Request for Comment: Draft Guidance from the Committee for Male Contraceptive Development and Regulatory Best Practices

Open Comment: Draft Guidelines
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Hello!

Thank you for your interest in reviewing and providing comments on the draft guidance developed by the Committee for Male Contraceptive Development and Regulatory Best Practices. This document (accessible via this link) was created by a group of international experts (listed below) in response to the growing momentum in male contraceptive development over the past decade which has moved at a rate that has outpaced the establishment of product-specific regulatory guidance.

This open call for comment is a critical step in shaping these recommendations. Your feedback will help ensure the most comprehensive and relevant considerations are reflected, ultimately supporting a more efficient and effective regulatory pathway for male contraceptive products.

To help ensure a productive and organized review process, we kindly ask that you follow the instructions below when submitting comments:

  • Please provide your feedback on the document using the comment box at the bottom of this page.
  • Refer to specific line numbers whenever possible to help us accurately understand and incorporate your input.
  • Please include your name and affiliation with your comment.
  • We welcome comments based on your area of expertise, including feedback on specific sections or topics. General feedback on the entire document is also appreciated.
  • If you have extensive comments, a response letter, or supplementary materials, you may upload them using the paperclip icon in the comment box.

If you wish to post a comment, you will be prompted to create an account. After creating an username and password, you will be sent a verification email. If you do not receive the email, please be sure to check your spam folder. If you experience any issues or have questions, please don’t hesitate to reach out to us at: :e_mail: guidance@malecontraceptive.org.

Thank you again for your time and contributions!

Committee for Male Contraceptive Development and Regulatory Best Practices

Leadership Team:
Erin R. Gardner, PhD
Gregory S. Kopf, PhD
Will Skinner, PhD
Heather Vahdat, MPH

Committee Members:
John Amory, MD, MPH
Jochen Buck, MD, PhD
Vargheese Chennathukuzhi, PhD
Lisa Campo-Engelstein, PhD
Chris DeJonge, PhD, HCLD
Julie Dumond, PharmD, MS
Kevin Eisenfrats, BA
Gary Gamerman, MS, JD
Shefali Goyal, MS
William Kelce, MS, PhD
Lonny R Levin, PhD
Nadja Mannowetz, PhD
Ajay Nangia, MD
Logan Nickels, PhD
Kyle Orwig, PhD
Stephanie Page, MD, PhD
Alexander Pastuszk, MD, PhD
Giovanni Pauletti, MPharm, PhD
Reshma Ramachandran, MD, MPP, MHS
Lisa Rohan, PhD
Regine Sitruk-Ware, MD
Lisa Soule, MD
Douglas Taylor, PhD
Alexander Travis, VMD, PhD
Yelena Tropsha, PhD
Marcel VanDuin, PhD
Darlene Walley, PhD
Michael Zitzmann, MD

Special Thanks to the following Patient Advocates:

Joseph Guy Gibboney
Logan Whitehead

https://www.malecontraceptive.org/uploads/1/3/1/9/131958006/250813_male_contraception_development_and_regulatory_best_practices_draft_guidance_for_comment.pdf

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Can I recommend an executive summary be inserted, to follow the table of contents (i.e. page 1)? I find this is a useful addition for long documents such as this - it sets the scene and primes the reader for key takeaways as they go through the main content
William Burch MD

2 Likes
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Congratulations on the development of these robust guidelines. It is such an exciting time in the development of male contraceptives and this is a much needed document. Overall I agree with the vast majority of recommendations, and have made a few notes below.

1277 - 2-7 days between ejaculation. The WHO Standard should be kept in this instance as it is widely accepted. However, studies are emerging that suggest shorter duration of abstinence might be more optimal, conflicting with results of other studies. https://raf.bioscientifica.com/view/journals/raf/1/1/RAF-20-0018.xml. Additionally, there is a thought amongst male fertility patients that the longer interval between ejaculation the better, so will aim for 5-7 days abstinence, however this can have a negative effect on morphology and motility parameters, and may lead to screening failures of patients with otherwise normal semen quality. Though for contraceptive trials, the inverse might be true and patient psychology might lead patients to aim for a shorter abstinence window. We should watch this space to see if the WHO standard is changed in the future. (Also correlates to line 1672)

1394 - I agree with the recommendation; however I think careful wording should be used at recruitment. For example, ‘Do you intend to stay in a monogamous relationship for the duration of the trial?’ rather than ‘Do you comply with the expectation to stay in a monogamous relationship for the duration of the trial?’

