On April 25, 2016, an FDA advisory committee voted not to recommend the approval of eteplirsen, an experimental drug that targets one of many genetic mutations causing Duchenne muscular dystrophy (DMD), a deadly degenerative disease that has no cure.1 After agreeing to study the real-world effects of eteplirsen, the FDA advisory committee rejected findings that patients who have been taking eteplirsen since 2011 were still able to walk because the clinical data did not meet the FDA requirements for a well-controlled study.
The FDA committee noted that the study in question involved only 12 patients without an adequate placebo control. Patients were also very knowledgeable about the drug, the FDA said, which could have led to patients inventing positive findings just to get the drug approved. The committee recommended new studies that randomly assigned patients to eteplirsen or placebo.
This rejection by the committee is even more remarkable because it had hammered out the study design with the drug manufacturer to rely less on randomized clinical trials and more on measures of patient response, which were developed in cooperation with patient groups and DMD experts.
Because randomized clinical trials assume that every patient is the same and will have the same response to therapy, they can miss individual differences in responses that drugs for rare diseases target. Studies need to measure benefit in combination with real-world experiences and the biologic diversity that new drugs target.2 Therefore, the study was designed, as Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research, stated, to “take the views of the patient community into account in determining the benefit and the risks of treatments.”3
That is what the FDA review team, as well as those who applauded the FDA advisor’s decision, rejected. Michael Carome, MD, Director of Public Citizen’s Health Research Group, said, “It would be a mistake for the FDA to approve this….It would be giving in to political pressure and essentially eviscerating their standard for approval....To put out a drug that’s not effective isn’t helping anyone.”4
Objections to the use of evidence from real-world use of a drug compared with historical controls of randomized clinical trials have nothing to do with concern about patients being harmed and has everything to do with the belief that patient involvement will lead to an increase in the development and use of new medicines, and, by extension, benefit drug companies that have a financial interest in getting drugs approved.
The financial stakes of drug approvals are significant. Health insurance companies, hospitals, the government, and other groups are seeking to create defensible ways to ration access to new drugs. Public Citizen and other groups have sprung up to “objectively” measure value in an effort to suppress the patient input they regard as biased.
For example, the Institute for Clinical and Economic Review (ICER) claims that it is a “trusted non-profit organization that evaluates evidence on the value of medical tests, treatments and delivery system innovations and moves that evidence into action to improve the health care system.”5 ICER, funded by health insurance companies, defines value and determines what drugs should be used. ICER wants the public to believe that the choice of how to measure effectiveness and value of drugs is simply a technical matter that is best left to the “experts.” But that is a way to guarantee that insurers and other health organizations are free to ration access to drugs.
ICER President Steven D. Pearson, MD, MSc, emphasized, “The resource allocation problems posed by orphan drugs are therefore a harbinger of things to come. Tomorrow’s medical care will feature a growing number of expensive therapies that offer benefit only to small populations.”6 Therefore, ICER must decide “orphan drug coverage decisions to ensure that an undue burden is not placed on others for the sake of a few.”6
Underlying this approach is the belief that patients cannot be trusted to make such decisions, because hope clouds their judgment. According to the American Society of Clinical Oncology, the use of more expensive diagnostic and therapeutic interventions is driven by “unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.”7
However, economist Tomas J. Philipson, PhD, notes, “Hope for new innovations increases demands and a willingness to pay for existing innovations. This hope is realistic: the first anti-AIDS treatments added ‘only’ two months of life in 1987. By 2006 a combination of new drugs added 15 years of life.”8
Similarly, children taking eteplirsen are able to stay alive long enough for future drugs to be developed; the father of one of the children with DMD echoed this sentiment, saying, “Eteplirsen has given us a reason to hope.”9
As one analyst said, “Sarepta has plans to begin work on seven additional exon-skipping drugs that, in a perfect world where every one hit the mark, would combine with eteplirsen to provide a therapeutic benefit for nearly half of all DMD patients.”10
Increasingly, medical advances determine not only whether we live or die, but also how we will live and die. Ordinary citizens—those who are potential patients and the friends and relatives of such patients—have as much to say about these innovations as any so-called expert.
To be sure, on June 2, 2016, the FDA announced a streamlined process for physicians to request “compassionate use” to investigational drugs. This initiative should not be regarded as a fix to the failure to open access to drugs established as safe. Compassionate use data are not included in the body of evidence used to approve a drug. Companies cannot charge for the product since it is not on the market. If patients apply for access to investigational drugs en masse it would not be financially sustainable. So why not simply allow patients with fatal diseases that have no other medical alternative access to medicines that are safe? Who or what are we protecting when we let people die by denying access to treatments? When there is no effective treatment, any progress is a quantum leap from the cost and burden of disease, which, in the absence of any medicine, is infinite.
DMD advocate Christine McSherry, Executive Director of the Jett Foundation, Kingston, MA, stated that the DMD community’s involvement in drug approvals “will change the way people confront barriers to justice in society. This will be historic not just in Duchenne, not just in rare disease, but for every ordinary individual who has felt the need to change a broken system but never knew how to do it.”11
