In this series: Overview • Part 1 • Part 2 • Part 3
These documents from 2006–2009 concern Merck’s response to postmarketing reports of persistent erectile dysfunction, male infertility and depressive disorders, among other adverse events, associated with use of finasteride. In 2006, the Swedish Medical Products Agency asked Merck for an analysis of all adverse events affecting the male reproductive system which persisted after stopping Propecia. In subsequent documents, there is a back-and-forth between Merck and the Agency as to the validity of these reports and the overall safety concern. Merck used an arsenal of arguments to discount these reports and claim its own data is superior to postmarketing data: “incompleteness” of reports; lack of lab testing data; co-occurring conditions including psychiatric conditions; implausibility of adverse events arising after discontinuation of Propecia; and background incidence of these adverse events in the population.
Ultimately the Swedish Agency required that Merck add a warning about persistence of erectile dysfunction after discontinuation of treatment (see Risk Management Plan, p. 61):
Persistence of erectile dysfunction after discontinuation of treatment with
PROPECIA has been reported in post-marketing use.
Following the label change in European markets, Merck issued a press release that questioned whether Propecia was the cause of this adverse event. In 2009 a confidential Risk Management Plan (RMP) set out Merck’s analysis and plans for safety concerns associated with the use of Propecia. Merck asserted that these reports provided no new safety information regarding persistence of erectile dysfunction, male infertility and depressive disorders (among other adverse events). The plan for each concern was: ‘Routine pharmacovigilance.’
In document excerpts below, emphasis has been added in bold. Page numbers refer to PDF pages, not page numbers appearing on the original documents.
Email correspondence between Keith Kaufman and Kathleen Peeples-Lamirande regarding impotence associated with Propecia use
Jan 11–12, 2006 • View document (2 pages)
Merck’s Kathleen Peeples-Lamirande (KPL) notes that a physician has asked for a reason for decreased libido associated with the use of finasteride. KPL requests guidance from Keith Kaufman, head of Propecia clinical development, asking if the following text used for Proscar* may be used for Propecia. Kaufman’s comment appears inline at the end:
Unpublished information from Merck Research Laboratories notes that a definitive cause for impotence in patients treated with PROSCAR has not been determined. The specific time to resolution of impotence following discontinuation of PROSCAR also has not been determined. As you are aware, each clinical situation is unique; it cannot be predicted whether impotence will resolve in an individual patient.” [Kaufman comment:] Note that this response relates to impotence, not decreased libido.
The bolded text reveals Merck was aware that impotence associated with the use of Proscar might not resolve over time. Kaufman clarifies that the statement concerns impotence (which today would be called erectile dysfunction) and not decreased libido. In a reply, KPL asks if it would be “true” to add libido to the same statement. No further emails are provided.
* Finasteride 5 mg, typically prescribed to older men for the treatment of an enlarged prostate. Proscar was approved by FDA in 1992.
Swedish Medical Products Agency: Preliminary Renewal Assessment Report for Propecia
Nov 28, 2006 • View document (2 pages)
The Swedish Medical Products Agency (MPA) notifies Merck Sharp & Dohme (Sweden) that it has become aware of reports “spread over Internet sites” regarding problems with the male reproductive system which persist after stopping Propecia. MPA requests Merck to provide a combined listing of all reported cases of adverse events related to the male reproductive system, including “any possible knowledge of the outcome in terms of reversibility of symptoms for individual cases.”
Merck Research Laboratories: Periodic Safety Update Report for Finasteride
Nov 30, 2006 • View document (7 pages)
Just two days after the MPA request, Merck submits this report addressing sexual adverse effects (AEs) which did not go away after discontinuation of Propecia. A summary of Merck’s clinical studies of Propecia notes:
In total, 72 men on finasteride reported sexual adverse experiences that were considered drug-related by the investigator during the 5 years of the studies. Twenty-four of these men discontinued therapy because of these adverse experiences while 48 remained in the study. Of the 24 men who discontinued, follow-up information is available on 23. Twenty-two men reported resolution of their sexual adverse experience while one reported that the adverse experience was still present 6 months after discontinuing finasteride therapy; however, no further follow-up information is available for this patient. 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.