1413 - The FDA approved age range for clinical trials of a medical device should ideally be 18+, not 22+. If trials don’t enrol 18-22 year olds, the product licence may not allow use in these patients, which would be disappointing as they could be a key user of vas-occlusive devices and the additional 4 years of contraceptive duration would provide better value to the patient/healthcare organisation.

1507 - Adding reversibility time-oriented objectives or guidance would be useful, similar to the recommendations about sperm suppression. As this will be a secondary endpoint in many pivotal trials, we should recommend 12 months follow up with multiple measurements i.e. 4,8,12 weeks then a reduced frequency at 24 weeks, and 48 weeks. For a less instructive recommendation it could be written as ‘following discontinuation of product or removal of device, extensive follow up with multiple measurements of sperm count and function with a reducing frequency over time’.

1792 - Superior or near-equivalent to a condom. Users who prefer not to use condoms but want a high (but not near-perfect) level of protection will likely accept similar failure rates. Difficulty lies in the perceived efficacy of condoms being higher than actual with one study showing 25% believing condom and the pill to be equally effective and 22% believing condom to be more effective. https://powertodecide.org/sites/default/files/resources/primary-download/fog-zone-full.pdf

2218 - Characterising the frequency of sexual acts is an important point, and there is the option to go one step further. For a subset of patients in phase 2 or 3 trials, luteinising hormone (LH) tests could be provided to the female partner to ensure that at least one sexual activity per month occurs within the window of implantation. Whilst this would add small cost and wouldn’t be strictly necessary as it hasn’t been implemented in all female contraceptive trials, it could add another element of robustness to trial design. Consequently, it may lead to some patient withdrawal from study due to failing to adhere to the protocol and hinder recruitment if patients knew they had to have intercourse during the window of implantation.

2751 - May read clearer as: Conversely, the EMA has centrally approved only a single contraceptive in the last decade. Drovelis (the same drospirenone and estetrol product as Nextstellis, marketedunder a different name) was approved in 2021 based on adequate efficacy in the European pivotal trial, which resulted in a PI of 0.44.201 Although a trial including US-based sites observed lower efficacy, with the European Public Assessment Report (EPAR) highlighting the failure to meet the expectations of hormonal contraceptives. The EPAR states, “The requirement for precision of the PI (2.42, 95% CI: 1.58, 3.54) was not met in accordance with the EMA Guideline on Steroid Contraceptives, since the difference between the upper limit of the corresponding 2-sided 95% CI for the Pearl Index and the point estimate was > 1.”

Additionally, for general trial exclusion criteria I would consider the following if not already included:

Male & Female Partner BMI < 35 (higher pregnancy rates and more robust data set if mean is <30, however will restrict future use and applicability to real world population so stratifying results by BMI could be useful)

Presence of Grade II or III varicocele

Daniel Barnett

Medical Scientific Liaison (MSL), Local Person Responsible for Pharmacovigilance (LPPV) & Medical Information Manager

IBSA Pharma UK

2 Likes
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Thanks for the opportunity to review the draft recommendations. I have minimal suggested edits that I will send to Heather via email as none are substantive discussion items! I look forward to the Sept 4th zoom conversation.

2 Likes
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** Moving new topic post to be included in the thread **

From Christina Wang:

Excellent comprehensive document to read. Minor questions/comments

Line 319-321 I am worried about nor preclinical toxicology before first in human studies. There must be suitable animal models for drug toxicities. The clinical studies may identify issues in tissues and organs that ae not the target organs for the new drug being tested.

