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

Nelson Vergel · 2025-12-11T11:34:19-0600

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Approved by European Medicines Agency in 2006 for surgically menopausal women but later withdrawn due to poor sales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 trials demonstrating:
- 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.