FDA faces regulatory challenges with new approaches to medicineBMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g1530 (Published 14 February 2014) Cite this as: BMJ 2014;348:g1530
The US Food and Drug Administration (FDA) faces unprecedented regulatory challenges not just with new products but with entirely new fields of activity that are likely to transform medicine in the decades to come. Among them are stem cell therapies, commensal microbial transplants, and personalized genetic testing. They are rapidly evolving and much remains unknown, or at least not definitively proven.
That uncertainty plays to the tension between emphasizing safety and affording opportunity for treatment that is at the core of the agency’s responsibility. Another often less apparent tension playing out is that between regulating interstate commerce, which is the legal basis for FDA authority, and the practice of medicine, which, to the extent that it is regulated, is the responsibility of state government.
The FDA regulatory paradigm historically is the model of infectious disease where a single drug targets an invading pathogen. Once that invader is neutralized, the body reverts to a normal state. But these new fields are characterized by the complexity of the intervention itself and its effect on the patient. The agency is struggling to understand and adapt to these new interventions.
Genetic testing services
One example occurred in November 2013 when the FDA told 23andMe to stop marketing its direct to consumer genetic testing services.1 It said that the company had failed to provide information necessary for approval and that consumers might misinterpret the information provided.
The company’s response, in an email to their clients, suggested that the FDA should have used a different regulatory pathway. It hinted that the disagreement was fundamental, not amenable to compromise, and might need to be resolved through the courts.
It is “a culture clash between Silicon Valley, with its devotion to libertarianism and self-knowledge, and a ponderous old school bureaucracy,” wrote David Dobbs on the New Yorker website.2 It also seems to be at odds with what most foresee as an oncoming wave of personalized medicine.
“At the same time that the NSA [National Security Agency] is secretly and illegally obtaining information about Americans the FDA is making it illegal for Americans to obtain information about themselves,” wrote economics professor Alex Tabarrok on the blog Marginal Revolution.3
“The FDA wants to regulate genetic tests as a high-risk medical device that cannot be sold until and unless the FDA permits it be sold . . . [it] wants to judge not the analytic validity of the tests, whether the tests accurately read the genetic code as the firms promise (already regulated under the CLIA [Clinical Laboratory Improvement Amendments]) but the clinical validity, whether particular identified alleles are causal for conditions or disease.
“The latter requirement is the death-knell for the products because of the expense and time it takes to prove specific genes are causal for diseases,” Tabarrok argued. It likely would mean channeling genetic tests into a strictly medical and much more expensive model. He believes the restriction is an unconstitutional impingement on speech.
Even the Presidential Commission for the Study of Bioethical Issues seemed to weigh in a few weeks later when it released a report on genetic testing that was completed before the FDA took action against 23andMe.
Referring to direct to consumer genetic tests it said, “Policy makers at the state and federal level should remain mindful of the principle of regulatory parsimony, limiting restrictions on the ability to freely engage in commercial transactions only to the extend necessary to prevent serious harm.4”
The FDA has offered several hypothetical situations where a person might misuse the information provided by 23andMe to make unwise medical decisions. But it has provided no evidence of harm, let alone “serious harm,” reported to it by the nearly half million people who have purchased the company’s testing services.
Stem cell therapies
The regulation of stem cell therapies also has been problematic. Researchers and patients alike complain that FDA regulation is cumbersome, expensive, and impedes progress in the field. At the agency’s request, the Institute of Medicine (IOM) examined those issues at a public meeting in November.
We could treat people off label with cord blood containing stem cells for a few thousand dollars, but “the moment I change it to a clinical trial, it is so much more costly,” said John Wagner, a pioneering researcher in the use of cord blood who works at the University of Minnesota. “Maybe we need to reconsider how we are doing things.”
Computer entrepreneur Michael Phelan told the IOM of his experience as a patient. He has multiple sclerosis and tried to enroll in two autologous stem cell studies in the United States. He even spent $10 000 (£6000; €7300) of his own money on tests such as magnetic resonance imaging to see if he qualified for a trial at Northwestern University, only to be told that he was not sick enough to enter the study.
That was when Phelan began to look overseas. He explored the medical literature and spoke with US experts. Then “I chose the Stem Cell Institute of Panama because they had published some of their research,” he said. Following the procedure of extracting, expanding, and injecting adipose stem cells back into his body, his vision problems resolved and other physical problems improved. He attributes improvement in his health to the procedure.
Phelan said more than two thousand patients have participated in studies using autologous stem cells, with no reports of serious adverse events. He believes that, in situations such as this, where safety is established but evidence of efficacy is scant, patients with lifethreatening conditions should be given more leeway in making their own risk-benefit calculations with regard to trying potential therapies.