Line 1542 to 1543 The recommendation should follow the WHO manual that indicates that manual counting is the gold standard at this time for counting spermatozoa. Counting sperm is easy to train. Operations of CASA requires specialized training. Each CASA machine is different.

Line 1589 to 1593 CASA is the only method used to assess sperm hyperactivity and should be recommended for the specific function assessment.

Line 1600 to 1601 CASA has not be n extensively validated for sperm morphology, vitality and DNA integrity. Suggest removing this sentence.

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  1. Lines 26–31
    Text: “The sole contraceptive options for males are vasectomy and condoms.”
    Problem: Overstates exclusivity. Withdrawal is widely used, though not a modern or effective method.
    Correction: “The only modern, effective male-controlled methods are vasectomy and condoms.”
  2. Lines 76–84
    Text: “Of the over 47M Americans aged 15–49 who relied on contraceptives, there is still a yearly unintended pregnancy rate of 45%…”
    Problem: Misrepresents statistics. The 45% figure refers to the proportion of pregnancies that are unintended, not an annual risk among users.
    Correction: “In the U.S., approximately 45% of pregnancies are unintended, despite widespread contraceptive use.”
  3. Lines 272–277
    Text: Blood–testis barrier limits drug distribution.
    Problem: Presented as absolute. Permeability varies; efflux transporters play major roles.
    Correction: “The blood–testis barrier restricts many compounds but permeability varies by drug class, with efflux transporters (e.g., P-gp, BCRP) contributing substantially.”
  4. Lines 378–414
    Text: Organoids and organ-on-chip as alternatives.
    Problem: Suggested as substitutes, but current models rarely achieve full spermatogenesis.
    Correction: “Organoids and organ-on-chip systems are promising for mechanistic studies but are not yet validated for regulatory safety assessment.”
  5. Text: “Quantifying drug levels in semen… can be readily performed.”
    Problem: Understates challenges (low volume, matrix effects, sperm vs plasma partitioning).
    Correction: “Drug levels in semen can be measured with fit-for-purpose bioanalytical validation, accounting for matrix effects, low volumes, and distribution between sperm and seminal plasma.”
  6. Lines 705–709
    Text: “Must require one dose… onset ≤1 hour… effective for hours.”
    Problem: Reads like regulatory requirement. Actually target product profile.
    Correction: “Target product profile: single dose, ≤1-hour onset, multi-hour duration; final label should reflect trial-tested parameters.”
  7. Lines 733–751
    Text: “Targeted degraders and covalent inhibitors” for sperm.
    Problem: Overstates feasibility; mature sperm lack transcription and proteasome activity.
    Correction: “Targeted degraders and covalent inhibitors are theoretically attractive but require proof of uptake, target engagement, and activity in mature human sperm.”
  8. Lines 771–773
    Text: “Standard semen analysis (post-liquefaction up to 1h) could overestimate effect.”
    Problem: Statement is valid but needs operational guidance.
    Correction: “For on-demand agents present only in seminal plasma, motility and function should be tested immediately after liquefaction or via cervical-mucus penetration models.”
  9. Lines 809–816
    Text: Azoospermia or low counts as PD endpoints.
    Problem: Azoospermia does not guarantee infertility; rare sperm can yield pregnancies.
    Correction: “Azoospermia and very low counts are accepted PD endpoints but contraceptive efficacy must ultimately be confirmed with pregnancy outcomes.”
  10. Lines 878–888
    Text: Sperm function assays (acrosome reaction, zona binding).
    Problem: Limited reproducibility, weak correlation with in vivo fertility.
    Correction: “Sperm function assays may provide exploratory mechanistic data but are not validated as surrogate markers of contraceptive efficacy.”
  11. Lines 944–960
    Text: Recovery after discontinuation.
    Problem: Suggests recovery within weeks; in reality, recovery may take months (full spermatogenesis + epididymal transit).
    Correction: “Recovery to baseline semen parameters may take several months, reflecting the full spermatogenic cycle and epididymal transit.”
  12. Lines 979–991
    Text: Pregnancy as endpoint.
    Problem: Draft does not highlight female partner fertility as a confounder.
    Correction: “Pregnancy-based endpoints must account for female partner factors such as age, ovarian reserve, and reproductive history to avoid biased efficacy estimates.”
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4 Recommendation: When enrolling couples for studies with a pregnancy
1395 endpoint, the only social criteria that should be applied is an expectation of
1396 remaining in a monogamous relationship for the duration of the study.
1397
1398 ● Unlike efficacy studies of female contraceptives, which merely require the
1399 female participant to record at least one occurrence of unprotected sex each
1400 month, independent of partner or relationship status, accurately measuring
1401 pregnancy risk of a male contraceptive requires enrolling a couple that
1402 intend to remain partnered and monogamous for the duration of the study.
1403 Additional non-scientific barriers to participation, such as requiring the
1404 couple to have been in a relationship for a minimum duration prior to
1405 enrollment, should be avoided, since they can hinder clinical trial
1406 recruitment and enrollment unnecessarily.

