# Presentation: 517436

## Application of Critical Path Principles to the Development of Drugs for Menopausal Symptom Therapy (MST) after the Women’s Health Initiative (WHI)

- Daniel Shames MD FACS
- Jerry Willett MD
- Stephan Ortiz R.Ph, PhD

## Disclaimer

- Our remarks today do not necessarily reflect the official views of the FDA.

## Outline of Presentation

- WHI (NIH-WHI Study - HT Sub study), MST/Challenges
- Critical Path Initiative, MST/Solutions
- Vasomotor Symptom Modeling
- Potential Alternate Methods of Assessing the Risk of Endometrial Cancer
- A Clinical Trial Endpoint Case
- Critical Path to Success for Developing Drugs for MST

## WHI

- The primary outcome was coronary heart disease (CHD) - nonfatal myocardial infarction and CHD death. Invasive breast cancer was the primary adverse outcome
- 16,608 participants randomized to receive conjugated estrogens 0.625mg/day plus medroxyprogesterone acetate, 2.5mg/d in one tablet or placebo
- Mean 5.2 years of follow-up
- Safety Monitoring Board stopped trial because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic indicated that risks exceeding benefits

## WHI

**Absolute EXCESS RISKS  per 10,000 person years attributable to Estrogen plus Progestin**
**7 more CHD events **
**8 more strokes**
**8 more PEs**
**8 more invasive breast cancers**
**Absolute RISK REDUCTIONS  per 10,000 person years attributable to Estrogen plus Progestin **
**6 fewer colorectal cancers**
**5 fewer hip fractures**

## WHI

- A Shock to Many
- Estrogens approved since 1942
- Endometrial cancer concerns since 1976
- Addition of progestins obviated concerns
- Hugely popular drugs for maintaining youth
- Hormone Replacement Therapy (HRT)
- Prevents heart disease, dementia, wrinkles etc.
- Approved for MST, osteoporosis
- Not for cardio-protection or prevention of dementia
- Breast cancer, thromboembolic risk in labeling

## WHI/MSTProblems

- Mass confusion
- Patients, Providers, Sponsors?, Experts?
- Miscommunication? Misperceptions? Data Overload?
- WHI
- Trial design issues
- Doses, Populations
- Are the results applicable to other Es and Ps?
- Are results applicable to other formulations?

## WHI/MSTInterim Solutions

- Labeling changes
- Think of other options
- Vulvar and vaginal atrophy-
- Osteoporosis
- Not for cardio-protection
- “in the absence of data, risks assumed to be similar for all products”
- Use lowest dose for shortest time

## WHI/MSTLong Term Solutions

- Critical Path Initiative
- Published 2004
- Many of the principles already embraced by DRUDP

## Critical Path, What?

## Critical Path, What?

- Assessment of Safety – how to predict if a potential product will be harmful?
- Proof of Efficacy  -- how to determine if a potential product will have medical benefit?
- Industrialization – how to manufacture a product at commercial scale with consistently high quality?

## Critical Path Initiative, What?

- 	An attempt to focus attention on modernizing the evaluation of safety, efficacy and quality of medical products as they move from product selection and design to mass manufacture

## Critical Path Initiative, Why?

## Critical Path Initiative, Why?

## Critical Path Initiative, Why Us?

- “FDA responsible for_*** assuring***_ the safety, efficacy...”  PLUS
- “....is also responsible for advancing the public health by _***helping***_ to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.”

## Critical Path Initiative, Why Us?

- FDA scientists are involved in review during product development--they see the successes, failures, and missed opportunities
- FDA guidance documents are known to foster innovation and improve chances of success
- FDA has convening and coordinating role

## Critical Path Initiative, PrinciplesRemember this Slide!

- Guiding principles for FDA collaborative efforts among government, academia, industry and patient groups
- Infrastructure and “toolkit” development, not product development (“_precompetitive_”)
- Build support for academic science bases in relevant disciplines
- Build opportunities to share existing knowledge & database
- Develop enabling standards (Guidances etc)

## Critical Path Initiative, MST

- DRUDP working on multiple projects to facilitate development of drugs for MST
- Modeling for lowest effective dose
- Endometrial protection assessment
- Efficacy evaluation for VMS (vasomotor symptoms)
- Others