Merck’s former physician-allies sowed doubt while Propecia litigation was pending

In a burst of output in the late 2010s, key opinion leaders stressed that a causal role for the drug couldn’t be proved—a welcome message for Merck’s litigation defense

After FDA approved finasteride for male hair loss in 1997, the drug’s reputation stayed unblemished for a dozen years in the United States. However, the tide shifted in the 2010s: label warnings were added about risks of depression and lasting sexual dysfunction. Lawsuits were filed against Merck, and later consolidated into a multi-district litigation with over 1,000 plaintiffs. As the case wore on in the mid-2010s, physicians formerly involved in Merck’s launches of the drug penned articles defending the drug’s safety. They drove home similar points, and in most cases their former involvement with the drug maker was undisclosed.

The authors drove home similar points, and in most cases their former involvement with the drug maker was undisclosed.

This post provides excerpts from these articles. The authors will be referred to as paid opinion leaders (POLs), a variation on key opinion leaders.1 These figures were rising stars in their specialty, whom Merck retained in support of its launches of finasteride (first for enlarged prostate, then for male pattern hair loss). In addition, the POLs had opportunities to co-author papers, gaining publication credits that would advance their career. Even better, these publications were sometimes ghostwritten, requiring minimal effort by the POLs.

By the mid-2010s their engagements with Merck had long since ended, so what led them to weigh in on finasteride safety? We will return to this question in the Conclusion.

Note: The terms 5-ARI and 5ARI refer to 5-alpha reductase inhibitors, the drug class of finasteride and dutasteride.

Dermatologists endorse Merck’s studies, dismiss others

Fertig et al, 20162 had three POLs as authors: Drs. Wilma Bergfeld, Jerry Shapiro and Antonella Tosti. Between them, these dermatologists had roles as investigators, consultants, speakers and co-authors for Merck’s launch of finasteride for male pattern hair loss. Even the title signals doubt: “Investigation of the plausibility of 5-alpha-reductase inhibitor syndrome.” An excerpt (emphasis added here and in all excerpts that follow):

Additionally, it is unclear whether symptoms such as depression were caused by the drug itself or if side effects experienced by the patient, such as sexual dysfunction, contributed to the depression. Due to the inadequacy of these studies, no definitive conclusions can be reached at this time. However, these study findings suggest that finasteride may induce psychological adverse effects in susceptible patients such as depressive symptoms and anxiety.

A literature review of adverse side effects associated with 5αRIs shows that persistent sexual side effects were only documented in low-quality studies with strong bias selection as participants were part of an Internet blog.

Invoking the hierarchy of evidence from evidence-based medicine, the authors privilege Merck-sponsored trials as high-quality evidence while dismissing smaller, preliminary studies as inadequate and “low-quality.” The economic background is relevant: Merck has reported spending $450 million on developing Propecia.3 The drug maker could afford to run large-scale prospective trials. Meanwhile, there was no mainstream funding for research on a drug-induced disease. The topic also threatens the interests of medicine, so it is politically risky. Fertig et al fail to acknowledge the political and economic factors that shape the evidence base. Furthermore, industry-sponsored clinical trials have a different research agenda from preliminary research on an emerging and complex disease. Papers with such disparate research goals cannot be compared head-to-head.

Also of note, Dr. Tosti was Editor-in-Chief of this journal.

The disclosures by Drs. Shapiro and Tosti are incomplete, as they do not specify that they worked on finasteride for hair loss. They only say “Consultant and Speaker over 3 years ago.” By contrast, Dr. Bergfeld’s disclosure does acknowledge she worked on finasteride. Also of note, Dr. Tosti was Editor-in-Chief of this journal, Skin Appendage Disorders, but this is not disclosed here.

