Preparing for access to PRO 2000 microbicide

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M e e ti n g r e p o rt M e e tin g re p o rt

Preparing for access to PRO 2000 microbicide

Report of a meeting

27–28 May 2009, London, United Kingdom

World Health Organization and UNAIDS

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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.

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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;

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• 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

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Background

At the February 2009 Conference on Retroviruses and Opportunistic Infections (CROI), 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 PRO 2000 compared with placebo gel. This reduction in risk was not statistically significant. The product raised no safety concerns and was highly acceptable to users. Subgroup analyses according to frequencies of product and condom use suggested considerably higher efficacy than the overall 30% effectiveness.

PRO 2000 is also being tested in a second trial by the Microbicides Development Programme (MDP) 301 group. Results from this trial are expected in late 2009. The MDP 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, it will be the beginning of different long and complicated processes. Communicating the complex concepts of partial efficacy, the difference between efficacy and effectiveness, and the importance of consistent product use, and conveying a realistic timeframe within which the product would be available are urgent needs even as the results are announced. Other complex processes would be needed to make the product available to women, particularly those in settings of high HIV incidence. An investment and policy case would need to be made that the reported level of effectiveness warrants further product development. Ownership and licensing;

formal registration of the product in the country/countries of manufacture and use; manufacturing and distribution; integration into comprehensive HIV-prevention programmes and other health services;

financing; and determining which women and communities should be prioritized for product introduction are among the issues to be addressed.

Following the results of the HPTN 035 trial of PRO 2000, and in anticipation of the MDP 301 trial being completed, 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 the actions needed to prepare for access to PRO 2000. This meeting, held in London, 27–28 May 2009, brought together advocates, product developers, clinicians, clinical and social science researchers, public health experts, regulators, potential donors, and representatives from the MTN and MDP study teams and study sites. The meeting 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 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.

This report summarizes key elements of the meeting discussions: existing data and analysis plans from both the MTN and MDP, and priorities for additional clinical research; ownership and licensing; cost;

manufacturing; regulatory review; policy and programmes; strategic communications and messaging;

and next steps. A chart and timeline summarizing the agreed action plan, roles and responsibilities, and timeframe are attached (Appendixes 1 and 2).

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What do (and can) we know about PRO 2000 from the HPTN 035 and MDP 301 trials?

Researchers from the HPTN 035 and MDP 301 teams presented overviews of the two trials of PRO 2000, the findings to date and plans and priorities for analysis.

Safety and effectiveness

The HPTN 035 findings announced at CROI in February 2009 showed that 0.5% PRO 2000 gel was safe and overall 30% effective in preventing HIV when compared to placebo gel and to no gel. The protective effect of PRO 2000 was supported by analyses stratifying on different levels of condom and gel use, with higher apparent protective effectiveness in the subgroup of women with low condom but high gel use, suggesting an efficacy in excess of 80% among consistent users. The overall 30% protective effect of PRO 2000 was not statistically significant. Additional evidence is needed to determine whether PRO 2000 is a safe and effective microbicide.

The MDP 301 team anticipates that it will announce results at the end of November 2009. The trial is designed to measure the safety and effectiveness of 0.5% PRO 2000 gel in preventing HIV infection when compared to placebo gel. It enrolled 9404 women in seven sites, and is powered under the assumption of effectiveness of 35%; as such it should provide a statistically significant result if the overall effectiveness is 30% or greater. The trial initially included a second active arm of 2% PRO 2000 gel, but this was discontinued in February 2008 when the study’s independent data-monitoring committee concluded that the higher-strength gel was not likely to show benefit in reducing acquisition of HIV. The final results of MDP 301 will provide information on HIV infections and side-effects among the women who received the 2% gel. These results will be important for a comprehensive assessment of the safety and effectiveness of PRO 2000.

