Except for devices used for pediatric patients, the SMDA prohibits the sale of an HUD “for an amount that exceeds the costs of research and development, fabrication, and distribution of the device.” An HDE is valid for a term of 18 months and is renewable for an unlimited number of 19-month terms so long as ap-proval criteria continue to be met. Finally, HUD manufacturers must comply with all FDA post-approval reporting requirements, including the reporting of all adverse effects.11
The press release that Medtronic issued on the FDA’s approval contained a statement that would prove controversial: “While OCD is estimated to affect 1 in 50 adults in the United States, it is anticipated that DBS therapy will be appropriate for a small subset of the patient population, below the threshold of 4000 patients per year allowed under an HDE.”9
The “HDE misuse” controversy
In February 2011, Medtronic’s claim, Reclaim’s eligibility for an HDE, and the very structure of the FDA’s HUD approval process were challenged in an article in Health Affairs.3 The authors, a collection of physicians, professors, ethicists, and philosophers from universities in the United States and Europe, wrap up the article with a dramatic conclusion: “With a humanitarian device exemption, a manufacturer can generate publicity and create a market for a device, to the advantage of the company’s bottom line but to the potential detriment of science and society.”
The authors buttress this conclusion with 2 principal arguments. First, they challenge Reclaim’s eligibility for an HDE for treatment-resistant OCD. The NIMH has estimated that 2.2 million adults have OCD. Between 20% and 30% “have a variant severe enough to be included in a deep brain stimulation study.” As a result, the eligible number of patients ranges from 440,000 to 660,000, or more than 100-fold the FDA maximum of 4000.
More pointedly, the authors assail the HDE program as a loophole that device manufacturers misuse to avoid paying FDA fees and to sidestep the cost of clinical trials. Indeed, the exemption, according to the authors, has stood FDA policy on its head: “It seems clear that the humanitarian device exemption is being used to give the device manufacturer access to patients, rather than giving researchers access to subjects, or patients access to sound scientific evidence.” The result is that patient safety is compromised and that a treatment that might benefit the many is limited to the few.
The Health Affairs article has “spurred impassioned debate among neurologists, psychiatrists, neurosurgeons, ethicists, the device manufacturer, and the regulatory agency.”12 This debate is most dramatically depicted in 3 letters published in the June 2011 issue of Health Affairs (1 by Medtronic, 1 by 3 of the authors of the “Misuse” article, and 1 by the FDA).13-15
Medtronic’s central contention is that the “Misuse” article authors overstated the prevalence of severe, treatment-resistant OCD. Medtronic contends that “published epidemiological data and criteria from physicians who specialize in treating OCD” reveal that there are fewer than 1000 eligible patients in the United States. And, more pointedly, since the approval of Medtronic’s device in 2009, fewer than 50 US patients with OCD have been treated with the device.
The authors of the “Misuse” article respond that they stand by the peer-reviewed data cited in their paper and add that “the number of eligible subjects, rather than the number who enroll in a study, is the criterion for an exemption.”
The FDA’s central contention is that “the article contains factual errors, omissions, and misconceptions regarding the humanitarian device exemption pathway.” Those errors include some obvious misreadings of the Food, Drug, and Cosmetics Act and its accompanying regulations. But, those errors are not central to the authors’ arguments about the prevalence of severe, treatment-resistant OCD or device manufacturer incentives to obtain an HDE.
The FDA does, however, raise 2 points central to the authors’ contentions. First, the FDA replies to the authors’ arguments about corporate financial incentives to obtain an HDE by noting that the governing statute prohibits profiting on HUDs, except for those approved for pediatric use. Second, the FDA challenges the authors’ assertion, as does Medtronic, that there are far more than 4000 people in the country who are eligible for the treatment. They con-tend that the appropriate population for the device is not all patients who have severe OCD, but only those adult patients who are treatment-resistant (ie, those in whom treatment with at least 3 SSRIs has failed). According to the FDA, there are fewer than 4000 such patients in the country. “In sum, humanitarian device exemptions have been, and will continue to be, reserved for devices that serve small, underserved patient populations and satisfy all regulatory and scientific criteria for approval. We appreciate the opportunity to provide clarification on the program.”
The future of DBS and a proposal for change
The FDA is resolute in its decision in this case. Moreover, Greenberg, the lead author of the 2008 article in Molecular Psychiatry has conceded that the granting of the HDE has likely made it more difficult for him to recruit subjects for his clinical trial.12 Once patients are aware of the treatment, they are reluctant to enroll in blind studies designed to evaluate the treatment.
So, the die has been cast. We can only hope for successful clinical trials. In the meantime, patients and clinicians are left with modest Reclaim programs that have so far, by Medtronic’s measure, resulted in fewer than 50 DBS implants for OCD patients.
But, this case does offer lessons. The discourse has raised a number of important issues, including the safety of patients, the effectiveness of the treatment, and financial incentives of device manufacturers. These issues will present again in the future, and their resolution will depend on the answer to a single question: are there fewer than 4000 patients in the United States who are eligible for the proposed treatment? If there are fewer, then even the critics of the Reclaim HDE would agree that the exemption is justifiable.
Given a small population, device manufacturers will not have the financial incentive to conduct costly clinical trials and produce a treatment. If there are more than 4000, even the supporters of the Reclaim HDE would agree that broad clinical trials provide the appropriate pathway to making the best decision on the safety and effectiveness of a given treatment.
There are risks to erring on either side of the answer. Overestimating the target population will lead to clinical trials and delay treatment for underserved patient populations. Moreover, in the long run, device manufacturers forced into financial-ly unrewarding arrangements will become reluctant to serve those underserved populations. On the other hand, underestimating the target population jeopardizes later clinical trials.
The current debate dramatizes this issue because it is occurring 2 years after the FDA granted the HDE. To the extent that the decision jeopardized the clinical trials, the damage may already largely have been done. This conundrum may actually sug-gest a relatively simple solution. The current statutes mandate that the FDA complete its HDE review within 75 days of receiving an application.11 The FDA could promulgate a new regulation allowing for public comment on the question of whether the targeted population for a medical device exceeds 4000 people in the United States. Framing the question narrowly would help avoid overly politicizing the process. In addition, it would make it feasible to limit the comment period to the first 30 days of the 75-day review period. That would allow the FDA an additional 45 days to review the application after receiving all comments. Most important, the public comment would allow for debates like the current one to occur before the HDE is granted.
The authors of the Health Affairs article suggest broad statutory and regulatory reform of the HDE process.2 The simple 30-day comment period would allay their concerns, not overly burden the FDA, not add to the burdens of the device manufacturer, and be much simpler to implement. Hopefully, the comment period would also increase public and professional confidence in the HDE program.