The lost men: how Merck, GSK papered over bad outcomes in trials

A re-examination of clinical trials of finasteride and dutasteride reveals warning signs of long-term harms to surface later

Once a drug has been on the market for decades, many will assume it is safe. The phrase “safe and well-tolerated” becomes shorthand for the copious trial data submitted to regulators in the distant past.

Yet upon a close review, red flags may be found in these early clinical trials. This post covers men who developed severe or unresolved adverse events (AEs) while participating in trials of finasteride or dutasteride. These cases are often concealed in elliptical language, and discounted or omitted from discussion sections.

For AEs to be recorded at all, they had to surmount several barriers under the sponsor’s control. The drug maker decided what qualified as an AE, whether it was drug-related, and how severe it was. In a phase III trial of Propecia, investigators determined AEs were drug-related in only 11% of the 308 men who had any AEs.¹ Moreover, there was usually no follow-up after the conclusion of a trial, so it remains unknown whether an AE ever resolved.

Savvy drug makers like Merck and GSK knew that safety concerns could jeopardize approval, marketing and distribution of their product, while a drug with demonstrated benefits and limited safety concerns could yield billions in profits. Since the drug makers control the levers that could increase or decrease adverse events in their trials, safety reporting is compromised by a conflict of interest. Nevertheless, these large-scale trials are widely considered to be the “gold standard” of evidence.

Following are the cases that made it past sponsors’ barriers (we can only speculate about those excluded). AEs in placebo groups are not reported here, except for the PLESS study. See cited sources for complete safety data.

These cases are also summarized in an Appendix.

The lost men

Proscar trials, 1990–1996

In two phase I trials, men took up to 100 mg of finasteride, which is 20 times the dose later approved as Proscar and 100 times the dose of Propecia. In one study, no safety information was reported.² In another study, the investigator hinted that symptoms were reported, but concluded that, other than headache, none “could possibly be drug-related.”³ There is no mention of AEs the investigator did not consider drug-related, nor the criteria used to rule them out. It is unclear how, at this early phase of drug development, the investigator could determine what AEs were drug-related.

In a phase II trial, 2 patients dropped out with impotence and decreased libido, respectively. Five dropped out without providing a reason. Seven serious AEs were reported, but investigators did not consider any of them drug-related. The specific AEs were not described, and it was not explained how these determinations were made. In summary, 10.4% of patients had serious adverse experiences and 22.4% discontinued the study. Undaunted, the authors proclaimed that “…finasteride continues to demonstrate an excellent safety profile.”⁴

In a phase III trial of finasteride for benign prostatic hyperplasia, two men in the group taking 1 mg of finasteride died—one by suicide and one from cardiac arrest. Seven men taking finasteride withdrew because of sexual dysfunction. It is unknown whether sexual dysfunction ever resolved in these men.⁵

In the Proscar Long-term Efficacy and Safety Study (PLESS), there were men in both groups who did not recover sexual function after leaving the trial. Merck reported these results in percentages, making the finasteride group look more favorable than placebo, when the opposite was true. About 28 men in the finasteride group and 13 men in the placebo group had a sexual AE that did not recover after withdrawal.⁶

Propecia trials, 1992–1997

A 35-year-old male left a phase II trial with an adverse event of ‘Impotence’. The table indicates (in confusing form) that ‘Impotence’ was still present 27 days after discontinuation of the drug. No further information is provided on whether it resolved. (This trial used a 5 mg dose.)⁷

During a four-year extension of a pivotal phase III trial, a participant left the trial due to a sexual adverse event, and it was still not resolved six months after discontinuing the drug.⁸ Merck concealed this outcome behind misleading language in a revised label (emphasis added):

[2001] Resolution occurred in all men who discontinued therapy with PROPECIA due to these side effects and in 58% of those who continued therapy.

[2002] Resolution occurred in men who discontinued therapy with PROPECIA due to these side effects and in most of those who continued therapy.

As of 2002, Merck had recorded a patient who still had sexual dysfunction 6 months after leaving a Phase III extension trial. In revising the Propecia label that year, Merck changed ‘all men’ to ‘men’. Since this fails to account for the patient who had unresolved sexual dysfunction, the statement is false. Moreover, by replacing 58% with ’most’, the revision concealed a significant proportion of men, 42%, whose sexual adverse effects did not resolve while in the trial. In normal English usage, 58% is too low to be described as ‘most’. In both of these changes, Merck replaced precision with vagueness to conceal safety concerns.

In this extension trial, 16 men had sexual adverse events which did not resolve during the trial. Investigators considered these events drug-related. No information was provided on whether these AEs resolved after the end of the trial.

In another phase III trial of Propecia for frontal balding, an unspecified number of men had sexual adverse events. These were resolved in “most patients…while continuing in the study,” according to a published report. This evasive phrasing omits the number of patients whose sexual adverse experiences did not resolve.¹¹

In another trial, Merck investigated the effect of finasteride on semen parameters. During the treatment period, one man taking finasteride had sexual dysfunction which did not resolve during the trial.¹² No information is provided as to whether it resolved after the end of the trial.

GlaxoSmithKline trial, 1999–2001

GlaxoSmithKline supported a study of the effect of finasteride and dutasteride on semen parameters and hormones.¹³ Five men withdrew with AEs. In the dutasteride group, one man had impotence and decreased volume of ejaculate; the other had impotence and decreased libido. In the finasteride group, AEs for three men were: decreased libido; gynecomastia; and ‘mental status change,’ respectively. The latter, also described as ‘depressed mood,’ was regarded as a Serious Adverse Event by the site investigator—yet designated as ‘moderate’ in severity.

