Context matters: a rebuttal to yet another analysis of adverse events of finasteride

Response to: Nguyen DD, et al. Disproportional signal of sexual dysfunction reports associated with finasteride use in young men with androgenetic alopecia: a pharmacovigilance analysis of VigiBase. J Am Acad Dermatol. 2022. doi:10.1016/j.jaad.2022.03.037

A recent paper by Nguyen et al. in the Journal of the American Academy of Dermatology analyzes sexual adverse events (AEs) associated with finasteride.¹ While the study acknowledges an underlying effect of the drug, it attributes reporting trends to stimulated reporting and a possible nocebo effect. The paper joins a subgenre of previous studies attributing finasteride AE reports to external and coincidental factors. These studies have several limitations in common: they overlook the role of stigma in sexual AE reporting, overextend the stimulated reporting concept, overlook limitations of a comparison with dutasteride, and exhibit a bias for the status quo prior to public awareness. This commentary offers a rebuttal to these arguments.

Looking for the essential points? See this rebuttal as a saved Twitter thread.

1. Social stigma mediates reporting of sexual AEs. Sexual AEs are not like headaches, rash or fever. They are embarrassing and inappropriate to discuss in everyday conversations. For sexual AEs to be reported to a pharmacovigilance database, the patient must first link them to the drug, and second, feel comfortable reporting them to a regulatory authority or their healthcare provider (HCP). If reported to the HCP, the HCP must accept the AEs as drug-related, then take steps to report them to a regulatory authority. Moreover, sexual AEs would not be expected from a hair loss medication without some prompting of a connection. Because of these several barriers, public awareness is needed to make men aware of the possibility of sexual AEs, and to overcome their embarrassment. HCPs also need to be aware of the risk of sexual AEs in order to be receptive to such reports. Dermatologists in particular may ignore or discount sexual adverse events since sexual function lies outside their specialty.

2. Stimulated reporting effects tend to be short-lived. Nguyen et al. attribute finasteride AE trends in part to stimulated reporting. Literature on this phenomenon identifies stimulated reporting effects lasting over a period of months, not years.^2,3 In contrast, since 2012, the proportion of finasteride cases containing sexual AEs has remained fairly stable (Figure). (Note: Nguyen et al. analyzed AEs from WHO VigiBase, whose publicly available data does not allow segmenting by age and year. The figure reflects data from FDA’s Federal Adverse Event Reporting System.)

Although Reuters has recently published several investigative stories related to Propecia litigation (with one picked up by the Daily Mail in 2021), it is not clear these are widely read by younger men considering finasteride for hair loss. Other than these stories, the topic has received scant media coverage in the past five years. Most Propecia lawsuits were settled in 2018. Yet in 2019–2021, the numbers of cases concerning young men were higher than in any prior year. During this period, there were nine times more cases than in 2002–2004 (Propecia was first marketed in 1998). Relatively high case counts in recent years cannot be plausibly explained by media coverage, litigation or label changes. An alternative explanation is simply that there is more information available and greater awareness of finasteride’s adverse effects than in the past.

3. Limitations of the comparison to dutasteride are not noted. The authors compare finasteride AEs with those of dutasteride, suggesting a differential signal of finasteride indicates stimulated reporting. There are several limitations of this comparison. First, dutasteride has different pharmacology, as an inhibitor of 5-alpha reductase (5-AR) types 1 and 2, whereas finasteride primarily inhibits 5-AR type 2. Second, dutasteride has different pharmacokinetics, with a half-life of approximately 5 weeks whereas that of finasteride is 5–6 hours. Third, dutasteride is not approved for the treatment of androgenetic alopecia in most countries (approvals have been identified in South Korea and Japan). This will reduce the number of prescriptions written for hair loss, and possibly introduce hesitancy to report AEs because of off-label prescription. Public VigiBase data yields an estimate of 16 reports of dutasteride AEs per year for men ages 18–44 from 2003–2021. (In FDA’s Federal Adverse Event Reporting System, the comparable figure is 5.8 reports per year.) The thin volume of reports, along with other differences mentioned above, raise questions about the validity of comparing reports for finasteride and dutasteride.

4. The potential impact of age on sexual AE reporting is not noted. Finasteride inhibits dihydrotestosterone (DHT) which is crucial for early sexual development in men. First, there could be a differential effect of DHT inhibition in younger vs. older men because of a changing role of DHT over the lifespan. Second, younger and older men have different baseline sexual function. Third, younger and older men may weigh the importance of sexual function, and the impact of sexual AEs, differently. Fourth, the reason for using finasteride—hair loss or prostate conditions—might influence the level of concern about sexual AEs. All of these factors may mediate the reporting of sexual AEs, and limit the validity of comparing AE trends in younger vs. older men.

5. Nguyen et al. show a bias for the status quo prior to public awareness. Nguyen et al. find differential reporting of sexual AEs among young men taking finasteride compared to other drugs and age groups, and also identify a stronger signal after 2012. The comparison implies that other drugs provide a valid baseline. The authors do not consider that sexual AEs might be drastically underreported in the absence of public awareness. Elevated reports may not be an artifact of stimulation; rather, they may represent a signal that would not otherwise have been detected. Media coverage, discussions on social media, awareness among doctors, and advocacy group efforts may be necessary in order to elicit a signal for sexual AEs (the same would apply to any AEs which carry stigma, such as neuropsychiatric AEs).

