Appropriate oversight is needed to change FDA behaviors, not more laws
© Joseph Gulfo

Oversight of the executive branch is a main duty of Congress that flows from the many and varied express powers of Congress in the Constitution, including appropriating funds, enacting laws, and impeaching and removing civil officers. However, as former House Speaker Tip O'Neill (D-Mass.) once exclaimed, "Members like to create and legislate, but we have shied from both word and deed of oversight."

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Not only has Congress shied away from oversight, it has been used more as a "fire alarm" than as "police patrol," in the words of Mathew McCubbins and Thomas Schwartz. Congress has been deficient in "police patrol" oversight — that is, constant watchful vigilance to ensure that Food and Drug Administration (FDA) laws are enacted dutifully. But it has been quite aggressive in exercising "fire alarm" oversight that comes from hearings in response to events, for example, adverse reactions with medical products.

There have been many high-profile hearings on drugs including antidepressants Vioxx, Rezulin and Avandia. In all of these, the FDA is basically accused of inappropriately approving products that are unsafe. Of course, the issues are not so cut and dry. This kind of knee-jerk oversight, which provide great theater and incentives of their own, greatly damages the cause of medical innovation: As former FDA Commissioner Alexander Schmidt said in 1974: "In all of FDA's history, I am unable to find a single instance where a congressional committee investigated the failure of FDA to approve a new drug. But the times when hearings have been held to criticize our approval of new drugs have been so frequent that we aren't able to count them. The message to FDA staff could not be clearer."

The case of Avandia is particularly disconcerting. Even when the FDA does the right thing — for example, approving an excellent drug that helps millions of patients — it is castigated and publicly humiliated. A New England Journal of Medicine publication of a meta-analysis of 42 small clinical trials revealed an increased likelihood of significant cardiovascular toxicity in patients taking the drug, so the FDA restricted the drug's use in response to pointed criticism at a congressional hearing. Here is what the FDA had to endure at a Senate hearing on the matter: "This report poses several troubling questions for this subcommittee. Most obviously, if Avandia is unsafe, how did it ever get on the market in the first place? For that matter, why is it still on the market, right now? And what does the case of Avandia tell us about the FDA's current ability to conduct its drug safety responsibilities?"

Subsequently, the FDA removed the restrictions from the label when the drug was shown not to cause increased cardiovascular problems, following a re-analysis of a very large prospective study, rendering the meta-analysis flawed. But the damage was done: The FDA changed the regulations to require larger and larger clinical trials and disease outcome endpoints for products that are intended for large chronic diseases, like diabetes. Knee-jerk oversight triggered by a flawed analysis had severe unintended consequence.

Sadly, Dr. Robert Califf, nominated to be the new FDA commissioner, was in full support of erroneously demanding larger and larger trials in the midst of the Avandia saga. As Matt Herper writes, "In 2008, after Steven Nissen from the Cleveland Clinic had openly criticized Avandia, the GlaxoSmithKline diabetes drug, he proposed a new standard for studying diabetes medicines that would insist they be tested in clinical trials involving thousands of patients to see if they had any effect on heart attack rates. When Nissen mentioned the idea at an open public meeting, Califf was fast to back it." And, these sorts of unnecessarily large, expensive and time-consuming studies have remained as the new standard; they were not walked back when the case of Avandia was shown to be a false alarm. Just last week, the FDA noted the following: "continued monitoring" of Avandia, Avandamet and Avandaryl had turned up "no new pertinent safety information" about the drug. So, the agency lifted the final layer of safety measures that it erroneously imposed. But sales of the drug were crushed; as reported by FiercePharma, "The safety questions drove Avandia revenues down from a peak of $3 billion before the controversy to $183 million in 2011, just before generics hit the market."

At the Senate HELP (Health, Education, Labor and Pensions) committee's confirmation hearing for Califf on Nov. 15, 2015, he doubled down:

Sen. Elizabeth Warren (D-Mass.): Do you agree with arguments to lower standards for FDA approval of drugs and devices?

Califf: I have never been a proponent of lowering standards for anything. ... I have been in favor of raising standards. In no case would I argue to lower the standard. I think I have been staunch in that regard.

It is understandable that the FDA would retrench when it is attacked. The agency then protects itself from future attack by: (1) raising the bar for product approvals by moving away from the statutory criteria of safety and effectiveness and demanding proof of clinical utility, clinical outcomes and survival; (2) demanding larger and larger trials that cost tremendous amounts of time and money; (3) shifting its emphasis to pre-approval requirements versus a balance of pre-approval data and post-market controls and surveillance; and (4) preferentially approving products for niche diseases rather than those that affect millions of Americans.

After the FDA retrenches in response to criticism and then issues new rules and guidance documents with alternative interpretations and implementations of the laws, Congress does not perform the appropriate police patrol oversight to re-direct the FDA back to its mandate, forcing the FDA to honor the letter and spirit of the laws that are passed. No, it does something worse: It actually passes more laws, for example, as part of each PDUFA (Prescription Drug User Fee Act) and MDUFA (Medical Device User Fee Act) reauthorization that takes place every five years, and in other legislation, like 21st Century Cures. This legislation, drafted in consultation with the FDA, then codifies the FDA's new positions taken in response to inappropriate fire alarm oversight.

The vicious cycle starts over again the next time an unfortunate adverse events occur with drugs and devices that are on the market, which will invariably come to be. And this is how regulation kills medical innovation and hurts patients.

In our latest MI3 Alert, we examine the effects of this vicious cycle and offer solutions to reducing regulatory burden so that medical innovations that can truly promote the health of tens of millions of Americans can flourish, keeping pace with the amazing scientific advances that are being made. Unfortunately, better oversight, alone, cannot accomplish this — we need some laws to undo the damage that many turns of the vicious cycle has wreaked. For example, the FDA must be made to return to safety and effectiveness (as measured by activity in modulating disease signs and symptoms, surrogate endpoints and biomarkers) and allow doctors and patients to determine clinical benefit. Of course, better oversight will require yearly reports of FDA performance with respect to product reviews and approvals in comprehensible terms, like calendar days and averages, as well as reports from the FDA ombudsman regarding issues that arise between the FDA and drug developers. And Congress should resist the temptation to publicly flog the FDA at fire-alarm hearings when unwanted unfortunate toxicities arise, which they invariably will; this is the nature of medical and scientific progress.

As Speaker Newt Gingrich said, "This is the city [Washington] which spends almost all of its energy trying to make the right decisions and almost none of its energy focusing on how to improve implementing the right decisions. And without implementation, the best ideas in the world simply don't occur."

We have excellent ideas that are not reaching patients. We need congress to start performing oversight appropriately to make the FDA's first priority is promoting health, not protecting itself from attack.

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.