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 Coitally Dependent

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 Coitally Dependent

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 ( ) 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) ApplicatorApplicator filling Microbicide tube + tube filling Total cost per use HTI prefilled10¢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

Possible Scenario for Bridging Studies Phase 3 Clinical Trial Microbicide A + Applicator A Bridging Studies Microbicide A + Applicator B

Possible Scenario for Bridging Studies Regulatory Submission Microbicide A + Applicator A, B Phase 3 Clinical Trial Microbicide A + Applicator A Bridging Studies Microbicide A + Applicator B

Possible Scenario for Bridging Studies Regulatory Submission Microbicide A + Applicator A, B Product Introduction In India Microbicide 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 Cohen Program Officer Maggie Kilbourne-Brook Program Officer