WHO/RHR/10.19 Preparing for access to PRO 2000 microbicide Report of a meeting 27–28 May 2009, London, United Kingdom World Health Organization and UNAIDS Meeting report Meeting report Contents Acknowledgements 3 Executive summary 3 Acronyms and abbreviations 4 Background 5 What do (and can) we know about PRO 2000 from the HPTN 035 and MDP 301 trials? 6 Safety and effectiveness 6 Further studies and analyses 6 Acceptability and users’ perspectives 6 Additional clinical research 7 Product ownership and licensing 7 Cost 8 Manufacturing 8 Regulatory review 9 Carcinogenicity study 10 Policy and programmes 10 Level of effectiveness 10 Modelling 11 Donors 12 WHO recommendations 12 Implications for other prevention trials 13 Strategic communications and messaging 13 Scientists 14 Policy-makers 14 Trial communities 14 Next steps 14 Appendix 1: Contingency planning list for PRO 2000 access 15 Appendix 2: Timeline for PRO 2000 access 21 Appendix 3: List of participants 22 Preparing for access to PRO 2000 microbicide Note: Since this report was prepared, the results of the MDP 301 study were announced on 14 December 2009 and published in The Lancet on 20 September 2010. (http://dx.doi.org/10.1016/S0140-6736(10)61086-0). The study showed no benefit of 0.5% PRO2000 in reducing the risk of HIV infection. All further development and investment in the product has ceased. Preparing for access to PRO 2000 microbicide © World Health Organization 2010 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Preparing for access to PRO 2000 microbicide Preparing for access to PRO 2000 microbicide Acknowledgements This report was prepared by Elizabeth McGrory (WHO consultant) and Tim Farley (WHO). Executive summary In February 2009, the Microbicide Trials Network (MTN) announced that its HIV Prevention Trials Network (HPTN) 035 trial showed a 30% reduction in human immunodeficiency virus (HIV) incidence in women using the microbicide PRO 2000 compared with placebo gel. This reduction in risk was not statistically significant. There were no safety concerns associated with the product and it was highly acceptable to users. PRO 2000 is also being tested in a second trial by the Microbicides Development Programme (MDP) group, with results expected in late 2009. The MDP 301 trial is larger than the HPTN 035 trial, and if it shows a similar level of risk reduction and confirms that the product is safe, PRO 2000 will be the first microbicide shown to be safe and effective in reducing the risk of HIV acquisition. If the MDP 301 trial does confirm the HPTN 035 results, this will mark the beginning of a long and complicated process to make the product available to women at risk of HIV infection. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) convened key actors involved in the microbicide field to identify and prioritize actions needed to prepare for access to PRO 2000. This meeting, held in London, 27–28 May 2009, was designed to: • review the results of impact models under different assumptions relating to effectiveness and imputed efficacy, targeting, and coverage, in order to inform policy recommendations and priority groups for access; • review plans and identify gaps for scale-up and availability of PRO 2000 gel, under the assumption that the second trial confirms safety and effectiveness; • identify and prioritize actions, roles and responsibilities of different actors, including a timeline and potential funding sources, for both the near and long term. Key issues that emerged during the presentations and discussion include: • Endo Pharmaceuticals acquired PRO 2000 in March 2009 and is evaluating the product’s fit in its portfolio; • the agreement between Endo and the UK Medical Research Council (MRC), sponsor of the MDP 301 trial, includes a provision for a “cost-plus” pricing structure in low-income economies. It also grants the MRC or its agents the right to manufacture and distribute the product for use in low-income economies if Endo does not develop it further; • if PRO 2000 is shown to be safe and effective, it is not clear whether Endo will develop the product, out-license to another private company, or license to a not-for-profit organization; • uncertainty around which entity will eventually develop PRO 2000 if shown to be safe and effective is hampering further development of and investment in the product; this has particular relevance to determining the best path to licensure, initiating further high-priority research, investment in scaled- up manufacturing, and other related issues; • it is important to build consensus around what level of effectiveness would warrant further investment in and development of PRO 2000. A wide range of views existed among participants at the consultation, who represented diverse constituencies within the microbicide and HIV-prevention fields, with their own sets of priorities. It is important also to engage other key constituencies, including national policy-makers and regulatory authorities, as well as women at risk of HIV infection who are the ultimate beneficiaries of microbicide-development efforts; • any regulatory submission is likely to take at least two years after the MDP 301 results are released, based on the need to validate scaled-up manufacturing and provide process and stability data, as well as completing additional safety and/or acceptability studies that may be required; 3 Preparing for access to PRO 2000 microbicide • there is a limited amount of PRO 2000 currently available for additional clinical and pre-introductory studies, so it will be necessary to prioritize how the available PRO 2000 will be used, balancing the need to answer priority research questions and any obligations (implicit or explicit) to trial participants and/or communities; • the microbicide field must work out how to convey clear and accurate messages about what the results of the MDP 301 trial mean for PRO 2000, for other microbicide research, and for HIV- prevention research. If PRO 2000 is going to be developed further, these messages need to clearly state plans for further research and access at the HPTN 035 and MDP 301 trial sites, and realistic timeframes and scenarios for more widespread access. Messaging must also be very clear, if the MDP 301 results do not support further investment in and development of PRO 2000, particularly if an encouraging, though not convincing, result emerges. Participants identified and prioritized action items and next steps, including, when possible, which agency or group would be responsible for following up, potential funding sources, and the timeframe (see Appendixes 1 and 2). WHO will play a coordinating role in tracking, monitoring and facilitating these follow-up activities. Acronyms and abbreviations AIDS acquired immunodeficiency syndrome ARV antiretroviral CROI Conference on Retroviruses and Opportunistic Infections DFID Department for International Development EMA European Medicines Agency FDA Food and Drug Administration HIV human immunodeficiency virus HPTN HIV Prevention Trials Network HPV human papillomavirus IPM International Partnership for Microbicides MCC Medicines Control Council MMCI Microbicides Media and Communications Initiative MRC Medical Research Council MDP Microbicides Development Programme MTN Microbicide Trials Network NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health PEPFAR President’s Emergency Plan for AIDS Relief SADC Southern African Development Community STI sexually transmitted infection TB tuberculosis UNAIDS Joint United Nations Programme on HIV/AIDS USA United States of America WHO World Health Organization 4 Preparing for access to PRO 2000 microbicide Preparing for access to PRO 2000 microbicide Background At the February 2009 Conference on Retroviruses and Opportunistic Infections (CROI), the Microbicide Trials Network (MTN) announced that its HIV Prevention