July 9, 2018

How Can the FDA Foster Greater Resilience in the Medical Marketplace?



What is the best way to regulate the market entry of new drugs and biologics in a manner that fosters medical innovation, yet does not make unsafe or unproven products available to doctors and patients? In a new paper—Fostering Resilience in the Medical Marketplace—we answer that question with a set of recommendations for improving the U.S. Food and Drug Administration’s (FDA) regulatory approval process.

The FDA was established to make sure that medical products are safe and effective prior to broad availability. But in recent years, the FDA has strayed from its original mandate, requiring not only evidence of safety and effectiveness but also evidence of clinical utility. That means that new drugs must prove that they are not only safe and effective, but offer, in some overall and ultimate sense, profound benefits to patient health from a product. Even the best science generally cannot produce conclusive evidence on such a question—even regarding drugs that have been used by millions of patients over many years. And so, for diseases that affect millions of Americans and are responsible for most of the morbidity and mortality in our country (i.e., heart failure, Alzheimer’s disease, COPD, diabetes, etc.) FDA-mandated pre-market clinical trials have become ever longer, larger, and more complex, in pursuit of that aspirational goal.

While gathering evidence about clinical utility is important and desirable, requiring proof of profound clinical utility as a condition of market entry blocks useful drugs from ever making it to the marketplace. That such drugs are now often blocked is the key reason that no new drugs to treat Alzheimer’s disease have been approved despite the many large drug trials conducted over the past decade.

Furthermore, the protraction of preapproval processes has taxed the FDA’s capacity to produce new-drug reviews, as greatly increased budgets have been necessary just for FDA to deliver the same number of reviews per year as it did a decade ago.  

Why has the FDA strayed from its mandate? The responsibility largely lies with Congress, which has often sought to castigate or humiliate the FDA at those moments when toxicities associated with approved products have emerged. For Congress to exercise oversight only at such stressful moments has led the FDA to react by moving to seek assurance of the clinical utility of new products, thereby becoming more restrictive than is necessary. This is one of the main reasons that most small companies, the cradle from which many new medical discoveries emerge, are now largely focused on orphan rare diseases. The hurdles for approval are lower because (1) clinical benefit is much easier to demonstrate and (2) if toxicities emerge the number of patients at risk is minimal.

Going forward, Congress should affirm that the FDA is to evaluate effectiveness in accordance with the labeling proposed by the sponsor, and that the FDA is not to require demonstration of clinical utility for approval. There should be an explicit list of acceptable measures of effectiveness that can support approval, including pharmacodynamics effects on disease parameters, clinical signs and symptoms, biomarkers, surrogate endpoints, patient-reported data, comparative effectiveness, clinical outcomes, and survival. And there should be a strong caveat that those last three measures—comparative effectiveness, clinical outcomes, and survival—are not necessary to demonstrate effectiveness. The FDA’s insistence on such measures has often needlessly delayed or suppressed useful drugs, rendered drugs more expensive by dampening market competition, and created unintended consequences in drug development patterns.

The FDA should also be permitted to establish categories of approval according to the nature of the evidence used to support effectiveness. For example, perhaps there could be four categories of approval for new drugs, corresponding to whether evidence shows that a drug is (1) effective upon biomarkers only, (2) effective upon clinical signs and symptoms, (3) effective at disease modulation or modification, or (4) effective in delivering clinical outcomes and survival. Such a system would put the FDA in the proper position of adjudicating safety and effectiveness, and it would help the FDA to clearly communicate to the medical marketplace its rationale for approval and the clinical effects that doctors and patients can expect when using new drugs.

Importantly, this system would expand the armamentarium of available drugs to be evaluated in novel combinations by medical researchers, drug companies, and expert clinicians. Combination therapy is key to curing the most vexing medical problems of our time, and if safe and biologically active drugs are not made available to be combined, discovery of vital combinations may be greatly diminished.

From the executive summary:

What is the best way to regulate the market entry of new drugs and biologics in a manner that fosters medical innovation, yet does not make unsafe or unproven products available to doctors and patients? The U.S. Food and Drug Administration was established to make sure that medical products are safe and effective prior to broad availability. Over the years, the FDA has strayed from its mission by mandating clinical trials that require far more than evidence of safety and effectiveness; this has driven up drug development times, costs, and prices. Poor Congressional oversight has not only failed to rein in the FDA; it has also significantly contributed to the problem. We propose categories of medical evidence upon which approval decisions can be made. This would refocus the FDA on judging products by using appropriate clinical measures and on communicating to the medical marketplace the nature of the evidence supporting its safety and effectiveness decisions.

Read the full paper here.