Further studies and analyses

The MDP team suggested several priority areas for additional clinical study, under the assumption that further investment in PRO 2000 was warranted following the release of their results. These included:

rectal safety, safety in pregnancy, safety in HIV-infected women, safety in high-frequency users and safety in adolescents. MTN has some data on pregnancies that occurred in women using PRO 2000 in the HPTN 035 study, but women were advised to stop using the gel once the pregnancy was identified.

There are relatively few data on “high-frequency users” in the HPTN 035 trial; the average number of gel uses per week was 2.76. Only 5% of gel users used the gel on average 5.5 times per week, and 2.2%

used it an average of 7 times per week. The HPTN 035 trial also has some limited safety data on PRO 2000 use among women with HIV infection.

The MTN and MDP teams are collaborating in several areas, and should identify priority analyses that will inform the interpretation of trial results; they are also contributing to the regulatory dossier. It is also important to determine which analyses could inform sponsors, funders and advocates on decisions about further investment in PRO 2000. Organizing a regulatory submission and the associated analytical work are the responsibility of the trial sponsor, and beyond the scope of activities of clinical trials networks such as the MTN or MDP. However, some meeting participants were concerned that the analysis priorities may be driven more by academic publication incentives, and cautioned that the MTN and MDP teams should focus on analyses that are critical to advancing and accelerating product development. It is important to ensure that the public-health concerns of making a safe and effective product available rapidly are not held up, or perceived to be held up, by such considerations.

The regulatory authorities to whom the product registration dossier would be submitted may require additional analyses and studies to be completed before reviewing and/or giving product approval. They should be consulted as soon as possible on “critical path” research.

Acceptability and users’ perspectives

The HPTN 035 trial collected relatively few data on acceptability and users’ perspectives, but participants generally reported liking the PRO 2000 gel, and overwhelmingly (98.6%) indicated that they would use

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it if it was shown to be effective. The main “likes” cited about the gel are that it may protect against HIV, may protect against other sexually transmitted infections (STIs), is easy to use and does not interrupt sex. About a quarter of the participants also said that it made sex more pleasurable. The team is planning additional analysis of secondary adherence and acceptability outcomes, including trends in adherence over time, as well as analysis of sexual behaviours and vaginal-hygiene practices, including trends over time and associations with possible gel use. Additional data collected in a substudy in Malawi and Zimbabwe on acceptability and users’ perspectives are being analysed, and will be available shortly.

The MDP 301 study placed much more emphasis on acceptability and user perspectives, and used a variety of methods to collect data. Some 98% of women in the MDP study reported that sexual pleasure was the same or greater with the gel, due to the increased lubrication. Women in this study also cited increased enjoyment (40%) and ease of use (38%), more than its potential to protect against HIV (20%), as reasons for liking the gel. Women also associated the gel with cleanliness and well-being. Based on these findings, the team suggested that it may be useful for marketing strategies to emphasize sexual pleasure, hygiene and well-being, as cited by trial participants. These rich data will continue to be analysed in the coming months and years, and it would be useful to identify priority questions that are most important to inform marketing and product introduction.

While these data are instructive, the complex issues around product marketing and positioning will need a specialized strategy. For example, some women reported liking the gel because it increases sexual pleasure, and it is possible that strategies for marketing and promotion could be built around this positive attribute. At the same time, in some settings, promoting a product for sexual pleasure may lead to negative connotations for the product or the women who use it. It will be important to better understand motivations and attitudes regarding product use in different contexts and population groups, once it is known that a product works to prevent HIV. Marketing experts will need to explore ways to market the product, help people understand what level of protection it offers, and motivate people to use it.

Additional clinical research

Researchers from the trials, and other participants, generally agreed on the priorities for additional clinical research: safety for rectal use, safety in pregnancy, safety in adolescents and safety in high-frequency use. The MDP has a protocol, trial sites and funding for a rectal-safety study among men and women, but will wait until the MDP 301 results to determine whether to proceed. Given the population that would use PRO 2000, many participants also felt that assessing safety in pregnant women and in adolescents was a priority, although it was not clear whether these studies would be required by regulators before they reviewed the registration dossier.

