Funny Numbers

If Enron were the name of a drug, we would have ample cause to question the validity of the clinical trials that resulted in its approval. When times are good, no one worries about funny numbers. But with more antidepressant lawsuits these days than antidepressant fan clubs, suddenly all that empirical data seems somewhat less empirical (see article). An article, "Hard to Swallow," by Thomas Moore in the Dec 1997 Washingtonian
takes us back to those heady early days of Prozac Nation when optimism was in the air, numbers didn't seem to matter, and accommodating public watchdogs made the kinds of decisions they would scarcely make today. The author is hardly an unbiased observer of the drug industry, but his narrative on how the antidepressant Serzone miraculously survived a series
of failed trials to win FDA approval makes very compelling reading:

In Serzone's initial trial, patients of the experimental drug reduced their Hamilton depression scores on average from 24 to 12 - representing the 50 percent success threshold that usually results in champagne corks bouncing off boardroom ceilings, but the placebo group improved by 11, rendering the results meaningless. In eight trials submitted to the FDA, according to the Washingtonian, Serzone failed to show a clear benefit in six of them. Three other trials were discontinued before results became available. Bristol-Myers Squibb convinced the FDA that too-low doses may have been a cause of the failures, so higher doses were tried, which resulted in one failure, two trials with borderline results, and two that were declared successes.

In the first "successful" Serzone trial, the placebo patients actually did better than the Serzone group by a score reduction of 17 to 14. The greatest placebo response came from 22 percent of the patients being tested at three centers, and when these centers were eliminated from the study after the fact, the findings tipped slightly in Serzone's favor at 13 to 12. Next came a statistical fiction called "last observation carried forward" (LOCF), which effectively keeps drop-outs in the study. For instance, if a Serzone patient had dramatically improved the third week but was not able to continue due to a bad side effect, that third-week benefit would be carried forward to the sixth and final week of the study as if he or she had stayed in the study the whole time. LOCF can also work against the drug, but in this case the final tally showed Serzone the clear front-runner at 11 to 7.

The second Serzone trial, according to The Washingtonian, "required an even more drastic statistical adjustment." That study treated patients at six psychiatric practices and seven family practices, and was an overall failure until the patients from the psychiatric practices - who fared less well against the placebo - were excluded.

In July 1993, the FDA's Psychopharmacologic Drugs Advisory Committee met to consider Serzone in the light of six failed studies and two so-called successes. The Washingtonian reports Dennis Charney MD, then of Yale and now chief of the Mood and Anxiety Disorders Program at the NIMH, as telling the panel: "It is that data that leads me to say it is an effective drug. But I do worry about the large number of failed studies." Regina Casper MD of Stanford University cited her misgivings: "We do not have overwhelmingly strong support for this drug being a strongly effective antidepressant." The FDA representative, Robert Tempe MD, was concerned about undiscovered side effects: "It seems that consumers need to start rethinking that there is a pill for every ill and that they are all safe."

Notwithstanding their misgivings, all but one of the 11 members of the committee voted to declare the drug effective. Dr Tempe, as it turned out, proved tellingly prescient. In January 2002, Bristol-Myers-Squibb put this black box information in its warning:

"Cases of life-threatening hepatic failure have been reported in patients treated with Serzone. The reported rate in the United States is about one case of liver failure resulting in death or transplant per 250,000 - 300,000 patient-years of Serzone treatment ... "

In June 2004, after removing the drug from Europe and Canada, Bristol-Myers Squibb took Serzone off the US and Down Under markets. (The drug is still available in generic form.)

But walking away from their own product won't stop the rash of lawsuits being filed on behalf of patients with bad livers. Entering "Serzone lawsuit" into Google reveals pages of law firms salivating over the prospect of turning Bristol-Myers Squibb into the next tobacco company. The day may come when the company rues the day its antidepressant was ever approved by the FDA. Perhaps future FDA panels will be so kind as to spare other drug-makers from similar fates.

For three free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

Updated June 8, 2004.

Issues and Advocacy articles All articles

Discussions

Albertina (March 17, 2003): I agree that we need to be very cautious with Serzone but would like to add that several people I know have tried a slew of antidepressants with poor results or intolerable side effects only to finally be helped by Serzone and I would hate to take that away from them.

McMan (March 17): I definitely agree with you, Albertina. Undoubtedly, far more people have been saved by Serzone than endangered by the liver risk. So, while I think the drug never should have been approved in the first place - and it wouldn't if it were submitted for approval today based on the same trials - I do not support taking it off the market.

Scott (April 26, 2003): I too took Serzone, and it was my saving grace. I was in a state of chronic depression. I remember the first time I had thoughts of killing myself I was 9. Though I suffered through this ordeal without trying to put the burden on my family for years. Finally when I went to college my world crashed down around me, I failed out mainly because from the second week of the spring semester until the end of it I stayed in my dorm room. I just laid in my bed and just felt hopeless, not self pity but more of a I have nothing to offer so why bother. Finally when I got picked up from college I did go to the doctor and was put on several different medications which caused me to gain over 100lbs. and was even more depressed than ever. Finally my doctor prescribed me Serzone and soon I was able to face the world, I even went back to college. Then, Bam, they took it off the market. I now struggle with my depression and am leery to take any other meds because I lost most of the weight I gains and don't want to go through that trauma again. Yet now I have another problem, I have been diagnosed with liver problems that are most likely the result of Serzone. So my cure became my disease.

Anonymous (April 28, 2003): A woman I know had horrible depression for years. Not long after she started taking Serzone, she was able to go back to school and finish her Ph.D.

Not everything works for everyone. People's biochemistry varies all over the map.

Drugs, food, anything can affect you in weird ways. I get depressed if I eat too many complex carbs — but I can eat sugar all day and all it will do is make me fall asleep in a contented if slightly overweight heap. Oh, and a restaurant-sized helping of blood-rare red meat 3 times a week is must.

Go figure. Guess my head's just wired backwards. But those of us with backwards-wired heads need stuff that works too.

Rather than being taken off the market, Serzone should be available if the more common treatments don't do the trick. Sort of like MAOIs. They're tricky and can be risky, but for a few people, nothing else works.

McMan (April 28): Hi, Anonymous. I would bring back blood-letting if it worked for just one person, so long as it caused no more harm than meds and ECT. You're right on the money.

Post your opinion here.

John McManamy

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