The co-authors of Invasion of the Prostate Snatchers, blog alternate posts weekly. We invite you to post your comments.

Tuesday, December 11, 2012

The FDA and Its Firing Squad (Combidex Part 3)


There are a number of things concerning Invasion of the Prostate Snatchers of which I am proud. Two in particular stand out.

First, that despite his full and demanding schedule, Mark Scholz and I were able to collaborate effectively to produce this book. I have received a whole heap of emails from men thanking us and pointing out that, as far as they know, it is the first time in the literature on prostate cancer where the voices of doctor and patient were heard speaking as peers, each presenting those aspects of the disease he considered of primary importance to the newly diagnosed.

Second, it was both surprising and gratifying to learn that Snatchers had been awarded the 2011 Nautilus Book Award Gold Medal for “Conscious Media and Investigative Reporting” as the result of our tracking down the FDA rejection of Combidex. Since many of you have not read our book, and I know of no other readily available report on that destructive process, I want to review it here as part of the Combidex story.

I was determined to find out why the FDA had rejected Combidex back in 2005. I started by tracking down Jerome Goldstein, the former CEO of Advanced Magnetics (Ad Mag), the Cambridge, Massachusetts company that had marketed Combidex. I found him through his golf club, the Country Club in Brookline.

         “So what do you want to know?” Goldstein asked.

         “What went wrong? Why did the FDA reject Combidex? And can I quote you?”

         “I’m retired now,” Goldstein said in a gruff voice. “so I suppose you can quote me.

Some of the blame was ours. Our application was too broad. We should have gone for disease specificity. But that’s only part of it. The FDA bureaucrats in ODAC were also to blame. ODAC—that’s the Oncologic Drugs Advisory Committee—has total control over the life and death of every new drug application. And because of ODAC’s decision, prostate cancer patients are dying and suffering needlessly.”

Ad Mag’s fatal error was that instead of specifying Combidex as a contrast agent for establishing lymph node involvement in one type of cancer—prostate cancer—they had tried to broaden its application to cover all cancers. They should have known better. Once it has FDA approval for a single “indication,” it is legal for doctors to use a drug “off label,” meaning, wherever, in their judgment, it is useful.

I asked Goldstein if it was possible to obtain a transcript of the ODAC meeting, and he told me that their meetings were a matter of public record. Then, in a low angry growl, he said, “Nobody should ever die from this disease. It’s a crime.” I was about to hang up, when he said, “You know I have prostate cancer. I was diagnosed two years ago. Gleason 6. My internist said I should do surgery or put seeds in.”

         “So what did you do?”



         “Well, not exactly nothing. I bought a new putter.”
Although the transcripts of FDA meetings are a matter of record, they are not that easy to find. What’s more, they are not indexed so you have to dig. When I finally read the minutes and watched a video of the March 3, 2005 ODAC meeting, it was painfully obvious that there was plenty of blame to go around. But the way Combidex—NDA Application 21-115—went down really pissed me off.

ODAC found lots to attack. One patient went into anaphylactic shock from the Combidex. They delivered CPR and epinephrine, but it was too late: the man died at the hospital thirty-five minutes later. The fact that this single death had occurred a decade earlier, and had resulted in an immediate shift in method of delivery—from injection, to dilution of the contrast agent in saline and use of slow infusion—did not reassure the FDA. When I went through the Combidex records, I learned that the man who had died was so eager to participate in the trials that he failed to disclose his allergic condition, or that he had gone into anaphylactic shock on other occasions. Ad Mag pointed out that the vast majority of test subjects had only very minor and transient adverse (mainly allergic) reactions and that only four out of 1,236 patients had experienced a more serious adverse reaction. There had been no further deaths and no serious side effects.
After interviewing several staff members at Ad Mag, I became very aware of the financial reality. Contrast agents are not economically viable. Subjected to all the same requirements as a drug, a contrast agent like Combidex can cost over $100 million to develop, and the likelihood of FDA approval is increased by having a narrow indication. But here’s the irony: the narrower the indication, the less chance the company will ever recoup its money.

And there is a fundamental problem with imaging substances in general. Contrast agents are regulated just like drugs: the same standards apply for a contrast agent as for an antibiotic used to treat a life-threatening infection. Apparently it takes an act of Congress to get contrast agents regulated differently from drugs, and so far that hasn’t happened. But it’s obvious that there need to be different rules for approving imaging agents. Just another disgrace. Add it to the list.

What a crock! A normal lymph node for somebody with breast cancer is no different than a normal lymph node for somebody with prostate cancer. Combidex is “taken up” only in normal tissue. If the tissue’s not normal, the contrast agent is not taken up, and you know there’s cancer.

So while it would appear that applying for a broad application not only made medical sense, it was the only hope Ad Mag had of getting their money back.

There’s a lot more to the death of Comidex. You’ll find it in two chapters of our book: Chapter 15, “Now Playing for a Limited Time Only: The Combidex Follies,” and more in Chapter 17, “Anatomy of an Assisted Suicide.”

I admit it. I’m pretty much obsessed with the fate of Combidex. But as some French person once said, Rien ne vaut un bon obsession . . . (“There’s nothing as valuable as a good obsession.”) And now I’ve found an ally (See prior Combidex blogs) in the courageous Prof. Jelle Barentsz

Combidex redux!


No comments: