This past week the US Food and Drug Administration (FDA), which has charge of drug approval and the content of the "label" for each drug (the hand-out of key information for patients and doctors), decided to include a warning on the 5-alpha reductase inhibitor drugs that their use "may" result in high-grade prostate cancer. This is an unsound, misleading, awful decision!
These drugs, Proscar (generically available as finasteride), Avodart (technically known as dutasteride but not generically available), Propecia and their international variants are approved by the FDA for reduction of benign prostatic hypertrophy/hyperplasia (BPH) and reduction of male-pattern-baldness. They are not approved for prostate cancer or its prevention, but are available under "off-label" procedures for those purposes. In the past decade two trials (the Prostate Cancer Prevention Trial - PCPT - and REDUCE) demonstrated convincingly that these drugs can prevent about 22% to about 30%, depending on what is counted, of lower-grade prostate cancer (Gleason scores up to 6). The FDA agrees with that.
However, now, due to the FDA's official action, those labels will all have to include the FDA's warning of possible promotion of high grade prostate cancer, meaning prostate cancer with a high Gleason score, especially in the range from 8 to 10. Finasteride has been an important element of my therapy, and I have been on it continuously since September of 2000.
At least the FDA used the word "may" in characterizing the possible link between these drugs and Gleason 8 to 10 cancer. In fact, their decision is extremely poorly based, and you do not have to be a genius to see that, if you just know the key facts and have a proper vantage point. I have been following finasteride - then Proscar - from early in 2000, before I started taking it. I have talked to some of the leading researchers, and I spent a whole day watching a webcast of the FDA's advisory committee hearing on whether to approve finasteride for prevention of prostate cancer last December 1.
While the whole hearing, including the backup materials, is available on the FDA website - a site we can mention because it is Government sponsored, the FDA submitted its rationale to the New England Journal of Medicine, and the NEJM published it this week (June 15), also choosing to make it freely available to all. It's a short paper with just two tables, really boiling down a long and complicated hearing and the follow-up FDA decision. While there are many arguments that can be made and facts that can be cited in support of the 5-ARI drugs for prevention of prostate cancer and its role in supporting therapy, to see how weak the FDA position is we need look only at what they state in the paper. The FDA omits a number of arguments against the 5-ARI drugs that were raised at the hearing, probably because those arguments were clearly weak and faulty, and boil their case down to a few key assertions, as follows, with my ordering and numbering:
THE FDA's CASE THAT THE 5-ARI DRUGS MAY PROMOTE HIGH GRADE PROSTATE CANCER
1. The patients randomized to the 5-ARI drug arms (finasteride or Avodart) in the two trials did not experience an increase in Gleason score cancers when all cancers in the 7 to 10 range were totaled. This was the analysis performed at the time of the trial, and everyone, including the FDA, agrees with this - no controversy. Of the cancers in the trials above Gleason score 6 - the Gleason score 7 - 10 range, most (75%) were Gleason 8 to 10 cancers, said the FDA. Therefore, the FDA decided to look just at the Gleason 8 to 10 cancers, comparing the 5-ARI drug arms to the placebo arms. (However, the second table in the paper shows that the preponderance of cancers were GS 7 cancers (70%), not 75% the other way around! To be specific, the second table in the paper shows that there were 243 cases of cancer ranging from GS 7 to 10 in the finasteride trial; of those, there were 73 cancers ranging from Gleason 8 to Gleason 10; that leaves 243-73=170 Gleason 7 cancers, which is 170/243=70%. I would really appreciate someone else looking at the paper and confirming that amazing discrepancy, as I'm concerned I may be so angry that I'm somehow not reading the information correctly. It's amazing because the FDA should have seen it, and the NEJM editors should have spotted it. But that is not why I am angry.)
2. That FDA analysis showed an increase in cancers diagnosed in the GS 8-10 range in the finasteride and Avodart arms of the two trials. How great was that increase? Well it was 0.5% for the Avodart trial (half a damn percent
and 0.7% in the finasteride trial well under 1%!
So here we have a tiny, miniscule increase for Gleason 8 - 10 cases versus substantial reductions for tumors up to Gleason 6 and what other data show to be no impact either way for Gleason 7 tumors.