The criteria by which sexual AEs were assessed or deemed drug-related by the investigator are not specified. In addition to the man who discontinued the trial due to a drug-related sexual AE and did not have resolution of the AE six months later, these data indicate that 16 men with drug-related sexual AEs who remained in the trial did not have resolution of these AEs during the trial.
(As noted in Part 1 of this series, the product labeling ignored the man who discontinued and did not have resolution six months later, stating: “Resolution of these side effects occurred in men who discontinued therapy with PROPECIA and in many who continued therapy.”)
The next section summarizes data on background incidence of erectile dysfunction (ED). For a deeper analysis of Merck’s rhetorical strategy in defense of the safety of Propecia, see this post.
In a Post Marketing Experience section, Merck notes “The majority of these reports (93%) were non-serious.” In at least some cases, this determination would have been made by a health care provider, not the man experiencing the AE. Merck excludes from consideration patients for whom an AE developed after discontinuation of therapy, reflecting an assumption that such AEs could not be drug-related.
A summary table shows 100 men who had not recovered even though therapy was discontinued. In addition, there were 63 men (last column) who had not recovered, where it was unknown whether they had continued or discontinued therapy.
On p. 6 of the PDF, the two cases which included an endocrine and/or urology work up are described:
WAES 0602USA01491: a 22 year old male emotionally healthy male with no prior history of sexual dysfunction was placed on therapy with finasteride for the treatment of early male pattern balding. Three to four months later the patient began to experience complete loss of sexual drive, including loss of spontaneous erections. The patient was evaluated by a urologist. Serum testosterone was within normal limits, 567, and testicular ultrasound showed calcifications. Therapy with finasteride was discontinued. Eight months later, the patient reported he continued to experience the same symptoms with no sign of any spontaneous resolution. The patient was evaluated by an internal medicine physician and endocrinologist in addition to the urologist. […A]ll of the patient’s studies have been unremarkable and his testosterone levels continued to be in the 500-700 range. The reporting physician also report [sic] that the patients’ prescribing physician did not feel that finasteride was causative. No further information was available.
WAES 0501GBR00133: An approximately 19 year old male was placed on therapy with finasteride 1 mg for the treatment of male pattern baldness. There was no concomitant therapy. No information was provided regarding concurrent conditions and medical history. Subsequently the patient experienced erectile dysfunction, gynaecomastia, fatigue and feeling “mentally unclear”. Therapy with finasteride was discontinued in May 2003. The patient’s experiences persisted. In January 2005 the patient had the following normal laboratory test results: […] The reporting physician noted that he had no further contact with the patient and presumed he was still waiting for an appointment with endocrinology. The reporting physician felt that the patient’s adverse experiences were ongoing conditions and was “unlikely to have any answers in the near future.”
In a Discussion, Merck highlights that erectile dysfunction and decreased libido are “very common” and “well-described in the CCDS [Company Core Data Sheet].” Regarding spontaneous reports, Merck states: “…despite attempts to obtain follow up information, in accordance with the Company’s standard procedures to obtain follow up, no further information was provided.” The standard procedures for obtaining follow up are not described. The discussion emphasizes incompleteness and variability in reports of AEs persisting after discontinuation.
The memo concludes: “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. The Company will continue to monitor reports of persistent male reproductive system symptoms following discontinuation of finasteride therapy.”
Email correspondence between Keith Kaufman and Patrick J Ruane
Undated (ca. 2006) • View document (1 page)
Writing to Keith Kaufman and Elizabeth Round, Medical Program Coordinator Patrick Ruane summarizes sexual adverse events (AEs) for years 3–5 of the Phase III clinical studies. He describes one patient who discontinued the trial due to drug-related sexual AEs. 66 days after stopping use of finasteride, erectile dysfunction was still present. Ruane added, “It does not look like the patient was contacted for resolution of the AE.”