6. Nguyen et al. show a bias against the agency and judgment of patients and the public. References to a nocebo effect and stimulated reporting reflect a view that patients and the public are impressionable and naïve; they simply respond to external stimuli without reflection or judgment. This implies that AE reports due to greater public awareness should be discounted. This reflects a cultural bias of medicine, where some doctors privilege their own knowledge over that of patients who are viewed as passive, naïve and unreliable.⁴

The paper by Nguyen et al. joins a subgenre of papers seeking to attribute finasteride AEs to factors other than the drug itself.^5-8 All draw on a similar set of alternative explanations: nocebo effect, stimulated reporting, Internet activity, litigation, media coverage, FDA advisories, co-occurring conditions (including depression and psychopathology), other medications, prior health history and, simply, “dissatisfaction.”⁸ Notably, the first of these papers to appear included a co-author who, it is disclosed in the article, was retained by Merck as an expert for its defense in Propecia litigation.⁶ The articles which followed performed a similar analysis, made similar arguments, and drew similar conclusions.^1,5,7

Indeed, these papers revive some of the same arguments Merck used in 2006–2009 when the Swedish Medical Products Agency requested information about adverse events of finasteride including persistent sexual dysfunction and depression.⁹ Merck had observed a case of persistent Impotence as early as its Phase 2 trial concluded in 1994,¹⁰ and a case of persistent sexual dysfunction in the 4-year extension of its Phase 3 trial. In the mid-2000s, Merck acknowledged 100 reports of unrecovered sexual dysfunction and 315 incomplete reports where unrecovered sexual dysfunction was a possibility.⁹

In the four papers cited above, physician-researchers have invested considerable time and resources towards discounting pharmacovigilance signals associated with finasteride. Their arguments are lopsided, emphasizing coincidental and external factors, while overlooking context and counterarguments that would challenge their conclusions. There is one explanation to which they devote little attention: that the drug itself, finasteride, may be the problem. This prompts the question: why have a pharmacovigilance system if, when it is actually producing a signal, doctors mobilize to discount its contents? These papers seem more concerned with guarding the status quo and acting as a gatekeeper for medical knowledge, than heeding alarm bells about the risks of finasteride, particularly when taken by younger men.

The risks of lasting sexual dysfunction and depression were known to Merck nearly three decades ago, if not earlier. In the past decade, physicians have defended the status quo either by ignoring these concerns or reciting alternative explanations—even as evidence accumulates that the drug entails risks of lasting sexual dysfunction, neuropsychiatric events and adverse impacts on fertility and reproduction.^11,12 For all their statistical trappings and explanations, the papers discounting finasteride AEs avoid a plausible and parsimonious conclusion: that finasteride entails risks of severe, lasting harms, particularly for younger men. These papers’ arguments appear increasingly strained against a 20-year trend of increasing pharmacovigilance signals, accumulating research and growing public awareness of the drug’s risks.

An earlier post describes limitations of three previous analyses of adverse events: Responding to a literature of doubt.

References

1. Nguyen DD, Herzog P, Cone EB, et al. Disproportional signal of sexual dysfunction reports associated with finasteride use in young men with androgenetic alopecia: A pharmacovigilance analysis of VigiBase. J Am Acad Dermatol. 2022 Mar 26:S0190-9622(22)00527-8. doi:10.1016/j.jaad.2022.03.037
2. MacKrill K, Gamble GD, Bean DJ, Cundy T, Petrie KJ. Evidence of a Media-Induced Nocebo Response Following a Nationwide Antidepressant Drug Switch. Clin Psychol Eur. 2019. doi:10.32872/cpe.v1i1.29642
3. Taylor D, Stewart S, Connolly A. Antidepressant withdrawal symptoms—Telephone calls to a national medication helpline. J Affect Disord. 2006. doi:10.1016/j.jad.2006.04.026
4. Berger AS. Arrogance among physicians. Acad Med J Assoc Am Med Coll. 2002. doi:10.1097/00001888-200202000-00010
5. Nguyen DD, Marchese M, Cone EB, et al. Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. JAMA Dermatol. 2021. doi:10.1001/jamadermatol.2020.3385
6. Baas WR, Butcher MJ, Lwin A, et al. A Review of the FAERS Data on 5-Alpha Reductase Inhibitors: Implications for Postfinasteride Syndrome. Urology. 2018. doi:10.1016/j.urology.2018.06.022
7. Harrell MB, Ho K, Te AE, Kaplan SA, Chughtai B. An evaluation of the federal adverse events reporting system data on adverse effects of 5-alpha reductase inhibitors [published correction appears in World J Urol. 2021 Nov]. World J Urol. 2021. doi:10.1007/s00345-020-03314-9
8. Ho RS. Ongoing Concerns Regarding Finasteride for the Treatment of Male-Pattern Androgenetic Alopecia. JAMA Dermatol. 2021. doi:10.1001/jamadermatol.2020.3384
9. Merck Research Laboratories Worldwide Product Safety. Periodic Safety Report for: Finasteride, 1 mg tablet and 0.2 mg tablet, MSD. November 30, 2006. View at pfsfoundation.org
10. Merck Research Laboratories. NDA 20-788: Application for Propecia, submitted to Center for Drug Evaluation and Research, Food and Drug Administration. December 20, 1996. View at accessdata.fda.gov
11. Samplaski MK, Lo K, Grober E, Jarvi K. Finasteride use in the male infertility population: effects on semen and hormone parameters. Fertil Steril. 2013. doi:10.1016/j.fertnstert.2013.07.2000
12. Zakhem GA, Motosko CC, Mu EW, Ho RS. Infertility and teratogenicity after paternal exposure to systemic dermatologic medications: A systematic review. J Am Acad Dermatol. 2019. doi:10.1016/j.jaad.2018.09.031