Polls vs. official data on side effect rates

KEY POINTS

• Results of 7 informal polls on finasteride side effects were pooled.
• In pooled results, 43.9% of 849 respondents experienced side effects of finasteride.
• In a Phase III clinical trial, Merck reported 7.7% of men had an adverse event related to finasteride.
• The rate of side effects in polls was 5.7x greater than the rate of adverse events in the Phase III trial.
• Results of clinical studies are often taken at face value, but social norms and the clinical setting may suppress safety concerns in sensitive areas such as sexuality and mental state.

Part 1 of a two-part series. Part 2 is Rules of engagement: how sensitive concerns are hidden from drug trials

Background

Official safety data on finasteride seems at odds with growing signals about the drug’s harmful effects when taken by younger men. In a Phase III trial, Merck reported that 7.7% of participants had a drug-related adverse event, about half of which were sexual adverse events (3.8%) [1].

Yet in a recent post, a user was torn between official information and other sources: “I honestly don’t know what to believe. I trust science. But I do realize that science can be deceiving and even flat-out wrong or compromised. What is the real consensus? …Who do I trust?”

The most commonly reported adverse events of finasteride are in the domains of sexuality and mental health. In many cultures, these topics carry social stigma, and may be considered inappropriate in formal settings [2,3]. Moreover, participants might lack awareness, vocabulary or motivation to articulate their concerns. Revealing sexual problems, in interviews or written questionnaires, calls up fears of being seen as insufficiently masculine [4].

Informal online polls have obvious limitations, but have the advantage of anonymity, reducing the risk of embarrassment or inappropriateness [4,5]. Respondents are in a real-world setting, unlike the artificial, formal setting of clinical trials. As for limitations, the population is not standardized for duration of using finasteride, age, co-occurring conditions or other factors. It is not even certain that they took finasteride at all. Even with these limitations, compiling polls from relevant forums, published at different times, may yield information about the incidence of finasteride side effects in the real world.

Methodology

Discovery. An online search was conducted to discover polls on finasteride side effects in online forums on hair loss, hair transplants and men’s health and fitness; and through a web search engine. To avoid selection bias, forums on post-finasteride syndrome or drug side effects were excluded. Polls were included if responses could be classified into two categories: any side effects or no side effects.

Selection. 10 polls were identified. Three were posted on web forums in 2004, 2017 and 2019. These polls remained open, accompanied by an open discussion thread. Over time, the discussion could attract people with side effects, introducing a selection bias. These three polls were excluded for this reason.

Standardization. After polls were selected, each poll’s results were standardized into two bins: any side effects or no side effects. Raw and standardized poll results are provided in an Appendix.

Results

Three of 10 polls were excluded as described above, leaving 7 polls eligible for pooling (Table 1). All eligible polls were on Reddit. Five were posted in forums about hair loss and treatments (including one about hair transplants) while two were in a forum on men’s health and fitness. Polls were posted from 2016–2022.

Three polls (P3, P5 and P6) included responses for severe or persistent side effects.

Mobile users: swipe left to see more columns.

Table 2 shows summary statistics of included polls. The mean proportion with side effects, giving each poll equal weight, was 41.4% (SD 9.8), with a range of 27.3% to 53.4%. When data were pooled, the proportion reporting side effects was 43.7%. The proportion experiencing severe or persistent side effects of finasteride was 16.1%.

(If all 10 polls were included, the unweighted mean would be 43.7% and the pooled rate would be 47.8%.)

Figure 1 shows a box-and-whisker plot of the distribution of poll results, with a black diamond representing the adverse event rate in a Phase III clinical trial of Propecia.

Table 3 compares side effect rates in polls to the rate of adverse events in a Phase III trial of Propecia (7.7%).

Discussion

Seven informal online polls on finasteride side effects were analyzed and compared with safety data from a Phase III trial of Propecia. Polled rates were between 3.5x and 6.9x the rate from the clinical study. This comparison is qualified by significant differences between the data sources.

In polls, selection bias is possible. For example, hair loss forums might attract users currently experiencing side effects of finasteride, or those who are more attentive to drug effects. However, as noted earlier, all forums had a broader focus than finasteride, covering hair loss or men’s health and fitness. Each forum has a particular culture and moderation style. For example, the Reddit forum r/tressless appears biased towards the benefits of finasteride, and against side effects and post-finasteride syndrome (one user commented: “I’ve literally seen post‘s [sic] talking about side effects get deleted right before my eyes.”) The Reddit forum r/MorePlatesMoreDates, the source of two polls, is focused on health and fitness, adding diversity to the sample. Since 7 polls were drawn from 6 different forums, the influence of a single forum‘s culture and user base is diluted.