The following is my submission on the above captioned.

Additionally it’s more safe to recruit participants(couples)who are legally married for the sake of surity and success of the study,furthermore we may target those couples who stick to one faithful sexual partner.And how will we address the issues of sexually transmitted disease prevention,from the look of things the type of male contraceptive seems to be abandoning the issue of STIs.We may wish to add participants who have not contracted an STD in the last 12months.

Andrew Kaonga,7th year medical student@ University of Lusaka,from Lusaka Zambia.

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Thank you for all of the hard work that went into putting together such an extensive document. Congratulations to all involved.

I believe that somewhere in the document, there is a statement about efficacy end-point preference based on a biomarker in a male-only population, especially for sperm suppression agents, with a recommendation for biomarker inclusion in the phase 3 studies where men only would be enrolled. This is inconsistent with the concept of proving efficacy as is the case for all other drugs. Clinical outcomes are absolutely necessary. Otherwise, for female systemic hormonal contraceptives, we could simply prove inhibition of ovulation and have approval. The high number of participants in female contraceptive studies is actually more for safety outcomes than pregnancy. I would expect the same for male contraceptives.

I had issue with this statement: “Male contraceptive efficacy trials that utilize pregnancy as an endpoint should prioritize clinical sites in states or countries with stable legal access to first-trimester abortion care.” Although I agree in principle, the statement is too limiting. For example, a patient who lives in St. Louis can easily obtain an abortion just over the border in Illinois. This has been the norm since the Dobbs decision. Telehealth abortion is quite the norm but potentially still a barrier. Thus, at the most, the statement should be simplified to “Male contraceptive efficacy trials that utilize pregnancy as an endpoint should prioritize clinical sites in areas with stable legal access to first-trimester abortion care.”

I find it odd that the document does not provide an upper age limit for men for efficacy and a slightly higher limit for safety only as is done globally for female contraceptives. Although there is some decline in male fertility beginning at 35 years, this is nothing like the decline in females at that age. From my look at the literature (which you all know better), a reasonable upper limit would be 45 years for efficacy and up to 55 years for safety, keeping in mind that the upper cut-off for the female will be 35 years. Thus, it will be unlikely that men exceeding 45 years will be a large part of any trial. Thus, using 45 years is reasonable. Keep in mind that women over 35 years have good fertility, it is just lower than at younger ages. Methods will physiologically work the same in women regardless of age but regulatory authorities want to assure that effectiveness is established in those “most” at risk. The same logic applies to male methods.

The following statement seems unnecessary and inconsistent with regulatory practice: “In recent years, the FDA has approved several female products with a PI>1, concluding that the benefit of new options for decreasing the risk of unintended pregnancy outweighed any method-related risks.” The requirement for a PI < 1 is typically used for IUDs and implants, not CHCs. Most CHCs have a PI>1 in studies for the past 30-40 years. This is not just recent. In addition, non-hormonal/non-IUD methods (including condoms) will have a PI >1. It makes no sense that the document tries to call out a PI of 1 for any reason. Regulatory authorities do not set an absolute on a method unless there are other similar methods, meaning it would be considered by clinicians and patients to be similar. Regulatory authorities do provide general goals with the simply concept that anything outside the goal is just a matter for discussion during review. Since male methods are unique at this point, whatever they are is what they are… A lot of this entire section starting on page 52 could be much shorter if made more relevant and realistic. Additionally, given that PI is likely the inappropriate analysis to use for male contraceptive efficacy, it makes even less sense.

