The World Health Organization will hold a two-day conference on September 4-5 where over 100 international experts will discuss how best to provide access to experimental therapies for Ebola virus infections.
This follows a teleconference with 12 experts that WHO held on August 11 to discuss the ethical implications and clinical decision-making on mobilizing Ebola drugs, vaccines, and passive immunotherapy products that have not yet been subjected to human trials.
The 10-page report from this meeting has been made available, and this is perhaps the most important overall recommendation of the panel:
"The panel strongly recommended that these investigational drugs or vaccines for patients with Ebola virus disease that have shown promising results in the laboratory and in animal models be urgently tested in humans by scientifically sound, rigorous methods. At the same time, the practical circumstances of outbreak response capacity call for exploration of innovative methods of rapid assessment, so that candidate interventions that show promise can quickly be tested in larger clinical studies. Without such testing, there is no certainty that experimental interventions are safe and effective."
The other ethical issues discussed, with somewhat less consensus, included how to prioritize and allocate very limited current supplies of any investigational medicines. The panel invoked the principle of distributive justice – fairness between countries and within populations of a country – but differed on how to decide on which groups were of highest priority for treatment.
Many, but not all panelists, argued that treatment of health care workers should be of highest priority because of "reciprocity (they put their life at risk to care for others) and social usefulness (they are instrumental to controlling the outbreak)." This would then include those involved in supportive roles such as sanitation and burials. But what about those most generally vulnerable to infectious diseases, such as infant and elderly persons?
Among the other critical issues are qualifying the clinical disease stage at which an experimental therapy should be given and assurances that they facility where they are given should meet minimal standards for supportive care.
Does ZMapp work, or not?
Last week saw the release of two American missionaries from Emory University Hospital after Ebola treatment, Dr. Kent Brantly and Nancy Writebol. During the institution's press conference, Emory infectious disease physician, Dr. Bruce Ribner, was more emphatic as to the role of strong, supportive care in their recovery rather than the ZMapp anti-Ebola antibody combination both had received in Liberia.
Ribner noted that managing electrolytes (potassium, calcium, and magnesium) and the balance of blood clotting abnormalities were two essential strategies that the Emory medical team would be communicating with their West Africa colleagues.
When asked specifically about the experimental antibodies, Ribner said that it was impossible to know if the treatment helped the patients, did nothing, or delayed their course of recovery.
So, when the announcement came yesterday that another ZMapp recipient had passed away, Liberian physician Dr. Abraham Borbor, colleagues on Twitter began discussing the current count of survivors and decedents of ZMapp recipients.
Knowing who has received one or more ZMapp injections can only be discerned from media reports at this point. From the front webpage of San Diego's Mapp Biopharmaceutical, Inc.:
August 12, 2014 at 8:30 AM - The available supply of ZMapp™ has been exhausted. We have complied with every request for ZMapp™ that had the necessary legal/regulatory authorization. It is the requestors’ decision whether they wish to make public their request, acquisition, or use of the experimental drug [emphasis mine]. Any decision to use ZMapp™ must be made by the patients’ medical team. Drug has been provided at no cost in all cases.
So, to the best of our current knowledge, we know that six patients have received some number of ZMapp doses: Dr. Brantly and Ms. Writebol; the 75-year-old Spanish priest, Father Miguel Pajares, who died August 12 after being transported to Madrid; and, according to Reuters' Clair MacDougall in Monrovia, Drs. Zukunis Ireland and Abraham Borbor from Liberia and Dr. Aroh Cosmos Izchukwu from Nigeria. No public word has been issued on the current status of Dr. Ireland and Dr. Izchukwu.
Just looking at the six reported subjects thus far, the treatment environments for each seems to vary considerably. To truly determine the effectiveness of ZMapp, not statistically possible with an n of 6 in even the best of circumstances, the inclusion criteria and site conditions would have needed to be as standardized as possible.
But with ZMapp supplies exhausted and new drug not likely available for months, will companies with other drugs be solicited for participation?
Update, August 26, 8:50 pm: The Guardian Will Pooley, will be treated with ZMapp the very legitimate question
This passage from Saddique's article is the best we know:
The Department of Health had apparently been trying to obtain supplies of ZMapp, but the manufacturer said high demand meant it had no remaining stocks. Jacobs [infectious diseases chief at Royal Free Hospital] said the team treating the nurse had sourced the drug through its clinical networks with the help of international colleagues. Pooley, who fell ill after five weeks volunteering at the Kenema government hospital, made the ultimate decision to take the drug, expressing enthusiasm at the prospect, said Jacobs.
The story emphasizes further that prioritization of patients to receive experimental treatments will continue to be a controversial one. In the commercial sector, patient selection criteria are devised by the sponsoring drug company, the investigators conducting the trial, and the institutional review board that monitors the trial.
In the case of ZMapp, the company has received $10 million of support from the Department of Defense to develop the drug. So, one would hypothesize that the federal government must have some say in how the drug is distributed. The WHO will certainly take up the question at their September 4-5 summit, where access will be a hot issue.
Human clinical efficacy trials not necessarily required for FDA approval
Over the weekend, a writer at the Dilatant Pharma blog reminded us that three drugs have already been approved in the U.S. without clinical trials for the indication, and that they anticipate ZMapp could be investigated under this special provision.
The U.S. Food and Drug Administration issued a guidance document, first proposed in 1999, called the "Animal Efficacy Rule" that offers a path to approval for drugs where human efficacy trials "are not ethical or feasible."
The author, Chris, is "a pharma exec with experience developing countermeasures under Animal Rule." He writes:
"In fact, 3 drugs have already been approved under the Animal Rule: Johnson & Johnson’s levofloxacin (Yersinia pestis), GlaxoSmithKline’s raxibacumab (Bacillus anthracis, inhaled) and Cangene’s heptavalent botulism antitoxin BAT (Clostridium botulinum toxin). You’ll notice all three of these drugs are intended for use as post-exposure therapies – the same, relatively easy, path as ZMapp."
Note that one, levofloxacin (Levaquin) is an already approved antibiotic.
The Animal Rule is based on meeting four criteria for efficacy in animal models that approximate the human disease (for infectious agents) or human exposure (for toxicants or radiation exposure) and "provide substantial evidence of effectiveness." However, the agents still ultimately require safety testing in normal human volunteers.
According to the guidance document, the type of agents eligible for such an approval path is quite broad:
"The use of the Animal Rule as a regulatory pathway to approval is not confined to the development of medical countermeasures for chemical, biological, radiological, or nuclear threat agents. Drugs intended to ameliorate or prevent serious or life-threatening conditions due to other toxic chemical, biological, radiological, or nuclear substances (e.g., emerging virus, snake venom, industrial chemicals) may be eligible for development under the Animal Rule when it is not ethical to conduct human challenge studies and when field trials to study effectiveness are not feasible."
What remains to be seen is how the sponsors of experimental drugs – Tekmira, Sarepta, BioCryst, and others - interface with the WHO at the upcoming September 4-5 conference. Unfortunately, the Ebola outbreak continues and time is of the essence for those stricken with the disease and drug makers who still have stocks of experimental agents ready to offer.
