The Ebola outbreak, which has claimed nearly 1,000 lives since its emergence in West Africa in December 2013, has brought renewed attention to policies surrounding the “compassionate use” of unapproved medications – i.e., the provision of unapproved medications to individuals outside the context of clinical trials. The issue rose to the forefront early last week when it was reported that two American aid workers in Liberia were treated with an “experimental drug that has never before been tested for safety in humans.” Both workers appeared to respond well to the drug, known as ZMapp. The drug was also provided to a Spanish priest, who died shortly thereafter; it was unclear whether he took the drug before he died. Following some controversy over the fact that the first three recipients of the drug were all foreign aid workers, on Tuesday it was reported that the drug’s manufacturer had sent its remaining stocks of the drug to Liberia for the treatment of two African doctors.
The FDA recognizes three broad categories of compassionate use, which are grouped under the general label of “expanded access.” These include expanded access for individual patients, including for emergency use; expanded access for intermediate-size patient populations; and expanded access for large patient populations under a treatment IND or treatment protocol. All of these categories are limited to patients who have serious or immediately life-threatening diseases or conditions for which no comparable or satisfactory alternative treatment exists. The FDA must determine that the potential benefits of the unapproved drug outweigh the potential risks, and that the risks “are not unreasonable in the context of the disease or condition to be treated.” In addition, the FDA must determine that allowing expanded access “will not interfere with the initiation, conduct or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.”
The FDA typically grants most requests for expanded access. When requests are denied, they most frequently involve emergency requests to use drugs that are not already undergoing clinical trials – precisely the situation facing ZMapp. On the one hand, it is understandable that the FDA would be cautious in allowing expanded access when no safety information exists and when there is no time to perform an exhaustive assessment. On the other hand, patients who are expected to die in a short time because they have no treatment alternatives may reasonably decide that they are willing to assume a high level of risk. Moreover, if clinical trials have not even been initiated, allowing expanded access cannot possibly interfere with the trials’ completion. While there is some possibility that systematically allowing expanded access in emergency situations would interfere with the initiation of trials, the manufacturer would have its own incentives to initiate trials once the expected demand for the drug is sufficiently high.
For now, all of these questions are moot, as existing supplies of ZMapp have reportedly been exhausted. When more supplies become available, further requests for expanded access are certain to arise. However, granting access to the drug through compassionate use programs is not a long-term solution. As an ethics panel convened by the World Health Organization concluded on Tuesday, the ideal way to introduce new Ebola medications is “in the best possible clinical trials under the circumstances in order to definitely prove their safety and efficacy or provide evidence to stop their utilization.”
Clinical trials of Ebola treatment will of course raise difficult questions in their own right. Unlike with expanded access, where everyone obtains the medication they have expressly requested, in a clinical trial some participants may be assigned to control groups that receive different medications or even placebos. Because no effective treatment for Ebola currently exists, placebo-controlled trials of new Ebola treatments would appear to be consistent with the ethical principles in the Declaration of Helsinki. Yet, particularly after American and Spanish foreign aid workers received the first doses of the experimental medications through compassionate use programs, asking African patients to enroll in placebo-controlled trials would surely be controversial. As the WHO panel delicately put it, the goal should be to devise “ethical ways to gather data while striving to provide optimal care under the prevailing circumstances.” The challenge will be to figure out effective strategies for carrying this out.