Disclosures for Drs. Tosti and Shapiro
Urologist plays up uncertainty

Dr. Steven Kaplan had roles in two trials of finasteride for men with benign prostatic hyperplasia (BPH), acted as a paid consultant to Merck, and co-authored four papers on Merck-sponsored studies. In 2021—after Propecia litigation was settled—an article co-authored by Dr. Kaplan appeared, analyzing adverse events reported to FDA.4 The article plays up uncertainty surrounding the causal role of finasteride. The first quoted paragraph points out that patients’ own “psychological and social issues” may be a factor:

These findings suggest that both psychological and social issues may be adding to the complexity of the constellation of symptoms experienced by those exposed to 5ARIs in the treatment of AGA…

There is no certainty that any reported adverse event was indeed due to the product… The FDA does not require that a causal relationship between a product and event be proven, and reports do not always contain enough detail to properly evaluate an event. Additionally, there is no information regarding the duration of the adverse effects reported, nor is there any information about their persistence after discontinuing the offending medication. It is therefore impossible to attribute causality to the associated medication.

The article contained no disclosure of Dr. Kaplan’s former roles in Merck’s launch of finasteride for benign prostatic hyperplasia.

Expert for Merck’s legal defense casts doubt in Journal of Urology

Dr. Kevin McVary was an investigator, consultant and co-author in the launch of finasteride for BPH. He was later retained by Merck as an expert in Propecia litigation. Among the POLs, he was the most active sower of doubt regarding post-finasteride syndrome. The first presentation took up an unusual topic: whether post-finasteride syndrome can occur in women.5 All other work from 2016–2018 casts doubt on the syndrome in men. At a 2016 meeting of the American Urological Association he gave a presentation entitled “Post-finasteride syndrome: Real or imagined?” The abstract stated: “Whether or not PFS is real or imagined is not discernable [sic] within this context and database.”6 At another meeting that year he gave a presentation entitled “Post Finasteride Syndrome: Guess Who—Demographics from FDA Database.”7 Here is an excerpt:

Whether this is a true medical disorder remains controversial.

The majority of reports of PFS-like symptoms from finasteride use were made from patients and not healthcare professionals… PFS findings require further exploration to discern its true existence, its putative cause(s), and mechanism of action.

“Guess who” is clearly a coy reference to younger men seeking to profit from litigation against Merck.

In 2018 Dr. McVary gave a presentation entitled: “Post-Finasteride Syndrome: An Evaluation of the FAERS Data on 5-Alpha Reductase Inhibitors. Fact, Fantasy or Forget About It?”8 Another presentation, delivered at a 2019 symposium in Bora Bora, French Polynesia, bore a similar title: “Post-Finasteride Syndrome: Fact, Fantasy or Forgetaboutit?”9

Dr. McVary was co-author of a 2017 expert review in European Urology, commenting on an article co-authored by J. Curtis Nickel, mentioned below.10 An excerpt:

[A]necdotal reports and poorly designed studies have received increased media coverage concerning the persistence of ED and SD following cessation of even a small dose of finasteride, putatively termed the post-finasteride syndrome (PFS).

[O]ne must control for baseline demographic and clinical characteristics that drive sexual dysfunction, including age, lower education level, obesity, and severe LUTS… Most of the above-mentioned flawed studies did not control for these risk factors driving nascent sexual dysfunction, which must be accounted for to prevent erroneous attribution of future ED and ejaculatory dysfunction.

…In…well-designed and controlled epidemiological studies, there is no evidence of a link between ED and previous finasteride exposure.

Biologically, the mechanism of action in PFS is questionable… ED is less directly related to androgen levels and is more indicative of vascular health. Vascular integrity requires a significant time to deteriorate and almost certainly would not occur within 1 yr of starting treatment, as is the case with most reports of PFS, without some pre-existing vascular disease.

…[G]ood science with appropriate controls and follow up is necessary to elucidate whether the effect is real and to ensure we do not shun effective therapy because of confirmation and selection bias.

With words such as “flawed,” “erroneous,” “questionable,” and “bias,” the doubt runs thick.