A second paragraph refers to 7 trial participants with unresolved sexual AEs at the time they discontinued or completed the study. It is unclear whether this includes the 6 patients described in the previous paragraph. Ruane adds: “I am planning on trying to determine as to whether the patients who’s [sic] AEs were still present were contacted for resolution.”
Merck letter to the Swedish Medical Products Agency regarding reports of persistent ED after quitting Propecia
Jun 18, 2007 • View document (10 pages)
Merck replies to the Swedish Medical Products Agency (MPA) regarding its requested changes to the Summary Product Information (SPC) for Propecia. Merck opposes MPA’s request regarding persistent erectile dysfunction after discontinuing finasteride:
With regards to the MPA request to update section 4.4 of the SPC with information on the persistence of erectile dysfunction after cessation of treatment, MSD [Merck Sharp & Dohme] wishes to confirm our position that the pre-clinical, clinical and post-marketing data do not support inclusion of precautionary text in the SPC.
In an attached report, Merck makes points to discount concerns about persistence of erectile dysfunction, referring to incompleteness, bias and low quality of post-marketing reports:
Post-Marketing
Although there is a significant amount of post-marketing data for finasteride, spontaneous reporting systems can only produce signals of potential cause-effect relationships because the information 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.
The report refers to “Only 75 reports […] where patients described an adverse experience which persisted after discontinuing therapy with finasteride, at the time of the report.” In 15 reports where follow up was available, “None […] reported a change in outcome of the event.”
In conclusion, Merck criticizes a study which found penile abnormalities in rats treated with finasteride; claims a lack of scientific basis for erectile dysfunction from finasteride; refers to incompleteness, biases and low quality of post-marketing reports; and asserts that in its clinical trials, “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.” Nevertheless, the next paragraph refers to a “report of the continued presence of a sexual AE six months following discontinuation of finasteride… No follow up data is available beyond this 6-month timepoint, so an ultimate assessment regarding persistence or resolution cannot be made.”
The closing paragraph suggests that data do not support inclusion of a warning about persistent sexual AEs:
The statement that undesirable effects have usually been transient during treatment or resolved upon discontinuation is accurate as regards the sexual AEs (and others included in the SPC). The pre-clinical data are predictive of what was seen in the clinical trials, in that no mechanism for lack of resolution of sexual AEs can be elucidated from the extensive preclinical database. The post-marketing data are subject to obvious limitations; however, despite the fact that not every outcome can be accounted for, they are generally supportive of the clinical data as well. Thus, the Sponsor considers the current SPC for PROPECIA to be appropriate and reflective of the available data and does not support inclusion of precautionary text in the SPC regarding persistence of erectile dysfunction following discontinuation of treatment.
Swedish Medical Products Agency: Final Assessment Report of Periodic Safety Update Report
Nov 16, 2007 • View document (12 pages)
The Swedish Medical Products Agency (MPA) provides a final assessment of Merck’s Periodic Safety Update Report on the period ending in November 2006. On p. 5, regarding persistent sexual dysfunction, MPA notes: “The case narratives of two reports only were provided, where the causal association with finasteride cannot be ruled out.” On p. 6, MPA further comments:
[the] statement “Resolution of these side effects occurred in men who discontinued therapy with Propecia and in many who continued therapy” may be misleading. Bused on the data provided, the additional warning on possibility of persistence of erectile dysfunctions should be included to [sic] the SPC [Summary of Product Characteristics].
On p. 8, MPA directs Merck to discuss the issue and possible mechanisms of finasteride’s influence on depression, and “consider updating the SPC.”
