microbicide applicator: overview and regulatory issues who/icmr/conrad/ipm regulatory issues in...
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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