It will be important for the MDP team to fully analyse data from the arm of MDP 301 that tested PRO 2000 at 2% concentration. This analysis may inform whether and how to study safety with high- frequency use (although it is not known whether studying a higher concentration would adequately reflect high-frequency use of a lower concentration). The MDP team could not disclose information about the 2% arm at the time of the meeting, but the participants noted on several occasions that the safety of 2%

PRO 2000 was a critical issue and would be important to the safety assessment of 0.5% PRO 2000.

Product ownership and licensing

One of the most critical considerations with PRO 2000 was determining which entity would ultimately own and market the product if it is shown to be safe and effective. PRO 2000 is currently owned by Endo Pharmaceuticals, which acquired it as part of its acquisition of Indevus. Endo is a speciality pharmaceutical company located in Chadds Ford, Pennsylvania, United States of America (USA), whose main market focus is branded and generic prescription pain medication. Endo has been conducting a strategic evaluation of the PRO 2000 asset through market research and assessing the degree to which it fits the company’s business plan. Based on this assessment, Endo may decide to develop and market PRO 2000 in house or to out-license it, either through licensing worldwide rights to one organization or through licensing regional rights to different organizations.

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The UK Medical Research Council (MRC) has contractual rights relating to developing country access for PRO 2000. The agreement between MRC and Indevus (now carried over to Endo) to conduct the MDP 301 Phase III trial included a provision that the company make the product available to MRC or its agents at

“cost-plus”, for distribution in certain “low-income economies” (the “Territory”). If the company decides not to market and distribute the product itself, the company is to grant the MRC or its agents the right to manufacture and distribute the product in the “Territory”. At the meeting, Endo was not able to be specific regarding the “cost-plus” agreement, or which countries were included in the “Territory”, although apparently all the countries that hosted the HPTN 035 and MDP 301 trials were included. Endo’s decision on when and where to pursue licensure would be based on the results of the MDP 301 trial.

At the time of the meeting it appeared that the MDP trial steering committee would advise on whether to proceed with further high-priority studies (e.g. rectal safety and safety in pregnancy), whether further development and investment was warranted and, with other MRC entities, whether MRC should exercise its rights to manufacture and distribute the product if Endo decides not to.

PRO 2000 as being tested – for prevention of HIV acquisition by women – did not seem to lie within Endo’s current area of business. It was not clear what other private or public entities had discussed possible licensing scenarios, although several key actors in the microbicide field (such as the International Partnership for Microbicides (IPM) and CONRAD) had been involved in some preliminary discussions.

Endo suggested that it would make a decision within the next few months. Although Endo was not specific whether this decision would be reached before or after the trial results were released in November, it seemed unlikely that any major decision would be made without knowing the trial results.

If the licence does revert to MRC under its agreement, the agency has a technology transfer unit that could help facilitate one or more licensing agreements with third parties, but this would take time to set up.

Finally, the licensing arrangements would have significant implications for the levels and sources of financing that might be needed to take PRO 2000 to market. Endo indicated that, while it was evaluating PRO 2000 and its fit within the company, further development would be beyond its means without outside investment. It is possible that Endo may be able to find a commercial partner to provide this investment, but it is also important to explore the willingness of key donors to make the potentially substantial investment in taking the product forward, whether with a private or a public entity. Several people at the meeting also noted the importance of ensuring that safe and effective products are made available to trial participants and the communities where they were tested. The uncertainty around the licensing of PRO 2000 – with implications for regulatory strategy, financing needs and sources, among other issues – was perceived as the main obstacle to any concrete strategy and momentum in moving PRO 2000 forward.

It was considered critical to resolve this as soon as possible.

Cost

Cost was considered during a somewhat circular discussion. Endo noted that costs had not been optimized during the manufacture of supplies for the clinical trials, and that there is clear potential for economies of scale, as well as a more streamlined manufacturing process for the drug substance and a more fully automated packaging line. The pre-filled applicators used in the trials are quite expensive, and other reusable or disposable paper applicators are another area where cost savings may be possible. Endo suggested that it would be useful to have information from the field on demand projections, and what cost would be “acceptable”, but did not disclose the cost per dose for the trial supplies or a cost per dose that might be achievable with economies of scale. Several donors present underscored that cost estimates will be critical to inform any decisions about investing further in PRO 2000.

