WHO/UNAIDS Preparing for Implementation of 1% TFV-gel Consultation

1. WHO/UNAIDS Preparing for Implementation of 1% TFV-gel Consultation Tim Farley Department of Reproductive Health and Research World Health Organization Geneva IAS Rome, 17 July 2011

2. CAPRISA 004 – Vienna – 20 July 2010

3. CAPRISA 004 – Vienna and Johannesburg • WHO/UNAIDS consultation "Next Steps with 1% Tenofovir Gel" Johannesburg, August 2010, 5 weeks after CAPRISA 004 results • Identify gaps and develop consensus on priority research to confirm safety, effectiveness and acceptability of 1% tenofovir gel; • Develop the most efficient pathways for licensure and guideline development, including regulatory dossier development and submission; • Delineate priorities, next steps and lead responsibilities in clinical research, programmatic research, and regulatory submission, and other issues; • Agree on mechanisms for coordination and execution, and identify funding sources and gaps.

4. Next Steps 1% Tenofovir Gel • 80 participants • Research teams • Providers • Clinicians • Programme managers • Women's health and HIV prevention advocates • Regulators • USA, Europe, Kenya, South Africa, Tanzania, Uganda, Zimbabwe

5. Recommendations • Additional safety studies • Young women, hepatitis B infection, impaired kidney function • Review range of current studies studies in pregnant women • Effectiveness • Trial in South Africa to confirm BAT24 regimen (FACTS 001) • Simplified dosing and HIV testing schedule (MDP302) • Relative priority controversial, potential for questions to be addressed with PK/PD studies • Implementation study • CAPRISA 008: feasibility, safety and effectiveness of providing through existing family planning infrastructures compared with clinical trial setting • Treatment outcome and resistance • Provide care and treatment for study seroconverters and compare treatment outcomes of TFR-containing and TFR-sparing regimens • Regulatory issues • Feedback from FDA, EMA process launched, MCC discussions ongoing

6. Progress – Clinical Studies • Follow-on African Consortium for Tenofovir Studies (FACTS001) Trial • 7 sites in South Africa • BAT24 dosing regimen • Placebo control • To start enrolment August 2011 • Study may have to be modified while underway when results of VOICE study known (results expected early 2013) • Importance of generating sufficient HIV endpoints to support licensure of BAT24 regimen • New uncertainties following release of results from Partner's-PrEP and CDC TDF2 studies, expected impact on oral arms of VOICE and potential impact on topical arms • Proposed MDP302 study of simplified dosing and HIV testing schedule not funded • Some questions may be addressed with PK/PD studies • Importance of clinical data to support single coital dose remains

7. Progress – Clinical Studies • CAPRISA 008 study • Offer tenofovir gel in open-label fashion to former trial participants • Regular HIV testing, resupply, counselling • Two service delivery models • Clinical trial setting – monthly visits • Family planning setting – 2- or 3-monthly schedule according to chosen family planning method • Endpoints – compliance and HIV incidence rates • Exact components of intervention and standard of care being reconsidered following release of results from Partner's-PrEP and CDC TDF2 studies • Other clinical studies • Suite of studies of tenofovir gel in pregnancy ongoing • Long-term monitoring of seroconverters from tenofovir gel studies underway

8. Progress – Regulatory Issues • Discussions with USA FDA (CONRAD) • Data being submitted to FDA as clinical study reports become available • FDA willing to consider CAPRISA 004 (BAT24 dosing schedule) and VOICE (daily dosing schedule) as two independent pivotal studies • Additional data on safety of tenofovir gel in younger women (< 18 years) required if label to be extended to lower age group • Similarly for older women (post-menopausal) • Requested clinical safety studies on potential interaction with other vaginal medications • Discussions with EMA (IPM and CONRAD) • First involvement of EMA in tenofovir gel • First sight of contents of product dossier • Questions about product and supportive pre-clinical and clinical data • Sponsors decided not to pursue scientific advice under Article 58 mechanism at this stage

9. Progress – Regulatory Issues • Discussions with South Africa Medicines Control Council • Led by ProPreven, licensee to manufacture and market tenofovir gel in African region • No clear opinion expressed on range of studies required for licensure in South Africa • MCC needs to see full product dossier before any formal opinion can be given • Potential for additional clinical studies to be requested, but important to know requirements well in advance • Regulatory authorities in other African countries • To be approached by ProPreven once product dossier complete • If EMA Article 58 procedure for Scientific Opinion is pursued, EMA will invite representatives of national regulatory authorities in African region to be involved in review process and formulation of opinion

10. Draft Timeline TFV Gel Guideline Development v02.1 TFV gel development and implementation Process31.03.07 - 19.04.17 2nd Half 1st Half 2nd Half 1st Half 2nd Half 1st Half 2nd Half Today 2nd Half 1st Half 2nd Half 1st Half 2nd Half 1st Half 2nd Half 1st Half 2nd Half 1st Half 2nd Half 1st Half StartSat 31.03.07 FinishWed 19.04.17 Supportive Clinical Development31.03.07 - 31.07.14 CAPRISA 00424.05.07 - 29.07.11 VOICE (MTN003)16.09.09 - 08.05.13 FACTS 00101.09.11 - 04.12.14 Dossier development without FACTS29.07.11 - 04.12.13 FDA review without FACTS04.12.13 - 03.12.14 EMA art. 58 Review without FACTS04.12.13 - 03.12.14 Regulatory Approval SA with FACTS04.12.13 - 22.04.15 Reg. Appr. Priority Countries23.04.15 - 27.01.16 WHO Guideline Development01.06.11 - 31.12.14 Regulatory Approval Subsequent Countries23.04.15 - 20.04.16 TFV gel Implementation Strategy Development01.06.11 - 01.01.15 Product Launch23.04.15 - 19.04.17 TFV gel Implementation Operations Planning01.06.11 - 24.05.16