24 weeks after the end of the trial, sperm motility (movement) was reduced 6–12% from baseline in both the dutasteride and finasteride groups, a statistically significant result. Moreover, three men had dramatically lower sperm counts during the trial, and levels remained well below baseline at follow-up, 20–24 weeks after discontinuing treatment. No information is provided on whether there was a return to baseline after follow-up.

Prostate Cancer Prevention Trial, 1994–2004

The finasteride arm had significantly more dropouts and missing questionnaire data at 6 months, and a higher dropout rate over the 7 years of the trial. An analysis noted: “sexual dysfunction side effects were often cited as the reason for dropping out.”¹⁴ No information is provided on whether sexual dysfunction later resolved in these participants.

Japan trial, 2006–2009

The report by Sato & Takeda is vague about safety outcomes.¹⁵ AEs occurred in 23 patients, but they are only specified for 13 patients. These were: decreased libido in 8 patients, liver disorder in 3 patients and enlarged breast in 2 patients.

Three patients discontinued due to decreased libido. Four discontinued due to: liver disorder; ‘disturbance of memorization’; enlarged breast(s); and palpitations, fever and headache, respectively. Sato & Takeda noted “most” of these were mild, but did not reveal which were not mild. “Follow-up data is unknown because of loss of contact,” they added.

Finally, they referred to adverse reactions which “showed no change during the treatment period”: decreased libido with orchiatrophy (shrunken testicles), reduced blood pressure, and growth of hair on the forearms. No information is provided on whether these AEs resolved after the end of the trial.

Conclusion

A theme runs through several of these examples. If the sponsor has unfavorable safety results, it discloses as little as possible, and discounts and obfuscates the rest. The sponsor also avoids generating new unfavorable information. Drug makers have used these tactics to the extent they can elude detection. The act of concealment itself is concealed, under the cover of science-like activity.

These tactics are symptomatic of a deeper problem: the sponsor controls safety methodology, measurement, analysis and reporting. The drug maker decides whether an AE is drug-related, whether it is serious and how severe it is. The sponsor also decides in advance what to measure. If they choose not to measure it, it does not exist. If they rely on spontaneous reports, they can expect underreporting, especially in taboo areas such as sexual function. The sponsor decides how to convert scaled questionnaire responses into AEs, a criterion which can easily be manipulated to produce fewer AEs.

A refrain of this post has been: “No information is provided on whether these AEs resolved.” Merck has the resources to find out what became of the lost men, but they have avoided doing so. Their own trials have shown that lasting sexual dysfunction is a risk of finasteride, but the company has consistently denied this risk in public communications. Merck’s business model depends on this doublethink.

As long as medicine and FDA remain in denial of the lasting harms of finasteride, they uphold this doublethink. A triple alliance of medicine, industry and FDA protect their own standing, while users of medical services face hidden risks and, in some cases, life-changing harms. The lost men are casualties of this regime.

Part 2 on adverse events reported after approval is forthcoming.

Resources

• Rules of engagement: how sensitive concerns are hidden from drug trials
• Bibliography: Clinical trials
• The Merck files

References

1. Merck Research Laboratories. Drug Approval Package: Propecia NDA #020788; Trial 087. Drugs@FDA. December 19, 1997.
2. Rittmaster RS, Stoner E, Thompson DL, Nance D, Lasseter KC. Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men. J Androl. 1989. doi:10.1002/j.1939-4640.1989.tb00097.x • PubMed
3. Gormley GJ, Stoner E, Rittmaster RS, et al. Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab. 1990. doi:10.1210/jcem-70-4-1136 • PubMed
4. The MK-906 (Finasteride) Study Group. One-year experience in the treatment of benign prostatic hyperplasia with finasteride. J Androl. 1991. doi:10.1002/j.1939-4640.1991.tb00277.x • PubMed
5. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med. 1992. doi:10.1056/NEJM199210223271701 • PubMed
6. Wessells H, Roy J, Bannow J, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology. 2003. doi:10.1016/s0090-4295(02)02401-9 • PubMed
7. Merck Research Laboratories. Drug Approval Package: Propecia NDA #020788; Trial 047. Drugs@FDA. December 19, 1997.
8. 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
9. Merck & Co. PROPECIA (finasteride) tablets, 1 mg. December 8, 2001.
10. Merck & Co. PROPECIA (finasteride) tablets, 1 mg. April 10, 2002.
11. Leyden J, Dunlap F, Miller B, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999. doi:10.1016/s0190-9622(99)70081-2 • PubMed
12. Overstreet JW, Fuh VL, Gould J, et al. Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol. 1999. PubMed
13. Amory JK, Wang C, Swerdloff RS, et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men [published correction appears in J Clin Endocrinol Metab. 2007 Nov;92(11):4379]. J Clin Endocrinol Metab. 2007. doi:10.1210/jc.2006-2203 • PubMed
14. Moinpour CM, Darke AK, Donaldson GW, et al. Longitudinal analysis of sexual function reported by men in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2007. doi:10.1093/jnci/djm023 • PubMed
15. Sato A, Takeda A. Evaluation of efficacy and safety of finasteride 1 mg in 3177 Japanese men with androgenetic alopecia. J Dermatol. 2012. doi:10.1111/j.1346-8138.2011.01378.x • PubMed