Key Historical Failures and Lessons Learned from Attempts to Get a Testosterone Product FDA-Approved for Women

FDA Approval of Testosterone Therapy for Women: An Analysis of Historical Failures, Regulatory Hurdles, and a Path Forward

Executive Summary

The landscape of testosterone therapy presents a stark gender disparity: while over 31 FDA-approved products exist for men, there are zero for women. This is despite a significant, evidence-based medical need for treating Hypoactive Sexual Desire Disorder (HSDD) in postmenopausal women, a condition affecting millions and recognized by the FDA as significant. The pursuit of an approved product has been marked by high-profile historical failures, including the Procter & Gamble Intrinsa patch (2004) and BioSante's LibiGel (2011). These attempts were thwarted by a combination of insufficient long-term safety data, the challenging post-Women's Health Initiative regulatory climate, and clinical trial designs unable to overcome a powerful placebo effect.

Today, the primary obstacle to approval is not scientific but economic. The active ingredient, testosterone, is a generic hormone that cannot be patented, making it financially unviable for most pharmaceutical companies to fund the requisite long-term safety studies, estimated to cost between $200 and $500 million. Consequently, an unregulated market of 4 million annual off-label and compounded prescriptions persists, often with questionable quality control and dosing accuracy.

The most viable path to a first approval involves a transdermal cream or gel delivering a low, physiologic dose (5-10 mg/day) specifically for HSDD in postmenopausal women, a strategy validated by the successful approval of AndroFeme in Australia. Overcoming the FDA's stringent safety requirements will necessitate comprehensive cardiovascular and breast cancer data from trials spanning 3-5 years. While advocacy, the gender equity argument, and recent FDA roundtables (July and December 2025) signal a potential shift in regulatory attitude, the fundamental financial disincentive remains the most significant barrier. Success will likely require a combination of regulatory innovation, such as market exclusivity, and a mission-driven commercial entity to bridge the gap between medical need and market failure.


1. Intrinsa Testosterone Patch (Procter & Gamble, 2004)

What happened:

• Unanimously rejected by FDA advisory panel (17-0 vote) in December 2004
• Withdrew application and never resubmitted
• Approved by European Medicines Agency in 2006 for surgically menopausal women but later withdrawn due to poor sales

Critical failures:

• Insufficient long-term safety data - Only 24-week trials with 487 patients (mean treatment ~24 weeks). FDA demanded extensive cardiovascular and breast cancer safety data
• Timing disaster - Application came just 2 years after Women's Health Initiative (2002) created massive hormone therapy concerns
• Efficacy endpoint mismatch - FDA focused on absolute number of sexual events (2.1 vs 0.7 additional satisfying events/month) rather than quality-of-life improvements and personal distress reduction
• Off-label use concerns - FDA worried about widespread use beyond narrow indication (surgically menopausal women)
• Gender double standard - Men's testosterone products never required same safety rigor

Lesson: Post-WHI environment demanded unrealistic safety burden that no company could afford to meet for a generic hormone.

2. LibiGel Testosterone Gel (BioSante Pharmaceuticals, 2011)

What happened:

• Failed Phase III efficacy trials (BLOOM 1 & 2)
• Never reached FDA approval stage
• Company essentially dissolved after failure

Critical failures:

• Massive placebo effect - Placebo arm showed equal or numerically higher improvement than treatment group
• Trial design flaws - Regular clinic visits, daily diary reminders, and patient expectations inflated placebo response
• Couldn't demonstrate efficacy - Failed on all endpoints despite achieving appropriate testosterone blood levels
• Safety study never completed - Had initiated large BLISS cardiovascular safety study (2,800+ women) but efficacy failure ended program

Lesson: Women's sexual dysfunction extremely susceptible to placebo effects; standard RCT design inadequate.

What Needs to Be Done for First FDA Approval

Regulatory Requirements (Based on Historical Precedent)

1. Efficacy Evidence

• Two adequate, well-controlled Phase III trialsdemonstrating:
  • Statistically significant increase in satisfying sexual events (primary)
  • Statistically significant increase in sexual desire (primary)
  • Reduction in personal distress (secondary)
• Must show clinically meaningful benefit, not just statistical significance
• Need to minimize placebo effects through trial design

2. Safety Requirements

• Long-term safety data (minimum 1 year, preferably 3-5 years)
• Cardiovascular safety - No increased MI, stroke, or CV death
• Breast cancer monitoring - No increased incidence
• Adequate safety database size - Likely need 2,000-3,000+ patient-years of exposure
• Monitoring for androgenic effects - Hair growth, acne, voice changes, clitoromegaly
• Liver function monitoring