Swedish Medical Products Agency: Preliminary Renewal Assessment Report
Apr 17, 2008 • View document (22 pages)
The Swedish Medical Products Agency (MPA) reports on whether to renew authorization of Propecia.
Unfortunately, the MAH [Marketing Authorization Holder, or Merck] has not presented any new data in his [sic] response. The MAH is of the opinion that data from clinical trials with finasteride should be considered over that of reports received from the post-marketing environment with regard to determining relationships between drugs and AEs. It is agreed, that clinical trials data are more reliable than post-marketing data. […] However, this setting includes several disadvantages too: limited number of patients, inclusion of ‘ideal patients’ (inclusion and exclusion criteria are applied for enrollment), limited duration of treatment. Approximately 1500 patients received finasteride in clinical studies for [sic]. In this cohort, only ADR with frequency 1:500 is likely to be detected. The cumulative exposure in post-marketing setting for Propecia is more than 4.5mln patient-year, therefore rare and very rare ADR can be identified. Thus, the importance of post-marketing data should not be underestimated. Many well known examples are supporting this.
The MAH interpretation of post-marketing surveillance (pharmacovigilance) is not in line with the Volume 9A Of the Rules Governing Medicinal Products in European Union. It is not only a tool for signal detection, but it is a system for continuous benefit-risk assessment of the product after marketing authorisation.
One clinical trial report of erectile dysfunction and several post-marketing reports showed that erectile dysfunction had not abated after treatment discontinuation. A typical time to recovery was 2-3 months with a range from 1 day to 4 years. Recently the MPA received one additional case report of persistence of erectile dysfunction:
• The report described a 30 year-old male who have been experienced [sic] erectile dysfunction, decreased libido and decreased sperm production for one year after discontinuation of finasteride 1 mg. These AEs appeared together with an increased hair grow.
The MAH is requested to update the SPC with information on possible persistence of erectile dysfunction after discontinuation of treatment with finasteride.
Merck had been asked to comment on a study regarding finasteride and depression by Rahimi-Ardabili et al. On p. 15 the MPA Assessor responded to Merck’s comments: “Unfortunately, in depth analysis is missing and only some generalised critical comments provided. Psychiatric disorders should continue to be monitored.”
The Assessor requested Merck to provide discussion of other AEs including “infertility (7), infertility male (8); […] haematospermia (22), semen discolouration (16); […] malaise (44), dizziness (37), headache (37), somnolence (22), hypoaesthesia (12), paraesthesia (13); […] flushing, hot flushes (6; 12).”
P. 21 indicates that Merck only included reports of Propecia AEs where it was identified as the primary suspected drug. The Assessor commented that this practice “does not comply with the Volume 9A. The MAH should present a total number of cases were [sic] Propecia was suspected therapy. Line listing of not included cases should be also provided.”
Regarding adverse events in the SPC:
The first sentence ‘Undesirable effects have usually been transient during treatment or resolved upon discontinuation’ should be deleted.
[…] Additionally, information on duration/persistence of some ADR (e.g. erectile dysfunction, breast disorders, and libido) should be included either in section 4.4 or section 4.8.
On p. 22, the Assessor concludes: “At the moment renewal of the marketing authorisation cannot be recommended.“
Draft news release: Merck Statement Regarding June 2008 Update to the Prescribing Information for Propecia in the European Union
2008 • View document (3 pages)
In this draft press release, Merck makes a statement about the update to the prescribing information for Propecia in Europe, including the following:
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.
After a thorough review of the data from the controlled clinical trials of PROPECIA, and a careful assessment of post-marketing adverse events, MSD believes that the data supports the continued use of PROPECIA in appropriate patients with male pattern hair loss. MSD will continue to communicate with patients and health care providers about PROPECIA in ways that will help inform their decisions about appropriate treatment choices.
Patients with male pattern hair loss should talk with their doctors if they have any questions about the benefits and risks of PROPECIA. They can also visit INSERT LOCAL WEBSITE ADDRESS for more information. Patients should not stop taking the medication without first discussing with their doctor.
