[GRG] Ebola ethics: in defense of randomization

“On the science and ethics of Ebola treatments”, by Joanna Monti-Masel:

> …The first two patients to be treated were Americans. Prior to this came the old (and historically justified) fear of testing potentially dangerous new treatments on vulnerable populations in developing countries rather than on privileged first world patients. The first ever treatment was not given to an African doctor because of this concern [[1] “Opting Against Ebola Drug for Ill African Doctor” http://ift.tt/1mFaAW5 , by Andrew Pollack, _The New York Times_, 12 August 2014.]. After Westerners were treated, complaints rose about giving infected Westerners access to a new drug while infected Africans went without. These two concerns are obviously mutually exclusive. People are concerned, they are just not sure about what, sometimes even voicing both concerns in the same article [[2] “Ebola, research ethics, and the ZMapp serum” http://ift.tt/1kuOWIx , by Laura Seay, _Washington Post_, 6 August 2014.].
> An important worry for any drug is that it might have damaging side effects. But if there were ever a disease for which this is not a big deal, it is Ebola
> …To learn about effectiveness, we need to test these treatments on Africans, in the midst of a terrifying epidemic.
> …The WHO has given an ethical green light [[3] “Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD)” http://ift.tt/1oGI3UH , World Health Organization, 12 August 2014.] to the use of these experimental therapies, with the caveat that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’ (access to an unapproved drug outside of a clinical trial).” They mention a number of ethical issues, but leave out the one that troubles me. The unethical behavior here, which was just given a green light by the WHO, is not doing an experiment, but doing an experiment without using a control group. There should be no compassionate use exceptions. Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them.
> Five patients have received the ZMapp serum so far. Two US missionaries recovered, a Spanish priest died, and reports are not yet in for two Liberian doctors. Unfortunately, the supply is now exhausted, and we must wait until more is manufactured. Another experimental treatment, TKM-Ebola, also now has a green light for use in patients [[4] “FDA eases restrictions on experimental Ebola drug as CDC warns of ‘inevitable’ spread to US” http://ift.tt/1yevy3B , RT.com, 8 August 2014.]. I don’t know how many people we can treat with the quantity of TKM-Ebola available today. I hope it is many more than the five we could treat with ZMapp.
> At least five patients have received a potentially effective treatment, but nobody has yet been assigned to a control group. This is the ethical travesty, and it needs to stop.
> With 1013/1848 = 55% of reported Ebola patients dying during this outbreak, you may think that we don’t need a control group. Surely we will notice if the death rate goes down from there [[5] “Ebola prizes revisited” http://ift.tt/1oH4Kcs , by Eric Crampton, Offsetting Behavior, 5 August 2014.]. But this is not as easy as you might think. Some of those infected patients haven’t died yet, but will die later, so the true death rate is likely a little higher than 55%. And neither the typically more privileged patients who receive the therapies, nor the care they receive during their treatment are likely to be representative of the average Ebola patient suffering and perhaps dying at home in their village.
> A control group is not only essential for good science backed by rigorous statistics, but it is also ethically sound. Many people are understandably concerned about deliberately withholding potentially life-saving treatment and giving a placebo instead. But this is a moot point; we have no choice about withholding treatment. There isn’t enough of it to go around. The fairest way to distribute it is by lottery. This fairest plan also happens to be the best scientific plan. The question is whether we capitalize on our inability in the service of science by implementing a well-designed lottery, or whether we squander it instead with a less systematic lottery of who gets treated and who misses out.
> This situation has an important and telling precedent. The very first randomized clinical trial ever published [[6] “Streptomycin Treatment of Pulmonary Tuberculosis” http://ift.tt/1vZ1Aoe / http://ift.tt/1v5VuhP , _British Medical Journal_, 30 October 1948.] in 1948 investigated whether antibiotics are effective against tuberculosis with Ebola-like death rates. Just like today, there was a shortage of a new drug, streptomycin. In the aftermath of World War II, Britain received only a very limited supply from American manufacturers. The Medical Research Council controlled this shipment, and seized the opportunity to dictate to doctors that if they wanted access to the drug for their patients, the only way to get it was by taking their chances within a randomized trial. Thus began a golden era of effective medical science [[7] “Controlled trials: the 1948 watershed” http://ift.tt/1vZ1Aoi , _British Medical Journal_, 31 October 1998.], led by a strikingly novel and extraordinarily effective gold standard. What is more, to everyone’s surprise, the streptomycin treatment had limited effectiveness against tuberculosis. Patients improved initially, but then the bacteria evolved resistance to the drug and patients deteriorated again. This phenomenon of drug resistance had never been seen before. The randomized trial allowed this failure to be quickly recognized, leading to the improved and effective treatment protocols we have today.
> We have so few doses available, and it is unethical to waste them in unsystematic tests that lack a control group. The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo. And then it should have given its second dose to Africa on the condition that it be randomly distributed to one out of two preselected patients in the same manner. This would have been the ethical thing to do.
> If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a “statistically significant” fashion, from that tiny but well designed trial, that the drug works. We think of randomized trials as huge affairs. And it is true that to detect subtle differences, we do need huge trials. But when the improvements are not subtle, trials can be quite small. Sixteen patients (eight per group) would be enough to have a 95% chance of detecting the effectiveness of a miracle drug. Even if the drug were slightly less miraculous, dropping the death rate from 60% to 30%, the 10-patient trial that we could and should have done with existing resources would have had a 42% chance of detecting the drug’s effectiveness. Our unsystematic trial of five patients will tell us much less, squandering this opportunity to make best use of the limited supply of ZMapp that we had.
> …What we should learn from the history of randomized trials is that the biggest danger with randomization comes from the urge to cheat. It is only natural for doctors to have special sympathy for particular patients, and to rig the game so that their favorite patients end up in the treatment group rather than the placebo. This is the real historical reason that trials were made “double blind” so that neither patient nor doctor knows who gets what. There is a lot of talk about the power of the placebo effect, and it is important for some conditions such as pain, but for most diseases the placebo effect is overrated. A placebo won’t stop you dying of Ebola just because you believe in it. But a double blind design is still an important precaution to make it impossible for well-meaning doctors to rig the allocations.

caption, slideshow photo #6:

> Liberian police depart after firing shots in the air while trying to protect an Ebola burial team in the West Point slum of Monrovia on August 16, 2014. A crowd of several hundred local residents reportedly drove away the burial team and their police escort. The mob then forced open an Ebola isolation ward and took the patients out, many saying that the Ebola epidemic is a hoax.


About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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