Manufacturing

PRO 2000 was synthesized in a two-step process and packaged in pre-filled vaginal applicators for the clinical trials. Little manufactured product will remain after the completion of MDP 301, with at most enough drug substance for some small clinical studies. Scale-up of drug-substance and gel-product manufacture would be needed to support commercialization, and validation of this scaled-up manufacture would be required for the regulatory dossier. Demand projections are needed for additional studies

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(clinical and bridging studies and operations research), initial introduction, and scale-up. While demand forecasting is an imprecise and iterative process (especially for a new product category), it is important for planning and costing and so should begin as soon as possible.

The licence holder(s) would need to identify manufacturers, and registration batches would be needed to provide process and stability data. A validated, scaled-up commercial process, including production batches, would be needed for a regulatory filing. If new processes (and manufacturers) are used for product launch, rather than those that were used for Phase III, there will be requirements for additional bridging studies. This process would probably take 2 years and would be on the critical path before a regulatory dossier could be submitted. As such, it could be a significant factor limiting the availability of PRO 2000 in the medium and long term.

While waiting for significant amounts of product to become available, priorities need to be set to use the existing product most effectively, balancing the need for additional critical path safety research, the need to inform marketing, distribution and introductory strategies, and any ethical obligations (implicit or explicit) to former trial participants and/or communities. Different estimates ranging from six months to two years were offered, regarding how long it would take to make more PRO 2000 available, even in the relatively modest quantities required for pre-introduction studies and key additional clinical research.

Regulatory review

It is crucial to clarify where to pursue licensure and which regulatory authority would conduct the first review of PRO 2000. This decision would be based on the results of the MDP 301 trial, and would be one of the most critical factors determining the availability, timing and cost of PRO 2000. The regulatory authority would have considerable influence in determining whether and which additional studies would be needed before licensure. The discussion returned to this topic repeatedly throughout the meeting.

Preparation of regulatory dossier(s) would take time; Endo noted that even when all the necessary data are available, 6–12 months are usually required to prepare the dossier. Given the additional data that would likely be required and the uncertainty around what entity would move the product forward, a number of participants felt strongly that at least 24 months would be required to prepare a dossier for PRO 2000, especially given the need to include information on a validated scaled-up manufacturing process.

Several possible regulatory scenarios were touched on and debated at various points in the meeting: the USA Food and Drug Administration (FDA); the South African Medicines Control Council (MCC); and review by the European Medicines Agency (EMA under the provisions of Article 58. The WHO prequalification process was also discussed; although this is not a regulatory review mechanism per se, it could help countries in their evaluation and monitoring of drug quality. These different approaches have critical implications for the requirements, timing and outcome of regulatory review.

It was not clear whether Endo, or another licence holder, would seek market authorization through the FDA. The FDA had been invited to the meeting but did not attend, suggesting instead that the developer should meet with them to discuss its strategy, including any additional research that might be required.

There was a fair amount of uncertainty about what the FDA would require; for example several people felt that a chronic toxicity carcinogenicity study would be required by the FDA, while others thought that the lack of systemic absorption of the active ingredient would obviate the need for this additional safety study. FDA guidance on vaginal products indicates that the need for such a study would be decided on a case-by-case basis. Given that the chronic toxicity carcinogenicity test requires 2 years of daily exposure in rats, preceded by some months for planning and for subsequent analysis and reporting, if such a study is required it could be an important rate-limiting factor in access to PRO 2000 (see page 10 for further discussion of carcinogenicity testing).

The South African MCC was also discussed as a possible agency to first license PRO 2000. The MCC representative noted that there is an accelerated review process that could potentially be applied to a microbicide, whereby the MCC must reach an initial decision within 9 months of filing. The decision could be positive, negative, to request more information, or to grant provisional approval. Approval by

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the MCC would not necessarily mean that other countries would automatically approve, although there has been increasing cooperation among national regulatory agencies in the Southern African Development Community (SADC) region to jointly review dossiers.