Background on post-marketing adverse event reports
MSD continually reviews post-marketing reports as part of its ongoing commitment to monitor the safety profile of its medications. MSD submits these reports to regulatory agencies around the world for their review. In addition to reports that MSD receives directly from healthcare providers and patients or their caregivers, we review information published in the medical literature and gather adverse event reports through data obtained directly by regulatory agencies worldwide. Each report is individually reviewed. MSD encourages healthcare providers and consumers to report any adverse experience associated with any MSD medication or vaccine.
Merck: Finasteride—Male Pattern Hair Loss: Risk Management Plan Version Number 1.0
Jun 4, 2009 • View document (72 pages)
This confidential document details Merck’s plans for managing risks related to adverse events of finasteride for hair loss.
Persistence of erectile dysfunction
Pages 31–33 address the risk of “Persistence of erectile dysfunction.” A subsection on public health impact states:
The safely profile of PROPECIA related to erectile dysfunction has been well characterized, and is included in the product label; it is not expected to change in the future. Cumulative analysis of postmarketing data since market introduction of reports of erectile dysfunction (see below) indicate that only 3.8% of reports of erectile dysfunction are considered serious, and that severity is based upon the consumer or HCP considering the ED disabling, or considering it an other [sic] important medical event, indicating minimal public health impact. Analysis of reports of persistent erectile dysfunction (see below) reveals minimal public health impact.
Comments on postmarketing reports include the following:
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.
Despite these reasons for discounting reports of persistent erectile dysfunction, the report goes on to describe cases “without evidence of other confounding variables”:
Within this cohort of 278 reports are cases that do appear to describe persistent erectile dysfunction after discontinuation of finasteride therapy, without evidence of other confounding variables. Three such representative cases are described below.
WAES 00111978 describes a 35 year old male who was started on treatment with finasteride 1 mg daily for the treatment of hair loss. After approximately 6 months of treatment the patient experienced impotence and decreased libido. Therapy with finasteride was eventually discontinued after 13 months of treatment. The patient reported he had been off finasteride for 4 months and his symptoms continued.
WAS 0611USA04853 describes a 38 year old male with no pertinent medical history, no drug allergies, and on no concomitant medication who was placed on therapy with finasteride 1 mg daily for the treatment of hair loss. Subsequently he noticed his erections were not as firm. The patient continued therapy with finasteride for 1 year. The patient underwent a complete blood panel, results negative; Doppler study and “every urological study”, results not provided. Approximately 1 year after discontinuation of therapy with finasteride, the patient was unable to obtain an erection.
WAS 0707SGP00011 describes a male, age not reported who was placed on therapy with finasteride 1 mg daily for the treatment of alopecia. Approximately 3 months after initiating therapy with finasteride, the patient complained of erectile dysfunction and itching. Finasteride was discontinued on 14-Mar-2007. In July 2007 the patient was referred to an andrologist for evaluation of erectile dysfunction and was treated with HCG 5000 units/3 x week.
Male infertility
A discussion of the risk of male infertility associated with finasteride use (p. 34) states:
Finasteride has no affinity for the androgen receptor and no direct androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. Inhibition of Type II 5ɑ-reductase by finasteride blocks the peripheral conversion of testosterone to DHT, which leads to significant decreases in serum and tissue DHT concentrations while maintaining mean circulating levels of serum testosterone and estradiol within the physiologic range.
The claim that finasteride has no “direct” anti-androgenic effects is technically true; however, its indirect effect is anti-androgenic. Merck does not acknowledge this indirect effect as a potential contributor to infertility.
In its discussion of postmarketing events (p. 35), Merck once more refers to incompleteness of reports and co-occurring conditions to question drug causation:
Of the 187 total reports received describing male infertility and related ADRs, 40 reports described the patient as recovered/recovering from infertility, 41 reports described the patients as not recovered at the time of reporting and the outcome of male infertility and related events in the majority of reports (106) was unknown at the time of reporting.
