See also: The Merck files: a series
In regulatory, internal and media communications in the 2000s, Merck responded to concerns about reports of adverse events associated with Propecia, including persistent erectile dysfunction and depression. These documents seek to discount the validity of these reports by way of the following points:
- “insufficient” information including lack of follow-up information;
- other medications, conditions, history, genetics and “background events” as confounding factors;
- lack of laboratory, urologic and endocrine “work up”;
- “no pattern” in nature, severity, time of onset or duration of adverse events;
- baseline prevalence of erectile dysfunction and decreased libido in the general population—described as “very common”;
- inconsistency with results of pre-clinical studies and clinical trials which were controlled, long-term and “extremely complete”;
- “no scientific basis” that finasteride would cause erectile dysfunction because the drug has “no androgenic or anti-androgenic effects”;
- biases, heterogeneity and low quality of data in post-marketing surveillance systems, making them unsuitable for drawing conclusions about cause and effect, and inferior to Merck-sponsored clinical trials;
- use of vague or stigmatized language to describe individual cases, for example “a history of stress reaction,” “seizures…aggression, antisocial behavior,” “malaise, memory impairment,” and “chronic fatigue syndrome…preexisting anxiety disorder”;
- description of erectile dysfunction as “non-serious”;
- exclusion of cases with ambiguous or incomplete information;
- exclusion of cases where AEs developed after discontinuation of finasteride; and
- criticism of an animal study demonstrating penile tissue alterations linked to finasteride treatment.
These points were distilled from Merck documents released in 2021.1
From 2015–2020, numerous articles in peer-reviewed medical journals made some of the same arguments (see ‘Safe and well-tolerated’ and a critique of three papers about adverse events).
Excerpts from Merck documents follow, with emphasis added in bold.
MERCK DOCUMENT EXCERPT
Periodic Safety Update for: Finasteride, 1 mg tablet and 0.2 mg tablet, MSD – November 30, 2006 [2]
9.1.4. Post Marketing experience
The majority of these reports (93%) were non-serious… One report… described a patient who obtained therapy from the internet, thus it is unclear if the patient ever received finasteride therapy, and 4 reports described patients who developed an adverse experience after therapy with finasteride was discontinued, these 5 reports are not included in the analysis below.
[…] In the remaining 200 reports which described the outcome as not recovered, 63 were insufficient for further evaluation. Information regarding action taken with finasteride therapy, dose and duration of therapy, concomitant medications, and/or current conditions/medical history was not provided. In 37 reports the patients continued on therapy with finasteride at the time of the report. Six of these reports described concurrent conditions, medical histories and/or other adverse experiences which may have contributed to the patient’s experience including stress, depression, sexual dysfunction, benign prostatic hypertrophy, hypertension, and/or erectile dysfunction. The remaining 100 reports describe patients whose adverse experience was reported to have persisted upon discontinuation of therapy with finasteride at the time of the report. One quarter (25) of these reports described concurrent conditions, medical histories and/or other adverse experiences which may have contributed to the patient’s experience including hypertension, cardiac disease, diabetes, urogenital surgery, hyperthyroidism, sexual dysfunction, anxiety, depression, and/or stress. The majority of the remaining 75 reports lack sufficient information for further evaluation. Information with regards to laboratory, urologic and/or endocrine work up, concurrent conditions/medical history, and/or concomitant therapy is not provided. Most of the reports do not describe how long the event had persisted following discontinuation of finasteride therapy at the time the event was reported. In the few reports, 22, where some information regarding time duration of the events was provided, there was no pattern as to the nature and degree of the adverse experiences, time to onset of the event, and/or length of time the event had persisted following discontinuation of finasteride therapy. The reports described patients with an onset of adverse experiences ranging from 1 week to 4 years and the length of time the events had persisted following discontinuation of therapy, at the time of the report, was typically described as a few months but ranged from weeks to years. Only two of the 72 reports described an endocrine and/or urology work up…
9.11.5 Discussion
Male reproductive system symptoms such as erectile dysfunction and decreased libido are very common with reported incidence rates of 25 per 1,000 man years and are well described in the CCDS.
In clinical trials… Of the 48 men who reported drug-related sexual adverse experiences and remained in the study, 32 men (56%) reported resolution of their sexual adverse experience while continuing on therapy with finasteride[.]
…In most of the reports the information was provided shortly after the onset of the adverse experience and despite attempts to obtain follow up information, in accordance with the Company’s standard procedures to obtain follow up, no further information was provided. …In reports where the events persisted, at the time of the report, one third were insufficient for evaluation and 18% of the patients reported continuing finasteride therapy. Of the remaining 100 reports, 25% described concurrent conditions, and/or medical histories which may have contributed to the patient’s experiences. In the remaining 75 reports where patients described an adverse experience which persisted after discontinuing therapy with finasteride, at the time of the report, the majority of the reports lacked specific information to allow for further evaluation. No information was provided about the duration of the event following the discontinuation of finasteride and/or no detailed urologic work up was provided. In the few reports which did describe information regarding length of time the events persisted at the time of the report, there was no pattern as to the nature and degree of the event, time to onset of the event and length of time the event persisted following the discontinuation of therapy.