Another possible route was the EMA, under Article 58. This allows for a “scientific opinion” on safety and effectiveness for drugs that will not be marketed within the European Union. This opinion could potentially be included in a submission to the MCC or other regulatory authority. It has significant implications for the potential market, as it would mean that PRO 2000 would not be marketed in the European Union unless it also underwent a regular regulatory review process.

The WHO prequalification process could facilitate but not replace review and authorization by a national regulatory agency. It is designed to prequalify manufacturers of priority medicines so they can be made more readily available in resource-limited settings. The process involves evaluation and inspection activities, and building national capacity for manufacturing and monitoring quality medicines. The list of prequalified medicinal products for HIV/acquired immunodeficiency syndrome (AIDS), malaria, tuberculosis (TB) and reproductive health is used by United Nations agencies to guide procurement decisions. However, this process requires an initial authorization by a recognized well-resourced regulatory authority.

Determining which regulatory authority would conduct the first review of PRO 2000 is an urgent priority and the decision rests with the licence holder. This decision should factor in the implications for funding for further product development, as well as donor support and eventual purchase by public-sector programmes such as the Global Fund, the President’s Emergency Plan for AIDS Relief (PEPFAR) and other bilateral agencies. Given the continued uncertainty about licensing, the need for validating the manufacturing process, uncertainty about which entity would conduct an initial regulatory review and what its requirements may be, several participants estimated that a regulatory decision would probably take some 2½ to 3 years after the MDP data are released.

Carcinogenicity study

It was not certain whether a carcinogenicity study would be required, but such studies are one element of a standard toxicological assessment, and a regulatory authority would need to indicate clearly that such a study is not needed. Animals in these studies are generally dosed for 2 years, and several more months may be needed for data analysis. These studies are expensive (estimated at around US$1 million), so it would be important to begin to identify potential funding sources. The National Institute of Allergy and Infectious Diseases (NIAID) indicated that it may consider funding this study but any study would need to be reviewed and weighed against other budget priorities. A protocol and other arrangements for this study should be put in place before the MDP 301 results are announced in November, so that it is ready to move forward rapidly if required.

Policy and programmes

Level of effectiveness

Underlying many of the discussions at the meeting and elsewhere about PRO 2000 – and all new prevention technologies – was the issue of determining what level of effectiveness would warrant further product development and introduction. The level of effectiveness would also probably influence how access is prioritized among different settings and risk groups, how partial effectiveness is presented and explained to potential users, and a host of other issues. The HPTN 035 Phase IIb trial had 80% power to demonstrate effectiveness of a product with true effectiveness of 44% but only 50% power if true effectiveness was 33%, and the MDP trial had 80% power if the true effectiveness was 35%.

However, there was a wide range of opinion about what levels of effectiveness shown in the trials would warrant further development. Even the relatively small and somewhat homogenous group at the meeting expressed a range of views about “how effective is effective enough”, from 20% to 80%, with most indicating an effectiveness between 30% and 50%. A decision on the minimum level of effectiveness would be influenced by the burden of disease in a particular setting, other HIV-prevention options available

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or expected in the near future, the opportunity costs of investment, and numerous other factors that affect the balance of risks and benefits. While participants agreed that it was important to contextualize the findings beyond “just numbers”, several noted that in the end the decision about whether to further develop the product (by Endo or another entity), and whether to register it (by a regulatory authority), would be based on a single headline number – the primary objective – which is the reduction in overall risk of HIV infection when compared with a placebo.