Next, Dr. McVary was last author of Baas et al, 2018 which appeared in the journal Urology.11 Again, this article cast doubt on causality. The article disclosed in fine print that Dr. McVary was retained as an expert for Merck’s defense in Propecia litigation.

Quality studies are a major problem in assessing the validity of PFS associated with finasteride. Many of these studies are inherently biased (particularly with selection bias), retrospective in nature, lack a control group, and employ unvalidated questionnaires.

The increased publicity of PFS can increase awareness and could increase the nocebo effect.

[A] patient could claim to have worsened sexual function after becoming aware of potential side effects, change in relationship status, other psychosocial events, or social media interactions. In the absence of objective findings, it is impossible to attribute causality to use of 5ARIs. When patients can self-report AE [adverse events] without medical training, the database becomes substandard in terms of assigning casual [sic] effects. Clearly, the potential biases in the FAERS database calls [sic] for a more scientifically rigorous process to determine the incidence of PFS and its putative persistence.

The fine-print disclosure that Dr. McVary was retained by Merck as an expert for litigation concerning alleged harms of finasteride.

Finally, Dr. McVary was quoted in a VICE article about finasteride12:

Urologist Kevin McVary, of Southern Illinois University, also has his doubts. When he crunched FDA data from thousands of reports of finasteride-related side effects, he found that men in their 20s and 30s taking a 1 mg dose for hair loss were far more likely to report side effects than older men taking a 5 mg dose for prostate problems. He finds that “fishy”

He wonders if perhaps younger men [who say they have post-finasteride syndrome] stumble upon a website or magazine article, such as this one, describing the symptoms and “power of suggestion” sets in… “What does exist is distressed men. That is real,” McVary says. “But is it causally related to this medication? There is no good evidence.

None of the above articles discloses Dr. McVary’s previous involvement in Merck’s MTOPS trial. Only one, Baas et al, 2019, discloses Dr. McVary’s engagement as an expert for Merck’s defense in Propecia litigation.

Study of ED risk disparages patient reports

Dr. J. Curtis Nickel had extensive involvement with both Merck and GlaxoSmithKline on finasteride and dutasteride, respectively. In 2016–2017, Dr. Nickel was co-author of three articles on risks associated with 5-ARIs. Here is an excerpt from the first, on the risk of erectile dysfunction (ED).13

5-α reductase inhibitors do not seem to significantly increase the risk of incident erectile dysfunction…

Unlike the published clinical trials, men…were free from diagnoses of and treatments for erectile dysfunction prior to cohort entry…

A major strength of our study is that it relied on doctor recorded diagnoses, rather than patient reported changes in sexual function, to identify cases.

…in some of the analyses the numbers of exposed cases were small…(n=36 exposed erectile dysfunction cases in the alopecia population…) thus the results for these analyses should be interpreted with caution.

…the results of this study provide reassurance that these drugs are not associated with a materially important increased risk of clinically meaningful erectile dysfunction in every day clinical practice.

Read a response to this article

An article on the risk of depression associated with 5-ARIs used by older men14 did not find an increased risk. A third article found a risk of gynecomastia but not breast cancer among older men taking 5-ARIs for benign prostatic hyperplasia.15

Dr. Nickel’s involvement in Merck’s development Proscar and GSK’s development of Avodart were not disclosed in any of these articles.

Bosley medical officer plays up controversy, denies causation

Dr. Ken Washenik, a hair transplant surgeon, was an investigator in one of Merck’s finasteride trials and a member of Merck’s Speakers Bureau. In the 2000s he became Chief Medical Officer at Bosley Medical Group, a network of hair restoration centers in the United States. Bosley was later named as a defendant in Propecia litigation (the lawsuit was settled in 2018 with no admission of responsibility by defendants).

