# Presentation: 521082

## Considerations for Topical Microbicide Phase 2 and 3 Trial Design: A Regulatory Perspective

**Teresa C. Wu, M.D., Ph.D.**
**Division of Antiviral Drug Products**
**Food and Drug Administration**

## Outline

**Pipeline**
**Regulatory Tools**
**Development**
**   ****Nonclinical **
**   ****Phase 1**
**   ****Phase 2 & 3**

**Phase 2 & 3**
**    ****Design**
**     ****Populations**
**     ****Endpoints**
**     ****Controls**
**     ****Level of Effectiveness**
**     *****Statistical Issues (duration,sample size etc): Dr. Bhore***

## Microbicides in Pipeline

##  Mode of Action

**Pathogen destruction by detergent-like chemicals**
**Maintenance of normal vaginal defenses by enhancing natural acidity**
**Blocking attachment of pathogens to target cells**
**Inhibition of HIV attachment, entry, reverse transcriptase **
**Unknown mechanisms**

## Microbicides in Development	

**~60 products in the pipeline**
**~20 products either planned for or tested in early phases of human testing *****(Source: Alliance for Microbicide Development, March 2003)***
**9 INDs filed**
**4 products planned for phase 2 or 3  trials**

## Regulatory Tools for Expediting Development

## Topical Microbicides 

***    ******Federal Food, Drug, and Cosmetic Act: ***
***    ******section 506 (a)***
**   ****Eligible for  ****Fast Track Drug Development Program**
**Ability to prevent a serious or life-threatening condition**
**Potential to address unmet medical needs**

## Fast Track Drug Development Program 

**(Pre-IND consultation), end-of-phase 1, 2-meetings, pre-NDA meeting**
**Rolling submission of NDA**
**Priority review (6 months, ****vs. standard 10 months****)**

## Development of Microbicide Products

##  Development Guidelines

**The International Working Group on Microbicides (IWGM)**
**    *****Mauck C. et al. AIDS 2001, ***_***15***_***, 857-868***
**Rockefeller Microbicide Initiative. Rockefeller Foundation, 2002:84**
**    *****http://www.rockfound.org***

## Nonclinical Studies

***In vitro *****antiviral activity, cytotoxicity, mode of action, resistance and cross-resistance; impact on vaginal microflora, pathogens causing STIs. **
**Animal models for demonstrating microbicide antiviral activity have limited utility in selecting compound.**
**Nonclinical studies to assess safety, general and reproductive toxicity and pk.**
**Formulation identification, stability, purity and strength**

## Phase 1 Trials

**Total  ~150-200**
**Local and systemic safety**
**Selection of dose, formulation; assessment of product acceptability**
**Once, twice daily use for 7-14 days**
**HIV-negative women; sexually abstinent; then sexually active **
**    **

## Phase 2 Trials

**Conventionally, several hundred women**
**Expanded local & systemic safety, acceptability**
**Microbicide Activity:Proof-of-concept **

## ‘Proof-of-Concept’

**No validated clinical correlates**
**In microbicide trials, ‘proof-of-concept’ for HIV prevention can only be measured in studies with very large numbers of participants (several thousand)**

## Low HIV Incidence Rates

**   ****In commercial sex workers (high-risk women) receiving condom counseling:**
**3-5/100 person-years (India, Zaire,Rwanda)**
**7/100 person-years (Cameroon)**

## Male Condom Promotion & Counseling

**‘****Standard of care’; services deemed ethically necessary for all participants.**
**High levels of condom use will likely  further reduce HIV incidence rates.**

## Phase 2 Run-In Phase 3 Trial

## Populations

**HIV-negative, sexually active, non-pregnant women at risk for HIV/STI in regions with high HIV prevalence **
**Such rates occur predominantly in developing countries, e.g. in Africa**
**Enrolling only frequent product users, e.g CSW, safety profile may not be representative of other groups of women**
**Adolescent (13-17 years), cultural and legal  constraints **

## Foreign Data

***21CFR 314.106:***
**As sole basis for marketing approval:**
** **
**‘****data are applicable to the U.S. population**
** ****and U.S. medical practice’**

## U.S. Population

**Primary goal: ****safety profile and acceptability****; exposure duration comparable to non-US participants**
**A subset of U.S. participants in phase 2 run-in phase 3 trial, or**
**U.S. data derived from contraceptive trials, or STIs prevention trials, e.g. chlamydia prevention in US women**

## Endpoints	

**Primary:  HIV seroconversion, Safety**
**Secondary:  **
**   ****Incidence of STIs****  (****chlamydia, gonorrhea, syphilis, trichomoniasis****)**
**   ****Incidence of other reproductive tract infections**** (****BV, vulvovaginal candidiasis****)**
**   ****- STIs are important co-factors. **
**    ****- The potential to increase susceptibility to one or**
**       ****more STIs should be assessed.**
**   **
** **

