Why Doesn’t the FDA Get More Respect?

It is surprising that a recent commentary in the September 21^st issue of the Journal of the American Medical Association entitled “The FDA – A Misunderstood Agency” seems to have received little attention.  Written by Dr. Joshua Sharfstein, the current Secretary of the Maryland Department of Health and Mental Hygiene and the former FDA Principal Deputy Commissioner, the article presents both an explanation and defense of the FDA’s policies and procedures.  I wish Dr. Sharfstein went further in his comments.

The FDA, while not perfect, is often criticized unfairly.  Here are three typical examples.  Invariably, after a new drug is on the market for a few years, the FDA will announce that this new medicine has some new safety issue that hadn’t been seen previously.  This issue is not unusual.  When a new drug is approved, it generally has been tested in perhaps 10,000 patients for a year.  Once it is on the market, if it is a chronically used drug, it may get used by millions of people over the period of a few years.  As it is more broadly used, more information is gathered on the drug and the FDA will react to this.  Unfortunately, when this occurs, there will be members of Congress (Sen. Grassley comes to mind) who will hold a press conference and rail against the FDA for its lax attitude in approving new drugs.  There are ALWAYS risk-benefit issues with any medicine, old or new.  Some politicians don’t seem to get this.  The FDA does.

Interestingly, there are those who criticize the FDA for being too slow in approving new drugs.  This can occur in diseases where this is no adequate treatment for life-threatening diseases.  In these cases, there are patient advocacy groups who want certain medicines approved as quickly as possible.  Their view is that, if there is a drug in trials that can save the lives of themselves or their loved ones, the FDA has no right to prevent patients from getting this medicine.  In these cases, the FDA generally has significant questions about whether the drug indeed is effective and will not approve it without hard data showing that the drug works.  It should be noted that the FDA has a good track record of reacting with alacrity to health crises, as evidenced by their actions in approving AIDS drugs in the early days of that epidemic.

But what I find most exasperating is the criticism that the FDA is beholden to the pharmaceutical industry because of the Prescription Drug User Fee Act (PDUFA).  Back in the 1990s, there was a “drug lag” – drugs were getting approved in Europe years ahead of their approval in the US.  Congress was outraged and demanded an explanation.  The FDA correctly said that the organization was grossly understaffed and that new resources were need to deal with the backlog of drugs awaiting approval.  Rather than allot the FDA more funds, Congress enacted PDUFA which essentially was a charge to the pharmaceutical companies on the filing of their New Drug Application (NDA).  In 2011, this fee is $1,542,000 for each NDA.  Critics say that, because the FDA is dependent on these user fees to support their division, FDA staffers feel beholden to pharmaceutical companies and, as a result, try to do all they can to help these companies. This view is ludicrous.

To a certain extent, the FDA is in a no win position.  It has to judge what medicines the US population should or shouldn’t take.  This is rarely a black or white decision.  As was stated above, all medicines have side-effects.  The question the FDA must answer is what is the risk-benefit of each new drug–this is always a judgment call.  The FDA tries to work closely with all of those dependent on its actions – patients, physicians, companies and government officials.  The FDA is not infallible, but it gets it right most of the time.  It’s time to respect this.

The FDA Is Justified in Asking For Outcome Studies

On August 10^th, the Wall Street Journal published a letter to the editor entitled, “The FDA Isn’t as Innovative as It Likes To Think It Is,” in which Skyline Ventures Founder, Dr. John Freund, lashed out at the FDA.  Specifically, he challenged the view espoused in Margaret Hamburg’s WSJ Op-Ed piece: “America’s Innovative Agency: The FDA.”  The FDA’s self-anointed role incenses Freund, who wrote:

“The FDA has tightened up the requirements for approving new drugs for adult-onset diabetes, a disease that affects approximately 25 million Americans.  The result is that performing the clinical trials for a new diabetes drug is so long and costly that no venture capital firm will finance a new diabetes drug.”

He also has doubts about the FDA’s desire to approve new drugs to treat obesity, writing, “In the past year, the FDA rejected three separate drugs to treat obesity, including one for which the FDA’s own advisory panel recommended approval.  As a result, no venture capital firm will now finance a new effort to develop a drug for the obesity epidemic.”

Despite the fact that I am a “Big Pharma” veteran, I am on the side of the FDA on this one.

First of all, the relatively conservative position taken by the FDA in obesity and diabetes is not unique to these therapeutic areas.  In fact, it is seen in new drugs for cancer, osteoporosis and heart disease.  No longer will the FDA approve a drug for obesity based solely on its ability to induce weight loss.  Similarly, the FDA wants to see more than blood sugar lowering before approving a drug for diabetes.  While both are meaningful markers for improving the respective disease condition, the FDA also wants to see outcome studies, that is, two to three year long studies showing that the weight loss or lowering of blood sugar actually correlates to a reduction in heart attacks and strokes, the unfortunate end results for diabetes/obesity.

Why is the FDA asking for long-term data?  Won’t weight loss and/or blood sugar lowering automatically result in enhanced survival?  Surprisingly, the answer is no.  A recent case-in-point was the widely prescribed anti-diabetic agent, Avandia.  This drug was approved on the basis of its impressive blood sugar lowering ability.  However, and to the surprise of many, this drug DID NOT reduce adverse cardiovascular events in long-term studies conducted after it was approved for sale.  In other words, lowering blood sugar had no impact on the ultimate desired outcome.

In the case for weight loss agents, the FDA’s rationale is likely different.  A true weight-loss drug is going to be widely prescribed and theoretically could become one of the biggest drugs in history.  With the likelihood of such broad usage, long-term safety of such a drug needs to be shown before unleashing it on the public.  This position is best supported by the diet drug phen-fen, which causes modest weight loss, but which is associated with severe cardiac damage on prolonged use.

The same is true for new drugs in other classes.  Studies have shown that just because a drug shrinks the size of a tumor doesn’t mean it enhances survival.  Or, if a compound stabilizes bone formation, it may not prevent fractures.  And there are a number of studies that show that raising HDL, the good cholesterol, doesn’t reduce heart attacks.  Faced with this situation, the FDA has done the logical thing – it wants outcome studies to justify approval for drugs that will need to be used by patients for decades.

The assertion that Dr. Freund makes that “no venture capital firm will now finance a new effort to develop a drug” for diabetes and obesity is not true.  Catabasis, a biotech company in Cambridge, MA, recently raised almost $30 million from VCs to support their exciting new approach to diabetes.  And Gelesis, a company that has been formed by PureTech Ventures (where I am a Senior Partner), is focused on obesity and has also recently raised funds to support its R&D program.  Despite this admittedly tough regulatory environment, good ideas are still garnering investments.

There is a positive aspect to all of this.  If a compound can successfully clear these hurdles, it will be a blockbuster.  The manufacturer will be able to say that its new compound not only causes weight loss, but it also reduces heart attacks and strokes.  The same would be true for a diabetes drug that reduces cardiovascular events as well.  Without question, the FDA’s regulations benefit everyone involved.