Now I have a background in statistical analysis, and what I saw next was revolting. While the results for the Gleason 2 - 6 and the Gleason 7 groups were quite tightly grouped - what statisticians refer to as the confidence interval, tight grouping that promotes confidence in the estimate, the Gleason 8 - 10 results were all over the map, a circumstance that should greatly decrease confidence in the reliability of the estimate.
The results ranged from "odds ratios" of likely higher grade disease for Gleason 8 - 10 of 1.01 (virtually no impact compared to placebo) to 2.26 (more than double the impact). What that signals to a statistician is that rather few data points were involved to support the conclusion, in sharp contrast to the situations for the Gleasons 2 - 6 and Gleason 7 -10 groups; it suggests that the true impact (from a heavenly viewpoint with the ideal total population of all possible patients) ranges from no impact to more than double the impact. It is upon that weak thread that the FDA chose to base its case!
Okay, let's assume for a moment that the FDA is right, that there actually is an increase, even though very slight, in high grade disease in the finasteride and Avodart arms of the study. Knowledgeable researchers and physicians who favor these drugs for prevention and therapy support are firmly convinced that these increases occur because the drugs increase detectability
but do not cause the high grade disease. The line of thought is simple. Imagine two circles that represent a prostate for a man not on the drugs and a prostate of a man on the drugs. The circle for the man on the drugs is a lot smaller because these drugs shrink prostates substantially. Therefore, when you take the same number of biopsy samples from each circle, the samples in the smaller circle each have a smaller area to cover. That means they can cover it more effectively. That means, if you have equal amounts of Gleason 8 - 10 disease in both circles, the biopsy for the circle representing the man treated by finasteride is more likely to detect that Gleason 8 - 10 cancer! To me, that is a compelling explanation for higher detection of high grade cancer in the finasteride and Avodart arms of the trials, easily explaining the miniscule increases of well under one percent of high grade disease.
Now this line of thought about the volume of the prostates was well raised at the hearing by the proponents of these drugs for prevention. The FDA acknowledged it as a possibility, and even acknowledged it in the NEJM paper. However, the FDA did not come to grips with it either at the hearing or in the paper. Rather, it states in effect that it's own analysis of the GS 8 - 10 cancers trumps the prostate volume argument. I considered that heavy-handed, misguided and unwise at the time of the hearing and in the NEJM paper. To repeat: the FDA has not directly refuted the prostate volume explanation for the higher percentage of Grade 8 - 10 cancers found in the biopsies of men in the finasteride and Avodart arms of the study!
Why does this matter to those of us who care about this disease and its impact? To me, it's not about prevention, because, as the FDA points out in the paper, these drugs are still available under unburdensome "off-label" prescribing procedures for prevention of prostate cancer if the physician and patient thinks they would be helpful. I myself am not in favor of broad-scale prescription of these drugs for prevention; it would waste money and be a minor burden on patients with too little benefit, especially now that we have active surveillance as an effective approach for diagnosed low-risk disease. Instead, I and I believe most other proponents think these 5-ARI drugs should be targeted to men at higher risk of getting the disease. I'm encouraged that we are getting a better handle on risk as each year goes by. We have good hopes of genetic risk profiles in the near future.
No, to me it is not so much prevention, but rather the potential of these drugs to both find high-grade disease earlier and to actually decrease the incidence of high-grade disease, the very reverse of what the FDA currently believes!
A number of analyses have been published that support both points. In fact, the second table in the paper mentions that, by one analysis, the incidence of Gleason score 7-10 cancers were reduced by 27%!
(odds ratio of .73 means a 27% reduction) These are the wonderful opportunities that are currently being lost!
You might be wondering why the FDA would do such a thing. An expert friend of mine is convinced its because the FDA is under such great political pressure not to approve drugs with serious side effects. That may be it. I'll admit I'm baffled. I'm usually a fan of the FDA, and I still believe they try to do a good job, but not this time.
Malpractice attorneys are already advertising their services in attempts to solicit customers who have taken the 5-ARI drugs and have experienced high-grade prostate cancer. Words cannot express my revulsion for what they are doing!
Most physicians are not expert and informed in the background of this controversy, and I'm convinced many are going to be intimidated by the prospect of malpractice lawsuits. Another likely effect of lawsuits, if this movement is not throttled before it gets going, is increased prices for these drugs.
I dearly hope that the prostate cancer patient community will once again rise up and demand that common sense and sound research prevail, overturning the FDA's label decision.
Let's win this one!