11. Development of WHO Guidelines for the Use and Implementation of 1% Tenofovir Vaginal Gel for the Prevention of HIV-infection in Women • Critical Questions to be addressed for the development of the guidelines • Product Use • What efficacy and effectiveness of the approved product should be assumed? • How should tenofovir gel be dosed? • What level of adherence should be targeted as minimal requirement? • What are the specific needs for counseling while using microbicides? • HIV testing – frequency, logistics, • Specific populations for priority access, • …

12. Development of WHO Guidelines for the Use and Implementation of 1% Tenofovir Vaginal Gel for the Prevention of HIV-infection in Women • Product distribution and implementation • Implementing and funding partners, public/private mix, … • How should the various HIV prevention methods be positioned and which mix of prevention methods should be offered and promoted? • Which minimum health systems resources will be necessary to ensure an effective roll out of microbicides? • … • Implementation Economics • What is the expected product price for the payer (not the subsidized user) for a single microbicide dose and what is the average product cost per prevention-year using TFR gel? • What is the expected demand for tenofovir gel over the first five years after approval by country differentiated for private and public markets?

13. Development of WHO Guidelines for the Use and Implementation of 1% Tenofovir Vaginal Gel for the Prevention of HIV-infection in Women • Objective • Have guidance ready for release soon after first regulatory opinion issued • To support • Country implementation • National policies • Implementation strategies and expansion of availability and use • Difficulties • Expected date of the "first regulatory opinion" • Developing draft guidance on the basis of anticipated data from ongoing clinical work and then updating as results become available • Ensuring sufficient information available on product use to develop guidance • Complexities due to rapidly evolving HIV prevention landscape, and potential requirement for comprehensive guidance on much broader topic of ARVs for prevention in wide range of populations and risk groups

14. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Purpose: • In anticipation of registration of 1% tenofovir gel in 2013 or 2014, identify priority actions to ensure rapid expansion of product availability and use in high HIV incidence countries following licensure. • 80 participants • Experts in product introduction and implementation • Manufacturing, demand forecasting, marketing, social marketing, distribution, provider and user education • Women's health and HIV prevention advocates • Clinicians and research teams • Programme managers

15. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Objectives: • Review plans and identify gaps to support rapid availability of 1% tenofovir gel, under the assumption that VOICE and/or FACTS 001 confirm safety and effectiveness and the product is registered in late 2013 or early 2014; • Identify what knowledge on key aspects of product introduction and implementation will be needed for normative guidance and product roll-out • Synthesize and build on existing knowledge on microbicides and other health innovations, particularly family planning • Articulate and prioritize key questions and approaches to compiling and/or generating this information • Review results of impact models under different assumptions on effectiveness, imputed efficacy, targeting and coverage to inform policy recommendations and priority groups for access; • Identify and prioritize actions, lead responsibilities of different actors, timelines and potential funding sources and gaps. Agree on mechanisms for coordination and execution.

16. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Background information • Resistance • Modelling and cost-effectiveness • Marketing • Lessons from introduction of other products • Experience with oral-PrEP consultations and preparations • Experience with preparing policy guidance with HPV vaccines and oral PrEP • Outputs • Priority actions to prepare for policy guidance • Priority actions for rapid and sustained product roll-out • Timed to coincide with licensure decisions in priority countries

17. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Key Recommendations • Support licensee in South Africa for technology transfer to South Africa, develop realistic demand forecasts and make key investment decisions • Price of single pre-filled applicator ($1 per dose) prohibitively high for successful and sustained product introduction • Need to move rapidly to alternate delivery systems, such as user-filled applicators or alternate mechanisms for drug delivery to vagina • Initial product launch and pilot introduction projects will require substantial subsidy of product • Need realistic demand forecast and impact estimates at different price levels • HIV testing • Importance of generating data on safety of less frequent HIV testing schedules • Monthly (clinical trials)  quarterly  annual • Frequency of HIV required testing for vaginal gel may be considerably lower than for systemic dosing (oral PrEP) • Acceptability and practicality of different HIV testing models critical

18. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Key Recommendations • Coordinated structure of different partners to ensure focussed and rapid progress toward getting tenofovir gel to women at highest need • Alliance of range of not-for-profit agencies has brought product to verge of registration • Need a new alliance and clear governance structure to ensure success of next stage in process • Funders: • Research and development (USAID, BMGF, …) • Programmatic research (USAID, BMGF, …) • Product programming (PEPFAR, GFATM, National governments, …) • Product developers and distributors • License holder, manufacturer • User representatives and Normative agencies • Civil society • National health authorities • WHO and UNAIDS

19. Preparing for Implementation of 1% Tenofovir Gel Johannesburg, June 2011 • Key Recommendations • Launch series of country and regional discussions on product positioning and product introduction • Consider position and "niche" for tenofovir gel in rapidly evolving HIV prevention landscape • Importance of range of prevention options to suit different women in and evolving different personal situations • Experience in one setting and environment may not predict experience in other settings