At the 2017 CalDerm conference, while litigation was pending, Dr. Washenik gave a presentation with a section called “Update on the Post Finasteride Syndrome Controversy.”16 It began with a thorough disclosure of conflicts of interest. After presenting adverse event data from Merck’s own trials, the slides cited the nocebo effect and referred to elevated rates of depression and erectile dysfunction in men experiencing hair loss. A summary slide read as follows:

Summary

• There are patients suffering from persistent sexual dysfunction (as well as other complaints).
• They have taken finasteride.
No causal relationship between the two has been established.
• They deserve a thorough evaluation and treatment.
• Persistent side effects to finasteride after discontinuing the drug are not consistent with my clinical experience.
• I strongly agree that patients should be informed of this issue when they are considering finasteride therapy.

Also in 2017, Dr. Washenik gave a presentation at the 10th World Congress for Hair Research entitled “Update on the post-finasteride controversy.”17 The abstract read in part:

…[T]here remains controversy in the literature as to the existence of a cause and effect relationship between these post-marketing, retrospective reports and their causative relationship to the drug itself.

In order to help understand the current understanding of the controversy concerning the cause and effect existence of a constellation of symptoms (e.g., decreased libido, erectile dysfunction, depression, oligospermia) referred to as the post-finasteride syndrome, this presentation will review the history of the controversy and look at the current understanding of the findings in the literature.

In 2019, Dr. Washenik gave a presentation entitled “Is there a post-finasteride syndrome?” at the World Congress of Dermatology. A report on the presentation made similar points to those above, referring favorably to papers by other POLs and colleagues in the field of hair transplant surgery.18

Conclusion

This post has reviewed statements by former Merck POLs who later weighed in on risks and harms of finasteride and dutasteride. They produced a formidable output from 2016–2021: seven journal articles, six conference presentations,19 and one quote in the popular media. Several papers appeared while Propecia litigation was pending. These works hammered at the same points, emphasizing controversy, uncertainty, psychological factors and pre-existing conditions, thereby casting doubt on any causal connection between finasteride and reports of serious, long-term adverse effects. They highlighted psychological deficiencies of patients in order to exonerate the drug. They favored evidence generated by Merck or other POLs while dismissing smaller, preliminary studies. In short, they defended the status quo which they had helped to shape in partnership with Merck.

In litigation against Merck over harms of Propecia, plaintiffs needed to show the drug caused these harms. The POLs’ pointed denials of a causal role, quoted above, would have been music to the ears of Merck’s defense team. Causality was a crucial point in the legal analysis, and with over 1,000 plaintiffs the stakes were high. Were the POLs telegraphing a message to Merck’s lawyers? There are circumstantial reasons to suppose there might be a link, although this has not been confirmed—except for Dr. Kevin McVary who disclosed he was retained by Merck for its legal defense.

As already noted, in most cases the authors did not disclose their former ties to Merck. Even if their contracts with the drug maker had expired more than a decade ago, the POLs might still be beholden to the company. These articles could be read as an expression of loyalty to the company that had helped them along in their careers, or as a defense of the profession against malpractice and reputational damage. Maybe the interests of medicine and drug makers are so intertwined that a defense of pharma is a defense of medicine, and vice versa. In any event, the POLs helped shape the status quo and benefited from doing so. When that status quo came under threat, they used their considerable influence to defend it, while in most cases leaving former ties to Merck undisclosed.