Limitations of safety reporting in clinical trials may be underappreciated, particularly in sensitive categories such as sexual dysfunction and neuropsychiatric concerns. Stigma, rules of politeness and clinical environments may suppress these concerns, as illustrated in Figure 2. Questions on the International Index of Erectile Function address matters that are widely considered private, sensitive, and inappropriate in most settings (Merck used its own questionnaire which is unavailable, but questions were likely similar). The language is graphic and clinical:

How often were you able to get an erection during sexual activity?

When you had erections with sexual stimulation, how often were your erections hard enough for penetration?

When you attempted intercourse, how often were you able to penetrate (enter) your partner?

During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?

During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?

How many times have you attempted sexual intercourse?

When you attempted sexual intercourse, how often was it satisfactory for you?

How much have you enjoyed sexual intercourse?

When you had sexual stimulation or intercourse, how often did you ejaculate?

Selected questions from International Index of Erectile Function (IIEF) questionnaire

In a clinical trial of a new drug for hair loss, hopes might run high, and the participant might wish to meet expectations of the sponsor, further discouraging expressions of concern.

Investigators determined whether adverse events (AEs) were drug-related—a judgment call which could suppress safety signals [6,7]. A number of investigators were dermatologists, who likely had no special training in sexual or mental health conditions. All of these factors could drive down rates of sexual AEs in both treatment and placebo groups, creating a floor effect which collapses differences between groups.

Sexual function questionnaires were administered, but the scores were on a continuous scale [1]. It is unknown whether Merck used a threshold to determine whether a score qualified as an adverse event, or another method such as an interview with the participant. In either case, the company would have opportunities to lower the sensitivity of AE detection. (Merck’s handling of Vioxx, which came to market in the same era, suggests that the company was not above such manipulation [8].)

When poll results were pooled, the rate of side effects was 5.7x greater than in trials—not a moderate difference, but a chasm. If we allow that both polls and trials have bias in opposite directions, we might compromise at the midpoint between the two: a rate of 25.7%. In this scenario, about one four men would experience drug-related AEs. This is still more than triple the rate reported in a Phase III clinical trial, and seems high for a cosmetic condition.

The medical literature and online discussions usually take clinical trial data at face value. Yet the very formality that makes clinical trials seem authoritative, could conceal safety concerns in sensitive categories such as sexuality and mental experience.

It is common for papers on finasteride adverse effects to end with a call for prospective, placebo-controlled studies. Yet there appears to be neither the will nor the funding to carry out such a study. Young men are left to navigate a morass of conflicting information, from the drug label to adverse event data, new regulatory warnings, advisories, media reports, social media posts, videos, articles, user reviews, physician concerns, and medical literature.

The Reddit user asked: “What is the real consensus?” Among 100 men who take finasteride for hair loss, how many will experience adverse effects: 8, 26, 44 or 53? (Respectively, these are Merck’s reported rate, the midpoint between polls and trials, the pooled rate across 7 polls, and the maximum polled rate.) It has become clear enough that Merck understated safety concerns of Propecia. The question is, by what multiple—three times? Six times? Seven times?

Go to part 2 of 2: Rules of engagement: how sensitive concerns are hidden from drug trials

References

1. United States Food and Drug Administration. Drug Approval Package: Propecia (Application No.: 020788). Approval Date: December 19, 1997. AE data cited is in the Medical Review, Part 3, Table 10.1.5.1. View on FDA website
2. Moore TJ. Finasteride and the uncertainties of establishing harms. JAMA Dermatol. 2015 Jun. doi:10.1001/jamadermatol.2015.37
3. Bonierbale M, Lançon C, Tignol J. The ELIXIR study: evaluation of sexual dysfunction in 4557 depressed patients in France. Curr Med Res Opin. 2003. doi:10.1185/0300799039117043
4. Akre C, Michaud PA, Suris JC. “I’ll look it up on the Web first”: Barriers and overcoming barriers to consult for sexual dysfunction among young men. Swiss Med Wkly. 2010. doi:10.4414/smw.2010.12968.
5. Gordijn R, Wessels W, Kriek E, et al. Patient reporting of sexual adverse events on an online platform for medication experiences. Br J Clin Pharmacol. 2022 Jul 2. doi:10.1111/bcp.15454
6. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010. doi:10.1056/NEJMp0911494
7. Seruga B, Templeton AJ, Badillo FE, Ocana A, Amir E, Tannock IF. Under-reporting of harm in clinical trials. Lancet Oncol. 2016 May. doi:10.1016/S1470-2045(16)00152-2
8. Krumholz HM, Ross JS, Presler AH, Egilman DS. What have we learnt from Vioxx? BMJ. 2007. doi:10.1136/bmj.39024.487720.68

Appendix: Poll data

Poll source data is in an Appendix.