As the Senate Committee on Homeland Security and Governmental Affairs meets next week for a hearing on "Connecting Patients to New and Potential Life Saving Treatments," it is important to remember the appropriate role of the Food and Drug Administration (FDA) in promoting the health of Americans. (Full disclosure: I have been called as a witness to testify at this hearing.)
Despite incessant pleas from doctors and patients for more safe and effective products that might help when used appropriately, the FDA continues to raise the evidentiary threshold for permitting a new product — recasting pre-market approval as a venue for the practice of evidence-based medicine to determine clinical utility, benefit, and health outcomes, pre-approval. This move is aimed at satisfying FDA critics, but it consumes precious time and resources, and it dissuades drug developers (and would-be developers) from pursuing projects.
The FDA has acknowledged the changes in its standards for product approval. In a March 10, 2015, opinion piece, two high-ranking FDA officials had this to say about the review process: "It is important to remember, however, that innovative therapies only save lives if they work properly. U.S. citizens rely on the FDA to ensure that the drugs they take are effective and that their benefits outweigh their risks. Improving a patient's life or lifespan must be central to the concept of drug innovation."
But the FDA is supposed to assure safety and effectiveness of drugs, not life outcomes for patients. A drug's proposed label indicates the effect it is purported to have; safety and effectiveness are to be determined in the context of that labeling. The physician and the patient, acting in the medical marketplace, are to determine whether and when taking the drug will be conducive to improving a patient's life. That we authorize physicians to prescribe drugs off-label is indicative of this division of labor.
Certainly, studies of life outcomes can be invaluable to informed decision-making by physicians and payers. But there are many and varied factors that contribute to disease development, progression and response to therapy. It is far harder to produce good knowledge about life outcomes for patients than it is to produce good knowledge about a drug's safety and effectiveness with respect to specific disease-related parameters.
Moreover, the appropriate place to evaluate life outcomes is in the post-approval setting, by the medical marketplace. Trying to do so pre-approval, before a new drug has settled into practice, is not scientifically prudent. The myriad of real-world factors that may modulate ultimate clinical benefit cannot be known or controlled in pre-approval studies, no matter the size, without informed data that become available only after a safe and effective drug has been in use for a period of time. Thus, the way that FDA currently approaches drug approval can actually mask clinical benefit. If clinical utility is used as the criteria for approval, many drugs that are safe and effective and could help patients will never see the light of day.
The other problem with the FDA's current approach is that it is directly contrary to the precision medicine movement. The FDA makes its determinations based on the responses of the average patient in clinical trials. While immediate- and near-term measures of effectiveness (reducing pain and tumor size, and increasing air movement in the lungs, for example) are appropriately evaluated by calculating average patient responses, clinical benefit is not appropriately assessed in this manner. Many patients may truly benefit from a drug; however, the benefit may not be seen in enough patients to pass the average patient hurdle. As long as the drug is safe and effective as per its labeled conditions of use, clinical benefit should be the domain of patients and doctors, not the FDA.
In essence, the FDA, which should be the gatekeeper of safe and effective products that enter the medical armamentarium, has put itself in the position of judging which drugs are most beneficial. The funnel diagram available here, in a piece I co-authored for the Mercatus Center, depicts the roles and responsibilities of medical marketplace constituents in the diffusion of new drugs and devices into practice. The law provides for the FDA to be at the top of the funnel and for the medical marketplace to decide from among the FDA-approved safe and effective products which are the most beneficial; therefore, which are used the most (bottom of the funnel). However, the FDA, in demanding data from drug developers, pre-approval, to determine which drugs are most beneficial, is putting itself at the bottom of the funnel as well.
At no other time in history have we been better equipped to perform real-world, large-scale outcomes and survival studies with regard to medical interventions, such as the use of safe and effective drugs and devices. There is no way that pre-approval studies of drugs and devices, in tightly defined patient populations under scripted medical management protocols, can produce the kind of evidence that is available through real-world data acquisition and the Internet of Things. What's more, in the post-approval, real-world setting, data that will enhance the selection of therapy for an individual patient can be made available in an unprecedented manner, which can truly drive personalized medicine.
The law instructs the FDA to consider new drugs for approval on the basis of the uses submitted by sponsors. Sponsors are responding to needs identified in the medical marketplace. The FDA should not be telling sponsors that their drugs must show improvement in clinical outcomes; rather, the FDA's role is to label drugs as "safe" for uses that the agency finds substantial evidence has been presented. It is then the job of doctors in the medical marketplace to determine the benefits and risks of using new drugs in individual patients, informed by the drug label, their experience with the drug, post-approval studies, and individual patient factors.
As discussed in my recent paper noted above, "The Proper Role of the FDA in the 21st Century," it is imperative that the FDA get back to focusing on safety and effectiveness as the pre-approval standards. The flow of new innovative therapies that can advance health is dependent upon all players in the medical marketplace performing their roles, starting with the FDA making safe and effective products available. We the public and Congress need to acknowledge that the FDA has a daunting enough responsibility to ensure that new medical products are safe and effective, and avoid the pitfall of also demanding perfect public and private health outcomes from the FDA, which is simply impossible. It is fear on the part of the FDA that has driven it to demand proof of clinical utility and benefit in lieu of safety and effectiveness. The first step is acknowledging that medicine is an art, not a science, and that the FDA is not the lone participant in the medical ecosystem that is responsible for advancing the health of Americans.
Gulfo is the executive director of the Rothman Institute of Innovation and Entrepreneurship at Fairleigh Dickinson University and author of "Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances" (Post Hill Press). He has more than 25 years of experience in the biopharmaceutical and medical-device industries and is the former CEO of Mela Sciences. Follow him on Twitter @josephgulfo.