Optimal Indication for First Approval

HSDD in Postmenopausal Women (most likely path):

Why this indication:

• Strongest evidence base (36+ RCTs, 8,480+ patients)
• FDA already acknowledged HSDD as "significant medical condition" (2011)
• Clearly defined diagnostic criteria
• Measurable endpoints
• Natural menopause easier to recruit than surgical

Critical specifications:

• Population: Postmenopausal women (natural or surgical) with HSDD causing personal distress
• After psychosocial factors addressed - Not first-line treatment
• Concomitant estrogen therapy acceptable but not required
• Exclude: Premenopausal women initially (too complex, hormonal fluctuations)

Formulation Considerations

Transdermal delivery strongly preferred:

• Cream or gel - Allows precise low dosing (5-10 mg/day testosterone)
• Avoid oral - Adverse lipid effects, first-pass metabolism
• Avoid injections/pellets - Risk of supraphysiologic levels, irreversible side effects
• Target levels: Premenopausal physiologic range (free testosterone ~6 pg/mL)

Strategic Path Forward

1. Learn from Australia's Success (AndroFeme)

• First and only approved product globally (TGA approval November 2020)
• 1% testosterone cream, 5-10 mg/day dosing
• Indication: HSDD in postmenopausal women
• Key success factors:
  • 20 years of Australian research led by Susan Davis
  • State-based regulatory pathway initially (Western Australia)
  • Built comprehensive safety database through years of prescribing
  • Global Consensus Statement (2019) provided international expert backing

2. Address FDA's Specific Concerns

Cardiovascular safety:

• TRAVERSE trial (2023-2025) showed no CV risk in men - use this data
• Design dedicated women's CV safety study with enriched-risk population
• Pre-specify success criteria (upper CI limit for hazard ratio ≤2.0)

Breast cancer:

• Emerging evidence suggests protective effect (2 large studies show reduced invasive breast cancer)
• Long-term observational data (80 years of use)
• Include as monitored safety endpoint, not exclusion reason

Off-label use:

• Accept this reality - 4 million prescriptions already written off-label annually
• FDA approval would improve dosing accuracy and safety monitoring
• Compounded products have quality control issues (±20% dose variability)

3. Build Political/Advocacy Support

Recent momentum:

• July 2025 FDA roundtable on menopause HRT - experts called for female testosterone approval
• December 2025 FDA testosterone panel - discussing outdated regulatory framework
• Gender equity argument - 31+ products for men, zero for women despite equal need
• Insurance coverage - No FDA approval = no insurance coverage = access barrier

4. Financial Realities

The patent problem:

• Testosterone is generic - cannot be patented
• No blockbuster ROI for pharmaceutical companies
• Estimated market: $286M-$1B, but heavy marketing required to convert off-label prescribing

Possible solutions:

• Regulatory exclusivity for novel formulation/indication
• Government/academic partnership funding
• Women's health-focused companies with mission-driven approach
• International approval pathway - start with EMA, Health Canada, build evidence

Timeline Estimate

Conservative path: 7-10 years minimum

• Phase III trials: 2-3 years
• Long-term safety study: 3-5 years (concurrent/sequential)
• FDA review: 12-18 months
• Total cost: $200-500M+ (prohibitive for generic product)

Accelerated path possibilities:

• Leverage existing data - 80 years of safety data, 36+ RCTs
• Use AndroFeme Australian data - already TGA-approved
• Real-world evidence - 4M prescriptions/year in US
• FDA flexibility post-recent roundtables

Bottom Line

The first FDA-approved testosterone product for women will most likely:

• Be for HSDD in postmenopausal women
• Be a transdermal cream or gel at 5-10 mg/day dosing
• Require comprehensive CV and breast cancer safety data (3-5 years, 2,000+ women)
• Demonstrate clinically meaningful improvement in sexual function and distress
• Need $200-500M investment with unclear commercial return
• Face gender equity advocacy as critical driver given financial disincentives
• Potentially follow AndroFeme model - seek FDA approval for already-marketed Australian product

Most significant barrier: Not science, but economics. Generic testosterone offers no patent protection, making the massive investment required for FDA approval financially irrational for pharmaceutical companies. This requires either regulatory innovation (exclusivity provisions), government funding, or a company with mission-driven rather than profit-maximizing objectives.

The recent FDA panels (July and December 2025) suggest regulatory winds may be shifting, but without financial incentives, approval remains unlikely despite clear medical need and supporting evidence.

 

More details: Trials and tribulations of TRT in women - Excel Male Health Forum