Conclusion
We consider the current labeling as presented in the side effect section of the CCDS to be appropriate and reflective of the extensive data available on finasteride…
MERCK DOCUMENT EXCERPT
Merck’s Response to Assessment report on PSUR: Erectile dysfunction after cessation of treatment – additional data – June 18, 2007 [3]
Post-Marketing
…A detailed review of 617 post-marketing reports of erectile dysfunction with finasteride was provided in the last PSUR… In these spontaneous reports the majority of reports, 93%, were non-serious…
…In reports where the events persisted, at the time of the report, many were insufficient for evaluation and/or reporting continuing finasteride therapy. Many reports described concurrent conditions, and/or medical histories which may have contributed to the patient’s experiences. …The majority of the reports lacked specific information to allow for further evaluation…
Conclusion
…In addition, since finasteride has been shown to be very selective in its desired pharmacological with no androgenic or antiandrogenic effects, there is no scientific basis for mechanistic explanation of erectile dysfunction in either laboratory animals or in men treated with finasteride.
…Information reported to a spontaneous post-marketing surveillance system is most often incomplete and the systems are sensitive to multiple biases including underreporting, length of time a product has been on the market, country, reporting environment, and quality of the data. …Follow-up information in a post-marketing reporting system is a snapshot in time and without continued investigation cannot be used to draw definitive conclusions.
…in the case of the long-term controlled clinical trials with PROPECIA, follow-up information on persistence or resolution of sexual AEs following cessation of treatment is extremely complete and provides a superior assessment compared to that possible through spontaneous AE collection.
In summary, a small number of spontaneous post-marketing AE reports of persistent sexual dysfunction exist which in the absence of additional follow-up information appear to conflict with data from controlled clinical trials. This is likely not unique to this AE or to finasteride specifically and simply points to the limitations of a post-marketing surveillance system. Post-marketing surveillance is a signal detection tool and should not be used to qualify and/or precisely quantify cause and effect relationships between drugs and AEs if better data from clinical studies are available. Thus the data from the clinical trials with finasteride should be considered over that of reports received from the post-marketing environment.
MERCK DOCUMENT EXCERPT
Draft news release: Merck Statement Regarding the June 2008 Update to the Prescribing Information for PROPECIA (finasteride, 1mg) in the European Union – July 2009 [4]
…There have been post-marketing reports of erectile dysfunction which persisted after discontinuation of PROPECIA. The fact that an adverse event has been reported does not reflect a conclusion that the post-marketing event is caused by PROPECIA. In general, a post-marketing adverse event may be caused by underlying disease, genetic condition, the medication, concomitant medications or background event that may occur coincidentally in any population…
MERCK DOCUMENT EXCERPT
Finasteride—Male Pattern-Hair Loss: Risk Management Plan Version Number 1.0 – February 11, 2009 [5]
Persistence of erectile dysfunction
No serious sequelae directly related to ED were identified in any reports…
In a majority of these 278 cases, critical data were not reported…limiting the value of these reports in assessing the relationship of finasteride therapy to persistence of erectile dysfunction… In addition, a number of cases were confounded by concurrent medical conditions that may affect erectile dysfunction, such as diabetes, psychiatric illness, or advancing age. Finally, many of the reports lacked information pertaining to diagnostic evaluation such as urological testing or thorough data regarding social and medical history. As a result, other environmental, biological or psychological factors that can potentially influence persistence of erectile dysfunction are difficult to rule out.
Depression
A review of the 10 serious reports involving depression revealed 3 reports were received from an agency line listing and contained minimal information. Of the remaining 7 reports, one described a patient with a history of stress reaction which may have contributed to the event of depression. Three reports described patients who reported multiple AEs (e.g. seizures, muscle wasting, aggression, antisocial behavior, vision loss, and empty sella syndrome) indicating possibly other etiologies for the depression events confounding evaluation. Another report described a patient that experienced depression 1 year after initiating therapy with finasteride. Action taken with finasteride therapy was not provided which limits assessment. One report described a male who experienced depression, malaise and memory impairment 1 month after initiating treatment with finasteride. Treatment was discontinued and the patient recovered. The last report involved a patient who was rechallenged on therapy with finasteride and depression reoccurred; although causality cannot be ruled out in this case.Overall, these reports, including only 1 episode of a serious positive rechallenge, do not provide sufficient evidence of a causal association[.]
…In the 9 suicidality reports, 4 contained in sufficient information to allow a full evaluation. Three reports were confounded by concomitant medical conditions (chronic fatigue syndrome, thyroid disease, and concomitant medication consistent with a preexisting anxiety disorder). In the remaining two reports, the symptom of suicidality began after the patient discontinued finasteride.
References
- Levine D. Judge orders Merck documents on anti-baldness drug Propecia unsealed. Reuters. January 25, 2021.
- Merck Research Laboratories Worldwide Product Safety. Periodic Safety Report for: Finasteride, 1 mg tablet and 0.2 mg tablet, MSD (PDF). November 30, 2006.
- Niedercorn E, Merck Sharp & Dohme (Europe), Inc. Response to Assessment Report on PSUR: Erectile dysfunction after cessation of treatment – additional data (PDF). June 18, 2007.
- Merck Sharp & Dohme Corp. Draft news release: Merck Statement Regarding the June 2008 Update to the Prescribing Information for PROPECIA (finasteride, 1mg) in the European Union (PDF). July 2009.
- Merck Sharp & Dohme Corp. Finasteride—Male Pattern-Hair Loss: Risk Management Plan Version Number 1.0 (PDF). February 11, 2009.