## 2 Parallel Control Groups

**Placebo group**
**   **
**‘****No-treatment’ group (condom-only)**
**   **

## Placebo

**The choice of comparator when there is no approved microbicide**
**Providing blinding, maximizing unbiased estimate of efficacy and safety**

## Placebo

**Vehicle**** of the candidate microbicide**
**   *****Some components may have activity against HIV & bacteria,****** ******e.g. carbomer***
**Universal placebo****: ****unrelated ‘inert’ chemical, gel-like substance; can be used for multiple microbicides trials, has been shown:**
**   ****-*****In vitro no activity against HIV, bacteria***
***    ******-Safe in limited nonclinical testing***
**   **

## Placebo: Uncertainties

**Placebo gel itself is a barrier which could have an unknown level of efficacy.**
**Placebo gel may have an unknown level of local toxicity when used in large numbers of women.**
***   ******Both uncertainties need to be addressed in the presence of a no-treatment control.  ***

## 2 Parallel ControlsAdvantages       Disadvantages

**Placebo**
**    ****- blinding**
**    ****- validate the **
**      ****interpretation of data**
**      ****from ****microbicide**** arm**
**No-treatment**
**    ****- placebo may have**
**      ****activity/toxicity**
**    ****- validate the **
**      ****interpretation of data **
**      ****from ****placebo**** arm**

**‘****No-treatment’ arm cannot be blinded.**
**Differential dropout rates**
**Differential risk behavior levels**
**Potential gel sharing**
**Cost increase**

## Effect Size

**Consistent condom use: decrease HIV risk by ~85% ****(*****NIH, 2001)***
**Measure incremental benefit offered over ‘imperfect’ (actual) use of condom alone.**
**In the context of ‘imperfect’ (actual) use of condom, most experts have considered an  effect size of 30% to 50% to be acceptable for microbicides.**

## Summary

**Phase 2 run-in phase 3 trial design**
**Population enrolled should be generalizable. Data should be applicable to the U.S. population.**
**Endpoints: HIV incidence, safety, STIs incidences**
**2 parallel controls:  placebo, no-treatment**
**Effect size expected to be 30%-50%in the context of condom promotion**

## Question 1: Design

**Please comment on the following:**
**A. A phase 2 run-in phase 3 design**
**B. A stand-alone phase 2 targeted at **
**     ****high-risk groups (e.g. CSW), **
**     ****followed by a phase 3 trial(s). **
**     ****Please comment on the feasibility.**
**C. Other alternatives**

## Phase 2 Run-In Phase 3 Trial

## Question 2: Controls

**   ****Please discuss and rank the following design options:**
**A. 3-arm design ****(microbicide, placebo, **
**     ****and no-treatment)**
**B. 2-arm design ****(microbicide, placebo)**
**C. 2-arm design ****(microbicide, no**
**     ****-treatment)**

## 2 Parallel ControlsAdvantages       Disadvantages

**Placebo:**
**    ****- blinding**
**    ****- validate the **
**      ****interpretation of data**
**      ****from ****microbicide**** arm**
**No-treatment:**
**    ****- placebo may have**
**      ****activity/toxicity**
**    ****- validate the **
**      ****interpretation of data **
**      ****from ****placebo**** arm**

**‘****No-treatment’ arm cannot be blinded.**
**Differential dropout rates**
**Differential risk behavior levels**
**Potential gel sharing**
**Cost increase**

## Question 3: ‘Win’/Success Definition

**   ****If the committee is in favor of the 3-arm design, please comment on FDA’s definition of a ‘win’/success:**
***   ******The microbicide arm has to show a significantly better reduction in HIV seroconversion rate than ******both****** the placebo and no-treatment arms.***
**  **

## Question 4: Follow-up Duration -  How Long?

**On-treatment**
**   ****A. 12 months for every participants**
**     ****B. 24 months for every participants**
**     ****C. Follow-up continues until the last participant enrolled**
**          ****completes  12 or 24 months.**
**     ****D. Less than 12 months.**
**Need an off-treatment follow-up? If yes, how long? **

## Level of Evidence

**For a single large well-controlled trial, does the Committee agree with FDA’s specifications that:**
**     ****- ****P < 0.001 ****(2-sided) ****: Convincing**
**     ****-**** 0.001 **_**<**_** P < 0.01: Possibly **
**       ****persuasive, ****if results are consistent  **
**         ****across subgroups **
**What other supportive evidence does the Committee like to have?**