Transcript Document

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
• Desk study
• Safety studies
• Consultation with
US FDA
• Cost analysis
• Dose-delivery
studies
• Scan of
international
manufacturers
• User compliance
and acceptability
studies
Primary Applicators in Clinical
Trials
• Most trials using prefilled, singleuse, 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
Coitally Dependent
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.
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 2003.
Clinical Study Confirms Applicator
Safety*
Objectives
Assess effect of applicator on signs and
symptoms of irritation of external genitalia,
HTI single-use
cervix, and vagina as seen on colposcopy
after a single use
Results
No severe cervical or vaginal lesions. HTI
HTI user-filled
single-use, HTI user-filled, and Norden-Pac
single-use applicators appear safe from
perspective of causing severe or repeated
vaginal trauma
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
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 userfilled (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.
Total cost
per use
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
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?
FDA Recommendations for
“Bridging” Data Required
Type of data
Could be done with
placebo
User compliance
X
Acceptability
X
Should be done
with microbicide
Dose delivery
X
Safety
X
Qualification of closure
system (tube)
X
Biocompatibility data
X
Possible Scenario for
Bridging Studies
Phase 3
Clinical Trial
Microbicide A +
Applicator A
Bridging
Studies
Microbicide A +
Applicator B
Possible Scenario for
Bridging Studies
Phase 3
Clinical Trial
Microbicide A +
Applicator A
Bridging
Studies
Microbicide A +
Applicator B
Regulatory
Submission
Microbicide A +
Applicator A, 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
[email protected]
Maggie Kilbourne-Brook
Program Officer
[email protected]
www.path.org