November 4 2011, 2:58 pm PT | Posted in: Drugs
Note: This post comes from one of our favorite readers (he has requested to remain anonymous), who has contributed posts in the past about FDA issues. He provides some insight into clinical trials, and sent this in to answer some of the questions/concerns posted in our comments section about Propecia data.
Finasteride side effects are a hot issue on various forums and on our own site, so hopefully this can clear up some of the hysteria that perpetuates online:
A recent post impressed me by referring to Propecia data from a FDA hearing (more updated and accurate information is in the U.S. Product Label) but may have been confused by how data is collected and interpreted in clinical trials. I am a veteran of overseeing clinical trials resulting in drug approvals.
1. The poster notes that the “rate of sexual side effects is 3.8 percent with finasteride versus 2.1 percent with placebo.” Actually, following the Advisory Committee hearing and in further review of the data, the US Product Label shows that in Year 1, decreased libido was 1.8% for the 945 men receiving finasteride and 1.3% for the 934 men receiving placebo (placebo-adjusted rate of 0.5% or 1 in 200 cases). Similarly, erectile dysfunction was reported in 1.3% of men receiving finasteride and 0.7% of those receiving placebo (placebo-adjusted rate of 0.5% or 1 in 200 cases). Approximately 1.2% of men receiving finasteride and 0.9% of men receiving placebo discontinue the study drug due to sexual side effects. No cases of irreversibility of sexual dysfunction were reported.
2. The poster asks (given that the reporting was “self-reporting”) whether the results “are scientific”. This latter sentence makes me wonder if the poster wonders if clinical trial data is collected similar to the uncontrolled self-selected questionnaire surveys often cited in other situations. It is not. Unlike self-selected questionnaires, where one does not know the denominator (how many patients are receiving the drug, only those reporting a complaint) or period of observation, a clinical trial is different. In a clinical trial, the physician investigator asks every participating patient at regularly scheduled visits through the entire study (and predetermined) follow-up whether they are having or have had any new or worsened effect in any organ system. By definition, this reporting has to come from the patient. But, it is as scientific as one can get (it is solicited rather than self-selected). In addition, any report of a side effect is attributed to the drug (active vs. placebo) regardless of the causality. That is, if a person gets hit by a car and sustains trauma and is on an active drug, trauma is tabulated under the drug (although an investigator may causally relate it to something else). This conservative approach is taken to capture any possible relationship (i.e., maybe the drug makes someone drowsy and more prone to accidents).
3. The (implied) gist of the poster’s real concern is whether any weakness of reporting in clinical trials relates to any weakness of reporting possible persistent side effects. It doesn’t, as patients are followed for variable periods (in all clinical trials) after discontinuation of the study drug, including completion of the trial. When an adverse event occurs, investigators are required to follow the patient longer and in most cases until adverse event resolution.
Instead, the limitation of issues of reversibility vs nonreversibility of any reported side effect have to do with the limitation of study patient numbers and durations. If an event is very rare, it will not occur when several thousand men are assessed but may occur when tens or hundreds of thousands of men are assessed in the postmarketing setting. The best example of this is with the PDE5 inhibitors (sildenafil, tadalafil) for erectile dysfunction. While the causal association between devastating visual events (termed NAION) and these drugs are unclear (because of their rarity), the occurrence of these events in 100-200 of the over 80 million men who take these compounds post-marketing (with zero occurrences reported in the clinical trials) is now in the Product Label as a possible consequence and underscores my point. rare events that may be related to a drug do not show up in clinical trials because of issues with ‘self-reporting”, but due to a smaller patient number and exposure that can occur in the ‘real-world setting” once a drug is approved.
4. I have not read the comment the poster attributes to the Editor-in-Chief of the Journal of Sexual Medicine. As someone who is asked to review journal articles for submission, my approach would have been to encourage scientists and patients to publish detailed descriptions of this phenomenon (irreversible finasteride-induced sexual dysfunction), excluding other known causes of sexual dysfunction. That would be scientific. To this date, I have yet to see a single case history in the medical literature (including the Journal of Sexual Medicine).