Microbicide Applicator: Overview and Regulatory Issues WHO/ICMR/CONRAD/IPM Regulatory Issues in Microbicide Research October 30, 2007.

Microbicide Applicator: Overview and Regulatory Issues

WHO/ICMR/CONRAD/IPM Regulatory Issues in Microbicide Research

October 30, 2007

Why Look at Delivery Systems?

• Microbicide gels require an applicator or delivery system for insertion into vagina.

• Delivery system characteristics impact correct use, dosing, acceptability and product price.

• Diverse populations will prefer different delivery systems.

• Need to plan now so a choice of delivery systems available the time of product approval.

PATH’s Work on Microbicide Delivery Systems

Goal:

Advance safe, cost effective delivery systems for microbicides, appropriate for women in low-resource settings.

Activities:

•Advancing optimal vaginal applicators•Evaluating SILCS diaphragm

PATH’s Vaginal Applicator Activities

• Consultation with US FDA

• Dose-delivery studies

• User compliance and acceptability studies

• Desk study

• Safety studies

• Cost analysis

• Scan of international manufacturers

Primary Applicators in Clinical Trials

• Most trials using prefilled, single-use, plastic applicators

• Optimal for clinical trials

• Ensures correct dose in applicator

• Blinds to product use

• Reduces variability between trials

• Reduces user variability

Gel Applicators: Prefilled, Single Use

Pros:

• Commonly used in clinical trials

• High degree of user acceptance in acceptability literature*

Cons:

• Cost likely higher than user-filled or reusable devices

• Product use linked to timing of sex--challenge for discreet use

• Portability, storage, disposal could be a challenge

• Lack of appropriate designs for rectal use

*Cohen 2007, Kilmarx 2006, Whitehead 2006, Morrow 2003, Coetzee 2001, Hardy 1998, LePage 1998.

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Gel Applicators:User Filled, Reusable or Single Use

Pros:

• May provide benefits related to cost

• Alternative materials (e.g., paper) allow for clean, efficient disposal

• Reusable design can minimize storage/portability requirements

Cons:

• Potential user concern with hygiene of reusable applicators*

• Difficult to ensure proper filling/dose delivery

• Requires additional step for user

*Cohen 2007, Bentley 2004, Morrow 2003.

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Clinical Study Confirms Applicator Safety*

Objectives

Assess effect of applicator on signs and

symptoms of irritation of external genitalia,

cervix, and vagina as seen on colposcopy

after a single use

Results

No severe cervical or vaginal lesions. HTI

single-use, HTI user-filled, and Norden-Pac

single-use applicators appear safe from

perspective of causing severe or repeated

vaginal trauma

HTI single-use

HTI user-filled

Norden-Pac single-use

*Brache, 2006

Acceptability Study (2003-2004)

Objective

• Characterize women’s PREFERENCES regarding applicator features (cost, reuse versus single use, safety).

Results

• Single use applicator preferred

• Preference related to perceived quality and safety

Sample Applicator Cost Estimates (2004)

Applicator Applicator filling

Microbicide tube + tube

filling

Total cost per use

HTI prefilled 10¢ 25¢–40¢ 35¢–50¢

Norden-Pac prefilled

4¢ 6¢–15¢ 10¢–19¢

Tekpack user-filled (PAPER)

3¢ 17¢ + 35¢ 8.2¢*

HTI user-filled (plastic)

8¢ 17¢ + 35¢ 6¢**

* Assuming microbicide tube contains 10 doses and 10 applicators are used.

**Assuming microbicide tube contains 10 doses and applicator is reused 10 times.

One Option for Alternative Microbicide Delivery

User Filled

• Could lower cost by as much as $0.42 per dose

Single Use

• Addresses concerns about spreading germs

Paper

• Burns easily for disposal

Example of a user-filled, paper applicator (TEKPAK, Inc.)

Case Study: FDA Consultation for a User-Filled, Paper Applicator

• Microbicide delivered with a user-filled applicator vs. a prefilled applicator.

• What data is required to establish equivalence if a sponsor wants to incorporate user-filled applicator in an application for market approval?

User-filled, paper applicator

FDA Recommendations for “Bridging” Data Required

XUser compliance

XAcceptability

XDose delivery

XSafety

XQualification of closure system (tube)

Should be done with microbicide

Could be done with placebo

Type of data

XBiocompatibility data

Possible Scenario for Bridging Studies

Phase 3 Clinical Trial

Microbicide A +Applicator A

Bridging Studies

Microbicide A +Applicator B

Possible Scenario for Bridging Studies

RegulatorySubmission

Microbicide A +Applicator A, B

Phase 3 Clinical Trial

Microbicide A +Applicator A

Bridging Studies

Microbicide A +Applicator B

Possible Scenario for Bridging Studies

RegulatorySubmission

Microbicide A +Applicator A, B

Product Introduction

In IndiaMicrobicide A +Applicator A, B

Next Steps for Microbicide Delivery

• Developing standard rectal microbicide

applicator

• Improving dosing with user-filled applicators

• Evaluating diaphragms for microbicide

delivery

SILCS Diaphragm: a new single-size cervical barrier

• Single size fits most women

• Easy to supply and provide

• Easy to insert and remove

• Comfortable for both partners

• Easy to wash and reuse

SILCS Diaphragm Microbicide Delivery System

• Combines chemical and physical barrier protection

• Offers dual protection

• Holds microbicide high in vagina

• Extends time from gel application to sex

• May reduce stigma

• Reduces need for an applicator

SILCS Microbicide Delivery System—current research • Feasibility/acceptability of applying gel to

both sides of diaphragm for added protection

• Impact of gel volume on women’s experience of handling and acceptability of SILCS

• Gel volume required on cervical and vaginal sides for comparable coverage/protection

• Comparative acceptability of different gel application methods when used by couples

SILCS Diaphragm and controlled release delivery

• Preliminary feasibility assessment of SILCS diaphragm as a controlled-release delivery device

• Laboratory testing for material compatibility

• Queens University of Belfast

Questions for Regulatory Consideration

• What is the regulatory pathway for seeking approval of an alternative delivery system?

• What bridging data will be required to confirm equivalence for safety and efficacy with prefilled applicators?

• How will data required change depending on the delivery system proposed?

Questions for Regulatory Consideration

• How can this guidance be shared with researchers/study sponsors?

• What next steps are needed to support this discussion among Asian regulatory authorities?

Optimizing Microbicide Delivery

The more options, the better!

Thank you to our Donors !

• USAID

• CONRAD

• amfAR

• PATH

Jessica CohenProgram [email protected]

Maggie Kilbourne-BrookProgram [email protected]

www.path.org