A Tale of Propecia That Could Induce Alopecia!
Sherman Frankel, University of Pennsylvania
In April, 1998 I was contacted by NBC for a possible appearance on a Dateline segment about Propecia, which is the new name for the drug, finasteride, which had been marketed as Proscar as a cure for benign prostatic hyperplasia. Proscar had been prescribed for older men with urinary problems because of the supposition that the cause of these problems is an enlarged prostate. Propecia, I was told, was now being marketed for younger men who wish to grow hair. I had never studied this particular use of finasteride, and for that reason declined the invitation to Dateline. Because of the ability of finasteride to suppress the conversion of testosterone to dihydrotestosterone, and therefore to promote the growth of hair, I thought it would be interesting to pursue the subject further.
By law, approval of a drug for a new use is based on data submitted by the manufacturer to the Food and Drug Administration (FDA). But I was unable to find the request for the approval of Propecia provided to the FDA by the manufacturer, Merck, on the FDA web site, although the data submitted on behalf of drugs approved at a later date were already there. I decided to obtain information on the Propecia submission using the Freedom of Information Act. After some months, the fiches were received and Dateline was helpful in printing them out, all three pounds of pages coming to me for study. I discovered beautiful data on the conversion of testosterone to dihydrotestosterone, which is the physical basis for hair growth. Having had considerable experience searching the medical literature (I had found 45 articles in my web search of finasteride, as is described in one of my earlier papers)1 I was puzzled by the absence of anything pertaining to the data supplied to the FDA by the manufacturer, Merck. I initiated phone and fax communications relating to Propecia with Keith D. Kaufmann of Merck. He affirmed that the data about testosterone had not been published. I asked why not, despite its having been sent to the FDA. Surely, he responded, I must know how difficult it is to get articles published these days.
That response convinced me to take time off from my other research endeavors for the purpose of investigating this bizarre circumstance. I diligently studied the huge amount of data, wrote up my results, and sent a prepublication copy to the ombudsman of the FDA for transmission to the persons at the FDA who had been responsible for approval of the drug.
In August, 1998, I submitted a manuscript titled, ``Study of the Food and Drug Administration Files on Propecia'' to the Archives of Dermatology. It is customary in scientific journals that, if the editors who read the article judge it to be of interest to their readers, it is then refereed. The editors play a crucial role, especially because they may reject an article they have read without sending it to referees. My article on the finasteride data was read by either Kenneth Arndt or Robert Stern, the senior editors of the Archives of Dermatology. It was deemed sufficiently interesting to them that it was sent to three referees, all of whom approved it for publication. The essay was put into the format of a Commentary, and after minor revisions were made, was accepted for publication. About a year after submission, it appeared in the March 1999 issue of the Archives.
I am not a physician, but a physicist with over a half century of experience in analysis of data, so I was naturally pleased to receive many e-mails that supported my assessment of the data as it appeared in print. I was concerned, nonetheless, that the FDA had not properly appraised the most quantitative data regarding Propecia in the submission to it by Merck.
My purpose was not to criticize Merck (and I did not), but to raise questions about the FDA's approval of Propecia. Toward that end, I traveled to Washington to speak with the director of the FDA, Jonathan Wilkin, and the chief physician responsible for the approval of Propecia, Hon-Sum Ko. I was troubled that not a single referee for the FDA had commented on the following key pieces of data: a) Conversion of testosterone to dihydrotestosterone fell to a low level at 0.05 milligrams and stayed there up to 5.0 milligrams. b) Efficacy had not been established below a dosage of 1.0 milligram.
Although side effects did not occur often at 1.0 milligram, effects of finasteride on the volume of ejaculate of semen and a big depression of the score for prostate specific antigen (PSA), a test for prostate cancer, were included in the data submitted to the FDA.
Through the ombudsman for the FDA, I had communications with the FDA and finally made the trip to Washington to ask why they had approved Propecia at a dose of 1.0 mg.
I then returned to my other interests in physics until, one day, in December 1999, a dermatologist friend asked me whether I had seen three denigrating pieces about my Commentary from Merck associates that appeared in the ``Letters to the Editor'' section of the Archives of Dermatology.
Those hostile Merck inspired Letters to the Editor must have been read before being approved by the editors, Kenneth Arndt and Robert Stern, who are expected to have enough competence to judge their scientific merit. The senior editors chose not to have any of those letters refereed, nor did they follow the usual process of informing me of the fact they were going to publish the unrefereed Merck responses and granting me the opportunity to respond to them.
My detailed responses to the three letters are technical in nature and are not repeated in this article. The interested physician can read them, however, on my web page: www.physics.upenn.edu/facultyinfo/frankel.html They are listed under ``Medical Research'' and entitled: ``Responses to Merck Comments in the Archives of Dermatology''. They will provide some insight on a prime example of faulty logic and science that is not uncommon in the drug field.