Further reading

References
  1. Sismondo S. How to make opinion leaders and influence people. CMAJ. 2015. doi: 10.1503/cmaj.150032 • PMC full text ↩︎
  2. Fertig R, Shapiro J, Bergfeld WTosti A. Investigation of the plausibility of 5-alpha-reductase inhibitor syndrome. Skin Appendage Disord. 2016. doi:10.1159/000450617 ↩︎
  3. Morrow DJ. The Elixirs of Life Style; Drugs Can Spark Sex Lives and Grow Hair, So Why Are Some Sales Listless? New York Times. Published November 11, 1998. ↩︎
  4. 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. World J Urol. 2021. doi:10.1007/s00345-020-03314-9 ↩︎
  5. Fiuk J, Butcher M, Kohler T, McVary K. 133 Female post-finasteride syndrome: It’s not just a man’s world. J Sex Med. 2016;13(5):S62-S63. doi:10.1016/j.jsxm.2016.02.139 ↩︎
  6. Butcher M, Baas W, Lwin A, […], McVary KT. MP89-08 Post-finasteride syndrome: real or imagined? J Urol. 2016. doi:10.1016/j.juro.2016.02.2469 ↩︎
  7. Lwin A, Butcher M, Holland B, […], McVary KT. 054 Post finasteride syndrome: Guess who—demographics from FDA database. J Sex Med. 2016. doi:10.1016/j.jsxm.2016.02.057 ↩︎
  8. McVary KT. “Post-finasteride syndrome: an evaluation of the FAERS data on 5-alpha reductase inhibitors. Fact, fantasy or forget about it? At: Indiana Urologic Association conference; February 24, 2018; Indianapolis, Indiana. Archived ↩︎
  9. McVary KT. Post-finasteride syndrome: fact, fantasy or forgetaboutit? Presented at: Advances in Urologic Care Presented by Brigham and Women’s Hospital; October 10, 2019; Bora Bora, French Polynesia. Accessed January 20, 2022. Related tweet ↩︎
  10. Gupta NK, McVary KT. Re: Risk of erectile dysfunction associated with use of 5α-reductase inhibitors for benign prostatic hyperplasia or alopecia: population based studies using the Clinical Practice Research Datalink. Eur Urol. 2017. doi:10.1016/j.eururo.2017.03.043 ↩︎
  11. Baas WR, Butcher MJ, Lwin A, […], McVary KT. 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 ↩︎
  12. Marshall L. The medical mystery behind america’s best-selling hair-loss drug. VICE. Published online November 21, 2016. Accessed June 20, 2024. https://www.vice.com/en/article/gqywem/the-medical-mystery-behind-americas-best-selling-hair-loss-drug ↩︎
  13. Hagberg KW, Divan HA, Persson R, Nickel JC, Jick SS. Risk of erectile dysfunction associated with use of 5-α reductase inhibitors for benign prostatic hyperplasia or alopecia: population based studies using the Clinical Practice Research Datalink. BMJ. 2016. doi:10.1136/bmj.i4823 ↩︎
  14. Hagberg KW, Divan HA, Nickel JC, Jick SS. Risk of incident antidepressant-treated depression associated with use of 5α-reductase inhibitors compared with use of α-blockers in men with benign prostatic hyperplasia: a population-based study using the Clinical Practice Research Datalink. Pharmacotherapy. 2017. doi:10.1002/phar.1925 ↩︎
  15. Hagberg KW, Divan HA, Fang SC, Nickel JC, Jick SS. Risk of gynecomastia and breast cancer associated with the use of 5-alpha reductase inhibitors for benign prostatic hyperplasia. Clin Epidemiol. 2017. doi:10.2147/CLEP.S124674 ↩︎
  16. Washenik K. Emerging technology in the treatment of androgenetic alopecia. Presented at: 2017 CalDerm NorCal Conference; June 16-18, 2017; Napa, California. View PDF ↩︎
  17. Washenik K. Update on the post-finasteride controversy (LC-6). Presented at: 10th World Congress for Hair Research [Program]; October 31, 2017; Kyoto, Japan. ↩︎
  18. Ramm-Fischer A. Gibt es ein Post-Finasterid-Syndrom? [Is there a post-finasteride syndrome?]. Kongressbericht: World Congress of Dermatology 2019. Schweizer Zeitschrift für Dermatologie. April 2019. German. View PDF ↩︎
  19. This excludes Fiuk et al, 2016 on post-finasteride syndrome in women, cited above. ↩︎