On page 59, the comments on ultrasound are inconsistent with standard research and clinical practice when evaluating early pregnancy. Ultrasound is the standard in both female contraceptive trials and clinical care for gestational dating. There is no reason that this document should recommend anything other than the standard. This is not a burden - this is simply normal care.

I also find multiple issues/have suggestions in the efficacy section which starts on page 60.

  1. Why is life table inadequate? This would be the preferred method. I find no rationale for the statement on line 2069 that life table doesn’t adequately characterize male contraceptive efficacy when the pregnancy outcome is in the female partner. Beginning in line 2127, the document argues for life table. I think the statement in line 2159 could be removed because no one knows what regulators will require.

  2. I find the section inadequately defines failure components for a drug. Pregnancies are on-treatment or off-treatment. For the purpose of male contraception, the on-treatment can be further divided to suppression phase and efficacy phase and the off-treatment needs to be clearly defined based on the type of product (how it works) and cannot be standardized as done for female contraceptives (EMA 2 days, FDA 7 days since last use). What occurs during these trials needs to be transparent to other researchers, clinicians and patients.

  3. The statement beginning in line 2163 also appears inexact. The variability is moot since this same issue occurs in barrier method and fertility awareness based trials. As long as a standard cycle length is stated, the life-table still provides an appropriate and adequate outcome. More important is to ensure that the 21-35 day length still includes females with little variability. A female that has consecutive cycles that are 21 day, 34 days, 28 days, 21 days, 35 days… does not have regular cycles. A variation in cycle length of 5 days of less (or 7 as an extreme) should also be part of the requirement. This requirement will further obviate the point in line 2163.

  4. The recommendation in line 2218 is problematic to me. The section should simply state that regulatory requirements for male contraceptives should not be more tedious than for female studies. One act per month is sufficient for female methods and should be the same for male. We showed years ago with spermicide studies that the more frequent the intercourse, the higher the failure rate. It is reasonable to suggest this outcome might want to be assessed during product development but approval requirements should be consistent with female methods. The section header should be about keeping things the same, not about considering exploratory analyses.

The risks section is missing that some women may lose out on some of the benefits of female contraceptives (the risks section states that this may reduce their risks of female contraception so there should be a corollary under the risks). Women can still choose to use their method as well but it is possible they may be less likely.

Mitchell Creinin, MD

Distinguished Professor, Dept. of Obstetrics and Gynecology, University of California, Davis; Sacramento, CA, USA

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Comments from Christopher ChoGlueck, PhD

Associate Professor of Ethics (Dept. Communication, Liberal Arts, and Social Sciences)

Faculty Adviser for Responsible Conduct of Research (Office of Research)

Adjunct Professor of Biology

New Mexico Tech

Pronouns: he/his

https://nmt.edu/academics/class/faculty/cchoglueck/

General comments: From my perspective as a philosopher and historian of science, I found the narrative clear and the recommendations accessible. I especially appreciated the points throughout about how male contraception poses unique challenges for clinical testing, such as how the intended effect of suppressing spermatogenesis here would be an AE in most other areas of medicine (p. 64). I also found very persuasive the claim there has been “a tolerance of risk and acceptance of a range of effectiveness in female contraceptives by the FDA” (p. 83, line 2744). Since my expertise is primarily related to analyzing values, biases, and assumptions in expert judgments about contraceptive safety, I will focus there. These are my suggestions based on my own understanding of the history of male contraception and the hurdles it has faced in terms of gender bias and double standards:

1) Male Sexual Functioning: I believe the draft guidance could use more explicit discussion and recommendation about the specific AEs that have stymied past trials and delayed male contraception’s development. First, the negative effects of hormonal methods on male sexual function, specifically male potency and male libido, have caused researchers considerable challenge during the 1970s, ‘80s, and ‘90s: The length between phase I and phase II trials was doubled in the 1970s-1980s in part because of this concern and the ways that supplemental androgens were used to combat these undesired effects, which in turn reduced overall effectiveness by promoting spermatogenesis (Oudshoorn 2003). Similar to the point about suppressed spermatogenesis in this field vs. elsewhere (p. 64), I suggest the committee note this challenge related to “interfering” with male sexual functioning and make some recommendation. I would point toward assessing the tolerability of sexual-function AEs partially through using patient experience data (p. 84, line 2889). This would at least reduce the potential of the implicit background assumptions of researchers/regulators negatively influencing the research through foregrounding the concerns and providing more direct evaluation of the tolerability of these AE by actual users (ideally both male participants and their partners).

2) Mood Impacts: In addition, I suggest an explicit discussion of the potential negative impacts of hormonal methods on mood. Elevated risks of mood swings, depression, and suicide risk were a major factor in the early termination of the ~2011 WHO study, despite comparable rates in female trials, raising concerns about gender bias and double standards in safety assessment (Abbe and Roxy 2020; ChoGlueck 2022). I think this would belong in the section of “Benefit-Risk Frameworks” about “subjective and inconsistent processes” (p. 76, line 2583). I think it is important to discuss specific AE that have been barriers in the past rather than remaining vague. Again, rather than allowing background assumptions to bias safety assessment, it would be better to lay out potential standards prior to the study so that they can be evaluated and critiqued.

3) Shared/Individual Risk: I appreciated the section “Shared Risk and Responsibility” (p. 81 line 2665), and I had one suggestion for elaboration/recommendation. The committee recommends earlier a separate male-only cohort with sperm-only endpoints as well as a couples group with pregnancy endpoints (p. 29, line 962). Accordingly, I suggest clarifying that the Shared Model works for the latter cohort with couple but not the former with only men. It would be apt to recommend that the Benefit-Risk be calculated both individual and shared, not either/or (see ChoGlueck 2022).

Works cited:

Abbe, C., & Roxby, A. C. (2020). Assessing safety in hormonal male contraception: A critical appraisal of adverse events reported in a male contraceptive trial. BMJ Sexual & Reproductive Health, 46(2), 139–146. https://doi.org/10.1136/bmjsrh-2018-200206

ChoGlueck, C. (2022). Still no pill for men? Double standards & demarcating values in biomedical research. Studies in History and Philosophy of Science Part A, 91, 66–76. https://doi.org/10.1016/j.shpsa.2021.11.010

Oudshoorn, N. (2003). The Male Pill: A Biography of a Technology in the Making (First Edition edition). Duke University Press Books.

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Comments from William Burch, MD
Pharmaceutical Physician, UK

Dear all - firstly thanks to everyone who put the document together! It’s very comprehensive and a brilliant guide for regulators and developers alike. Looking forward to seeing the final version inclusive of comments.

FYI @heatherv and @jacrapster I have additional comments from my first comment so am putting them all into one reply.

General comments:

  • Can I recommend an executive summary be inserted, to follow the table of contents (i.e. page 1)? I find this is a useful addition for long documents such as this - it sets the scene and primes the reader for key takeaways as they go through the main content

  • Throughout the document, can we include terminology to align with ex-US/FDA usage? Existing references to IND etc NDA could be easily adjusted to make the document more globally applicable, e.g. IND/CTA and NDA/MA

  • The document lacks a conclusion. I would add one to summarise and reinforce key takeaways.

  • There is no discussion of establishing a solid post-marketing/medical affairs strategy early in development. Given the novelty of male contraception, a clear launch and post-marketing strategy will be critical for both commercial viability and public adoption. Developers will need to plan early for stakeholder education, engagement with healthcare providers, and real-world data generation to support confidence and uptake. This includes key marketing messages, anticipating blocks/barriers to uptake, aligning with public health bodies on communication strategies, and anticipating potential sociocultural or policy barriers to market entry.

