384(9948):e45-e46.

To the Editor Dr Joffe1 argued for the importance of randomized study designs to ensure the acquisition of scientific knowledge required for the response to the Ebola epidemic to progress, as well as to ensure ethical treatment of patients. Many calls for RCTs have culminated with the establishment, by the Wellcome Trust, of an international consortium to conduct clinical trials of experimental therapeutics for Ebola virus disease in West Africa.2 Joffe’s focus on randomization and controls appears to suggest standard RCT study designs. However, adaptive clinical trials should be viewed as the most efficient way to assess efficacy and safety, and hence the more ethical path on which to proceed. Unlike standard RCT designs, adaptive designs allow for prospective adaptations to their statistical procedures after initiation, without undermining their validity and integrity.3 Although several designs may offer efficient decision making, approaches with adaptive randomization and stopping rules, such as the play-the-winner design, provide distinct advantages. Allowing the randomization schedule to be modified to unequal probabilities of treatment based on observed probabilities of success (adaptive randomization) will reduce the number of patients exposed to less effective treatments while acquiring scientific knowledge. For example, if after the first week, the probability of survival is twice as high in the treatment group, then patients will subsequently be randomized at a 2:1 ratio in favor of treatment. Ebola treatments lend themselves well to this design because treatment duration is relatively short. Conventional RCT stopping rules allow for premature trial termination due to an overwhelming signal of effectiveness, while adaptive stopping rules allow for flexible and more ethical trial termination. An adaptive stopping rule in Ebola RCTs could be set as a maximum acceptable observed difference in mortality rates between treatments and the associated statistical certainty. The World Health Organization Ebola Response Team estimated a 70.8% case fatality rate among patients with known clinical outcomes, and the current death toll is higher than all previous outbreaks combined.4 In response, health authorities have deemed ethical the use of experimental treatments to help curb the Ebola outbreak,5 despite not following the conventional (and drawn-out) RCT process. (Reprinted) JAMA January 27, 2015 Volume 313, Number 4

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Letters

Randomization and controls are needed, and using experimental designs that further accelerate knowledge of effectiveness, such as adaptive designs, is the next logical step. Steve Kanters, MSc Kristian Thorlund, PhD Edward J. Mills, PhD Author Affiliations: School of Population and Public Health, University of British Columbia, Vancouver, Canada (Kanters); Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada (Thorlund); Stanford Prevention Research Center, Stanford University, Stanford, California (Mills). Corresponding Author: Steve Kanters, MSc, School of Population and Public Health, University of British Columbia, 2206 E Mall, Vancouver, BC V6T 1Z3, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Joffe S. Evaluating novel therapies during the Ebola epidemic. JAMA. 2014; 312(13):1299-1300. 2. Wellcome Trust. Ebola treatment trials to be fast-tracked in West Africa. http: //www.wellcome.ac.uk/News/Media-office/Press-releases/2014/WTP057419 .htm. Accessed on October 5, 2014. 3. Chow SC, Chang M, Pong A. Statistical consideration of adaptive methods in clinical development. J Biopharm Stat. 2005;15(4):575-591. 4. WHO Ebola Response Team. Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371(16): 1481-1495.

Steven Joffe, MD, MPH

5. Butler D. Ebola drug trials set to begin amid crisis. http://www.nature.com/news /ebola-drug-trials-set-to-begin-amid-crisis-1.15813. Accessed October 5, 2014.

Author Affiliation: Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia.

In Reply Dr Folayan and colleagues and Mr Kanters and colleagues offer thoughtful responses to my Viewpoint, which advocated for RCTs of therapies against Ebola virus disease and cautioned against compassionate use. Their contrasting criticisms of and support for the use of RCTs demonstrate that consensus on this controversial and emotionally charged question is far off. Folayan and colleagues correctly note that RCTs should not be performed if sample size constraints due to limited drug availability preclude valid and reliable answers to clinically relevant questions. The ethical requirements for social value and scientific validity, however, are universal and should equally preclude the use of uncontrolled designs if they are likely to yield misleading results.1 Uncontrolled trials can give accurate answers when certain stringent conditions are met, including preliminary evidence of large effect sizes and the availability of data from historical cohorts that permit valid comparisons.2 Critics of RCTs for Ebola virus disease have yet to demonstrate that these conditions can be met. The first-come, first-served, compassionateuse approach advocated by Folayan and colleagues, in which no effort is made to specify eligibility criteria for who will receive the experimental drug, would provide even less opportunity to draw valid inferences about efficacy or safety than a prospective uncontrolled trial.

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Kanters and colleagues argue that adaptive designs, in which randomization probabilities shift in response to emerging data, offer ethical and efficiency advantages over traditional fixed-ratio designs. The ultimate aim of therapeutic development for Ebola virus disease is to identify safe and effective interventions that merit substantial resource commitments from the international community and wide distribution within affected regions. The design of trials for Ebola virus disease must therefore prioritize 3 goals: (1) ensure valid and reliable estimates of efficacy and safety; (2) arrive at those estimates as rapidly as possible so that effective therapies may be implemented; and (3) maximize the degree to which study participants can benefit from the trials themselves. If adaptive designs can better achieve these goals than traditional designs, they deserve support. Critics and advocates of RCTs of novel therapies for Ebola virus disease all acknowledge the urgency of developing effective treatments for this lethal disease. Moving forward requires simulations of the candidate designs,3 with transparent and evidence-based assumptions about background event rates; consideration of a range of plausible effect sizes; and honest debate about the interpretation and policy consequences of the answers that may result from competing research approaches.

Corresponding Author: Steven Joffe, MD, MPH, Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, 3401 Market St, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being a paid member of a data monitoring committee for Genzyme/sanofi until November 2012. 1. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283(20):2701-2711. 2. Miller FG, Joffe S. Equipoise and the dilemma of randomized clinical trials. N Engl J Med. 2011;364(5):476-480. 3. Holford N, Ma SC, Ploeger BA. Clinical trial simulation: a review. Clin Pharmacol Ther. 2010;88(2):166-182.

CORRECTION Incorrect Footnote Order: In the Original Investigation entitled “Association of the 2011 ACGME Resident Duty Hour Reform With General Surgery Patient Outcomes and With Resident Examination Performance” in the December 10, 2014, issue of JAMA (2014;312[22]:2374-2384. doi:10.1001/jama.2014.15277), the footnote order of a and b in the notes below Table 4 should be reversed. This article was corrected online.

Revised Wording: In the JAMA Viewpoint entitled, “The Role of Private Payers in Payment Reform,” published in the January 6, 2015, issue of JAMA (2015;313[1]: 25-26 doi:10.1001/jama.2014.15904), part of the basis for efforts to slow health care spending was reworded. On page 25, the last sentence of the second full paragraph should read, “Combined with the sizeable share of US health care spending deemed wasteful, slowing the rate of increase of health care costs becomes increasingly important.” Additionally, on page 26, the fourth complete sentence has been omitted. This article was corrected online.

JAMA January 27, 2015 Volume 313, Number 4 (Reprinted)

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