“Perhaps we need to start thinking about this [autologous stem cell therapy] like transplantation and surgery, much more so than drugs and biologics,” said J Glenn Cohen. The Harvard Law School professor is writing a book on medical tourism. He believes an outdated and overly cautious regulatory environment has helped push patients “to go offshore” in seeking medical treatment.
Last April the FDA declared that fecal microbial transplants (FMT)—where gut microbiota obtained from the feces of a healthy donor are given to a recipient through a variety of methods—fell under their regulatory jurisdiction as a biologic agent. Because it had not approved any such products, the FDA said further use could take place only as a clinical trial under an investigational new drug (IND) protocol.
That caused an immediate backlash from supporters of FMTs. There is a growing body of medical literature on using the procedure to treat refractory Clostridium difficile infection, including a study published earlier that year in the New England Journal of Medicine5 that shows a cure rate above 90%.
The FDA decision “wasn’t based on safety. If they said, we see a problem; stop doing this,” it would be one thing, argues Neil Stollman, a gastroenterologist in private practice in Oakland, California. “They didn’t say that. They just came out and arbitrarily decided, stool is a drug; as a drug it is an investigational drug; you need to do an IND.”
Stollman has exercised caution in treating an estimated 60 to 70 patients with C difficile using FMTs over the past five years, and he has published on those outcomes. He acknowledges a role for the FDA in protecting against false claims and particularly in regulating future standardized products developed by companies for wider use. But he criticizes the agency for the way it chose to implement its decision, calling it a disservice to patients and to the physicians who care for them.
Some supporters of FMTs believe that current practice is more akin to surgery and is better handled through guidance issued by professional societies rather than regulated along the industrial model of small molecule drugs used by the FDA.
The FDA backed off a bit in July, saying it would “exercise enforcement discretion” in the use of FMT to treat C difficile on an interim basis while it develops guidance for the study and use of FMT products under IND.6
It maintained the ban on other potential clinical uses of FMT unless conducted under an approved study protocol. Basic research in mice and observations in people who have undergone bariatric surgery suggest that modulating the gut microbiome might benefit a number of conditions, including diabetes and obesity.
The agency also might have been influenced by a growing willingness of patients to try a do it yourself approach to fecal transplants, as evidenced by a proliferation of “how to” postings on the Internet. They perhaps reasoned that it is better to allow some procedures under medical supervision and screening of donor samples than have them occur completely outside of regulation.
The FDA has also allowed a new non-profit organization, Open Biome,7 to distribute screened frozen samples of feces to physicians for use in transplant to treat C difficile. Open Biome is careful to say that it is only providing screening services, similar to those for blood products and organ transplant; it is not selling feces products.
Toward a new regulatory paradigm
Much of the traditional authority of the FDA has been based on information submitted to it by drug companies and protected by rules of confidentiality. Because they cannot reveal the proprietary data that helped shape their decision, often the agency has been reduced to saying to critics, “Trust us: we have more information than you.”
But trust in government is at an all time low because of political gridlock, the ineptitude of implementing Obamacare, and the revelation of massive spying on average citizens by security agencies. Americans have also seen politics play a role in health policy questions such as access to the “morning after pill” for emergency contraception and even mandatory health insurance coverage of contraception.
At the same time, multiple long term forces are driving medical research and care towards increased openness. Among them are trials registries, data repositories, an increased willingness by companies to open their data, personalized medicine, and more active engagement of patients in their own care.
Peter Huber of the Manhattan Institute, a libertarian think tank, offers a series of recommendations for reforming the FDA, intellectual property rights laws, and the tort system to take advantage of the torrent of genetic and biomarker information on disease that is becoming available. In his new book The Cure is in the Code, he says that too often the FDA refuses to approve a new drug because it doesn’t work for everyone, when the goal should be to find those patients for whom it does work.
“Different stakeholders may arrive at divergent conclusions when balancing the expected benefits of a drug against the harms it might cause,” a group of European researchers and regulators argue in a recent journal article.8 Additionally, clinical trials are too small to answer all questions; many will be understood only after the intervention is used in a large patient population over an extended period of time.
Risk aversion in drug regulation carries its own costs, they say. “Beyond a certain point, the call for more data is expected to result in diminishing benefits for public health.” They recommend that regulators also consider opportunity costs in making their evaluation, though that will not be easy; “The difficulty with opportunity costs is the difference between that which is seen and that which is not seen.”
They urge creation of a regulatory framework that leaves maximum room for patient autonomy in deciding what risks each may be willing to assume; a reduced reliance on animal models and greater post-marketing surveillance of use in actual patients; and consideration of opportunity costs in demanding additional research before approval.
The tensions the FDA faces in carrying out its mission are never going to go away. But regulations that are flexible, nimble, and leave space for patients and doctors to take advantage of personalized and locally generated data are likely to prove beneficial in the long run.
Cite this as: BMJ 2014;348:g1530
Competing interests: I have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; not externally peer reviewed.