Specific comments:

  • Line 271 - swap round order of paragraphs on lines 249 and 271 to improve flow when reading

  • Line 665 - commercial realities will inevitably steer decision-making in drug repurposing! I would recommend expanding this section substantially on the importance of seeking strong commercial, legal, and intellectual property advice, given securing an indication for an off-patent medication in a common indication is commercially challenging. The only practical way to protect against a generic manufacturer entering the market using your clinical trial data is through a strong IP position, e.g. by developing a new formulation or delivery system.

  • Line 1067 - in the ‘Global Considerations’ section, I recommend including a section on bridging studies to support regulatory acceptance outside of the UK and US. Bridging studies, for examples, are often needed for approval in Japan. ICH E5 is the relevant guideline.

  • Also under ‘Global Considerations’, it would also be valuable to advise developers to consider what pathways available in the EU or UK to incentivise development.
    For instance, the UK MHRA has an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP). This supports innovative medicines that address a significant patient need, and is not limited to life-threatening or rare conditions. This could apply to male contraception if a strong case is made around public health impact, unmet need, and innovation, such as a novel non-hormonal mechanism. If accepted, it provides access to a Target Development Profile and coordinated input from MHRA, funding agencies, and other key bodies.
    For the EMA, PRIME (PRIority MEdicines) is a pathway for medicines offering a major therapeutic advantage in areas of unmet need and is open to small companies and academics. Benefits include early engagement, scientific advice, and a rolling review of the marketing authorisation.
    There could also be a comment about the need for developers to make a case to the regulators for why a treatment like this would be eligible for this support, if there an element of shoehorning male contraception studies into these pathways may be needed.

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Comments from Netta Hirschberg, COO and Co-founder of Proventis:

1. Regulatory Pathway Clarity

The current guidance is more drug-centric, which creates uncertainty for device developers in some aspects.

For example: Lines 146, line 820 refer to IND (and not IDE), or line 360 that should also include ISO 10993 and FDA’s guidance for biological safety. Another example is line 453: The GLP statement and “primary pharmacodynamic” framing are drug-centric, not device-centric.The sentence “these studies are considered primary pharmacodynamic studies and are not required to be performed under GLP” is not appropriate for device submissions. For devices, to support safety studies, FDA’s animal studies submitted to support safety of a medical device are expected to comply with 21 CFR Part 58 (GLP), with any deviations justified.

2. Occlusion and Reversibility:
For occlusion efficacy, the committee proposed that: Vasectomy alternatives and vas-occlusive devices may choose to use the American Urological Association’s guideline for successful vasectomy (≤100,000 non-motile sperm per mL) as a target value. (line 1497)

We agree with this suggestion.

For fertility restoration rate, the committee proposed that “Reversibility and post-treatment recovery should be defined by a return to sperm parameters above the 5th percentile of the reference population range for fertile men as described in the most current version of the World Health Organization Laboratory Manual for the Examination and Processing of Human Semen, as opposed to individual baseline values. (line 1507)”.

We recommend defining additional standardized reversibility metrics, such as: time to return of motile sperm, percentage of users achieving reversal within 3–6 months, etc.

3. Human Factors and Usability

Device performance depends not only on biology but also on procedural success. We encourage the inclusion of FDA-recognized human factors and usability testing requirements, covering insertion, removal, provider technique, and patient acceptability, to better reflect real-world conditions.

4. Medical Devices failure modes

We encourage the committee to benchmark reversible device’s commonly expected failure modes such as loss of sterility, and mechanical failures (leakage, breakage etc.) as common grounds for device verification activities

5. Reimbursement

Last but not least is the matter of male contraception REIMBURSEMENT. Our team identified this heavy and critical issue to be also relevant in early development stages as it affects our indication for use statement, our clinical goals and sample size etc.. I may even classify it as a higher blockage to market entry than the regulatory blockage.

I would like to kindly ask you, as head of MCI, if this is a topic that MCI is currently addressing (as part of the guidance document) or intends to address in a different project.

Again, we wish to thank MCI for this important activity.

Our goal is mutual - to promote male contraception towards a truely shared family planning responsibility.

Best regards,

Netta