FDA Disappoints Lung Transplant Patients

Many close observers of the Food and Drug Administration believe that the recent criticism the agency has received in the media and the manhandling it has received by some camera-keen Congressmen are making rank-and-file regulators more cautious when it comes to new drug approvals.

Medical reviewers inside the FDA, the logic goes, are scared they will become the next sacrifice along a Congressman's way to the cameras or a trial lawyer's search for the next big payday.

But a series of lopsided votes from the agency's outside advisory committees to turn down otherwise promising new drugs leaves the overwhelming impression that the criticism has cast a darker shadow of caution over these outside advisors that even over rank-and-file FDA staff.

The latest came on Monday with a stunning split decision on an effective new medicine called Pulminiq to prevent rejection in lung transplant recipients, a condition that is fatal in more than half of all cases once the malady sets in.

That the advisory panels would be the first to grow skittish seems to make sense. It is one thing when the media and Congress go after rank-and-file FDA reviewers and agency hands. Most people who work at the FDA expect the criticism, and there are many institutional protections built into the agency that shield its professional staff from gratuitous attacks.

But members of the FDA's outside advisory committees, who are drawn from the ranks of academic medicine, are rewarded for serving only by the enhancement to their reputation, and don't have similar protections or expectations.

When these advisors are investigated for puffed-up charges of conflicting interests (advisory committee members from the Vioxx hearing were recently sent letters from Senate investigators that they were being scrutinized) or negatively profiled on the pages of the biggest newspapers, the reputation-enhancing value of serving diminishes. So does the value of taking a courageous medical stance in favor of a lifesaving new medicine that still has certain doubts.

Such was the case of Pulminiq, an inhaled version of a common immunosuppressant, developed by Chiron and used to help lung transplant patients hold on to their new organ in the face of chronic rejection. Chiron acquired rights to the drug from Novartis and was seeking accelerated approval for the drug to treat the rare but serious medical problem.

Nervously deadlocked members of the FDA's Pulmonary-Allergy Drugs Advisory Committee voted 8 to 8 on whether or not the long-approved and commonly-used immunosuppressive drug confers a significant survival benefit among lung transplant patients when it is taken in an inhaled solution.

A treatment for the rejection transplanted lungs is arguably a small market, but more than 50% of lung transplant patients who reject their new organs die, and there are no approved drugs for the problem--nor are there highly effective treatments. Those panelists voting in favor of Pulminiq felt that the drug's impressive results--12% of patients on Pulminiq died versus 47% on placebo--were too good to ignore.

Panelists voting against approval said they were worried that the two-year phase II trial of Pulminiq included too few patients (just 56, all drawn from a single center), and that the trial missed the primary end point of acute rejection. They also worried that results may have been biased because patients may not have been appropriately randomized to treatment or to placebo.

The failure of the study to reduce death from acute rejection caused concerns among the FDA's review team because acute rejection is a risk factor for chronic rejection. But it has since been scientifically established that acute rejection is understood to be a function of a vascular process, not just an attack by the immune system.

Pulminiq aims to interfere with the latter. Chronic rejection is believed to be related to problems with the lining of the airway, which an inhaled treatment like Pulminiq should directly impact. So the biological basis for the drug's observed benefits was strong.

In fact, about 10% of all lung transplant centers in the U.S. already used inhaled cyclosporine treatments like Pulminiq, only they mix it up themselves since there aren't any approved versions yet. For that reason, if Pulminiq doesn't win approval, doing follow up studies with the drug, especially studies where patients are randomized to placebo, is going to be hard. Facing death, who is going to want to inhale a placebo when their doctors can brew up something closer to the real thing?

There has been a series of lopsided panel votes. Earlier this year, the FDA panel voted unanimously against Proctor & Gamble's female sexual stimulant, a testosterone patch called Intrinsa. Plus, there were cautious votes by the FDA's cancer drug advisory committee against Johnson & Johnson's drug Zarnestra. It's become clear FDA's advisors are taking a go-slow approach to new drugs.

It used to be conventional wisdom that companies would push to have their drugs reviewed by the FDA's outside advisory panels, believing that the clinicians on these panels, being more closely tied to the rigors of clinical practice and the need for effective treatments, look more favorably upon promising treatments.

Now, it seems that companies would be wise to avoid these panels altogether.

These are the wages we pay as our politicians strut about in Washington attacking anything that is seen holding a pill bottle.

It makes for some fun theater and will advance a few political careers along the way. But how many lives will it cost when promising new treatments are kept out the hands of patients who otherwise are going to die?

Scott Gottlieb is a resident fellow at AEI and a practicing physician. He maintains an FDA policy blog at www.FDAInsider.com.

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