Review of the 15 serious reports revealed most did not include important clinical information such as baseline fertility evaluation/sperm analysis, or details regarding concurrent conditions and/or concomitant therapies which could predispose to infertility thus limiting a proper causality assessment. In addition, no details of evaluation for female infertility factors were provided in these reports.
Depressive disorders
Pages 39–42 address the risk of depressive disorders associated with use of finasteride. Merck uses similar arguments as in previous sections to discount this adverse event.
The section begins with a discussion of background incidence of depression.
Regarding severity, the report comments: “The impact of depression in patients on PROPECIA does not appear to have a significant impact on public health.”
Merck discounts the value of certain reports based on their provenance:
In January 2006, PROPECIA […] was launched in Japan. A number of reports (8) were received from Japan during 2006; this is characteristic of the Weber effect [1488]. In addition, during the first year of product approval in Japan, reports of adverse experiences are actively solicited as part of an Early Post-marketing Phase Vigilance (EPPV) program and are thus not truly spontaneous reports.
In 2006, the MAH received a letter from a consumer that outlined a number of consumer-reported events; the author of this letter stated that he had gathered his information from a consumer-driven website on which patients were asked to ‘rate’ the drugs that they took. The author claimed there were multiple consumer-reported events of ADRs related to PROPECIA on the website. A list of all events from this website was obtained by the MAH and was reviewed. These were all consumer-generated, and all had minimal information that would have allowed any assessment of causality with respect to PROPECIA.
Subsequent research found the Weber effect, referred to above as a mitigating factor, to be generally invalid.
Merck once again discounts the possibility of drug causation by reference to co-occurring conditions and lack of information:
One fatal report was received from a sheriff’s office and described a male who committed suicide by shooting. The medical examiner did not think this event was related to PROPECIA, in addition, the report provided insufficient information to allow for assessment.
An analysis of serious depression reports (10) and serious and non-serious suicidality reports (9) are presented below. Of the 9 reports of suicidality, 6 were serious.
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. On 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[.]
Regarding suicidality:
There were a total of 9 suicidality reports (suicidal ideation, suicidal attempt, suicide), six of which were serious. There was one completed suicide. In the 9 suicidality reports, 4 contained insufficient 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.
Reports of these events have been reviewed as part of the MAH’s ongoing pharmacovigilance activities and reporting and the MAH has not observed an increase in frequency of events. This cumulative review has revealed no new safety information regarding depressive disorders.
Planned pharmacovigilance actions
Section 2 details Merck’s plans for each safety concern. For persistence of erectile dysfunction, male infertility, and depressive disorder, the planned actions are “Routine pharmacovigilance” (p. 57). For all three safety concerns, “detailed further measures” are described thus: “Upon review of the data, appropriate measures will be taken if new information alters the benefit/risk profile of finasteride” (pp. 59–60).
Email correspondence between Keith Kaufman and Cynthia Silber
Jul 20, 2009 • View document (3 pages)
Keith Kaufman, head of Propecia clinical development, informs Cynthia Silber that they need to “re-review reports of ‘persistent erectile dysfunction’ from postmarketing use.” In reply, Silber refers to “278 reports that we reviewed for the RMP [Risk Management Plan].” A subsequent email from Silber notes:
The way we approached it for the RMP (this is just for Propecia) was that we looked at the over 2000 cases of ED that had been reported, and separated out the subset of those with a reported outcome of “not recovered’. There were 278 of these, and we reviewed each of them. They were of limited value, as you can imagine, due to lack of information, lack of followup, etc.
There is no MedDRA term for “persistent erectile dysfunction”, which complicates the issue of assessing it in a postmarketing environment. There is also no definition of “persistent”, either medical or from an agency.