Advertising Drugs in Medical Journals:
It is astonishing to basic scientists that medical journals take paid advertisements from drug companies. It puts the editors at times into compromising situations that must, on occasion, cause a twinge of conscience. I have written about that matter in an article that appeared in Urology2, an interaction between me and the New England Journal of Medicine. The editor of that journal rejected one of my articles about finasteride, and said that it would have been published had it been submitted when the original Merck data about finasteride was published. One can only infer that if a published claim about research is found to be flawed, it cannot be refuted by the discovery of the error at a later time! Parenthetically, my conclusions on Proscar were later verified in a double-blind comparison of Proscar, Hytrin, and Cardura carried out by Dr. Lepor at New York University.
Discussions with the Archives editors:
When I discovered the negative letters related to my study of the data submitted by Merck to the FDA, I called and wrote the senior editors of the Archives to discuss the matter with them. My letter of December 5, 1999, and subsequent phone calls went unanswered so on January 5, 2000 I again wrote asking that an editor call me. That letter also was ignored. I decided to Fed Ex an earlier larger and detailed version of this article, including my detailed response to the Merck criticisms. In February, I received a letter of rejection of that piece. I attempted again to reach Robert Stern by phone. After many attempts, he called me and we had an interesting conversation, some of which I record now.
Stern responded to my questions about his unusual decision to neither inform me of the Merck Letters to the Editor nor give me a chance to respond by asserting that he does not send submitted letters to referees. But because he had to have approved of publication of those three letters, he must have known of their content. He apparently decided that the Merck letters had validity and made no effort to find out whether or not that was correct. Stern said he had taken the time to read my prior articles on finasteride and that he had examined my work on the frequency of prostate cancer caused by finasteride. But I have never published any article saying that finasteride caused prostate cancer. This remark seemed to be a mere invention in order to justify his rejection of my new article. He communicated that the article was actually rejected by Dr. Arndt but that he concurred in the decision. The reason stated was ``enough is enough'', thereby setting a new standard for worthiness of publication. He also averred that one reason for rejection was the journal had ``a limited number of pages.'' Stern ended by saying that ``The problem is between you and the FDA and Merck and is not between you and the Archives of Dermatology.''
Interactions with the FDA:
While my article preceded my discussions with the FDA it seems useful to report now on comments I received about it, in writing from the FDA:
a) The FDA dismissed the data on the testosterone to dihydrotestosterone conversion measurements as ``surrogate'', even though there were no low dosage measurements on efficacy. That beautiful data cannot be ignored in order to justify the dosage approval by the FDA. Surrogate can only be applied to physical data if the efficacy data are done over the same dosage range. Otherwise ``surrogate'' has no scientific meaning. But the efficacy studies were not done below 0.2 mg, and the 0.2 and 1.0 mg efficacy studies showed no advantage in the higher dose.
b) ``Dr. Frankel is minimizing this trial by saying the number of participants was only 100. In fact 466 patients were enrolled and 382 completed (92-98 patients completing in each arm).'' Can it be true that the director of the FDA does not know that the number of patients receiving zero or .01 mg is irrelevant to the comparison of the patients receiving 1.0 and 0.2 mg? They have nothing to do with the statistics of the 1.0 and 0.2 comparison, each with about 100 participants.
The data submitted about Propecia a half year after my written request is, at this writing, still not on the FDA web.
Selling Drugs:
There was a time when drug stores had druggists who ``filled prescriptions'' supplied by physicians. Now the huge conglomerates, like RiteAid, using addresses taken from prescription, send their customers materials obtained from drug companies and suggest that they buy that company's drug. There may be a better drug on the market; the buyer is being provided information that is biased. I received a pitch for Proscar, but there are other drugs used for treating benign prostatic hyperplasia.
Conclusions:
I have examined the responses to my article on Propecia by persons representing Merck, as well as some who represent the FDA. I believe my responses will be compelling to an unbiased reader. Physicians recognize that the drug companies are driven by a motive for profit. They are aware of the underfunding and mediocre performance of the FDA in the process of approval of drugs. Very few articles by physicians appear about this subject. I will soon submit a citizen's request to the FDA in order to have it reconsider its approval of the dosage of Propecia, and I plan to ask the many dermatologists from whom I have received e-mail letters to join in this request. But what really is needed is physicians, not physicists, making an effort to improve practices in medicine. Organizations like the Institute of Medicine of the National Academy of Sciences need to engage meaningfully in a study of how to make the FDA a model of what a federal agency should be, and the Archives of Dermatology needs to operate in a strictly scholarly fashion devoid of commercialism.