Several meeting participants underscored that it will be important to contextualize the trial findings appropriately so that different stakeholders – policy-makers, journalists, donors, potential users, community members, advocates and others – have a clear sense of what “the numbers” mean and do not mean. The headline trial result will be the overall reduction in risk of HIV infection in women randomized to PRO 2000 compared with placebo gel. This is a measure of product effectiveness, which combines the efficacy of the product (proportionate reduction in risk when the product is used perfectly) and the degree to which the product is used. Since product use cannot be guaranteed and relies on self-reported gel and condom use, the Phase IIb and III studies as designed can only assess overall effectiveness and make indirect estimates of the product’s actual efficacy.

This complex topic needs further deliberation among different groups and constituencies. One suggestion proposed was for WHO to work with others to convene an expert group to develop guidance on what level of effectiveness would warrant further development of PRO 2000. This process should include a broad range of stakeholders: key policy-makers, regulators, researchers, advocates, community members and potential users. Many would be concerned about potential risk compensation (increased number of partners and/or reduced condom use) and not undermining existing risk-reduction strategies, though the weight to place on such concerns was difficult to determine objectively and may be context specific.

It was not clear whether such an expert group could make progress on the issue in advance of release of the MDP 301 results.

One consideration was how different products will be delivered. It is possible that PRO 2000 could be licensed for over-the-counter distribution through clinics and commercial outlets. In contrast, the new prevention technologies other than PRO 2000 for which results are expected in the near to mid term are all based on antiretroviral (ARV) drugs (for either oral or topical use). This will have implications for prioritizing users, health infrastructure, service delivery, prescription-only use, resistance and other issues. Users will probably require periodic HIV testing before and during product use, which may limit acceptability and have implications for counselling and testing services. Even if the ARV-based products are found to have a higher level of effectiveness than PRO 2000, they will also take considerable time to become available to users, and will be accompanied by additional complexities in introduction and monitoring that may limit their use and offset some of the potential public-health impact of any new ARV-based prevention technology.

Modelling

Modelling is one approach to frame and address some of the difficult questions around how the clinical trial results may be translated into policies: partial efficacy, introduction strategies and priorities, and potential impact. Working as part of the MDP, a team at the London School of Hygiene and Tropical Medicine has continued to refine its models to address some of these questions, using concrete data and more realistic and specific assumptions. They are continuing to work to incorporate trial data into the models as they emerge.

Participants made a number of suggestions where further modelling work would be particularly useful:

analyses to develop estimates of imputed efficacy; helping convey what the trial results represent for the individual and at a population level; a range of unit costs for cost-effectiveness analyses for donors; and impact projections for different epidemic and distribution scenarios. Drawing on the experience with the male circumcision Decision Makers’ Programme Planning Tool, it would also be very useful eventually to develop an impact model aimed at policy-makers.

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Donors

Several participants noted that it was important to engage in serious discussion with donors to the microbicide field, to explore interest in additional investment in PRO 2000. While it was possible that Endo, or another private-sector company or companies, may license and develop PRO 2000, further development would be likely to require possibly substantial additional investment from public-sector or philanthropic donors. Several ideas were proposed as appropriate venues for a donor discussion about PRO 2000: IPM was to have its donor meeting in early June 2009 and the Product Development Partnerships funders’ group was to meet on 6 June. The UK Department for International Development (DFID) was the current chair of this group and could put PRO 2000 on the agenda, although it would be difficult to have an in-depth discussion without more clarity around the trial results and Endo’s intentions.

Another possibility was to plan a meeting focused specifically on PRO 2000 and potential funding needs.

This meeting could be co-convened by DFID and the National Institutes of Health (NIH) as the main investors in the MDP and MTN trials, and with complementary links among key donors in Europe and the USA. Several people suggested that this meeting should be scheduled in advance for December 2009 or January 2010, after the results of the MDP trial are known.

WHO recommendations

WHO plays an influential role in reviewing evidence and, through issuing recommendations, legitimizing new products and interventions for public-health use, particularly in middle- and low-income countries.

WHO recently adopted a more systematic and rigorous process for reviewing and grading scientific evidence for a new product or intervention. This process includes developing recommendations based on systematic compilation of peer-reviewed literature, tables that grade evidence for the most important recommendations, and a detailed background paper. The recommendations address both clinical and programmatic issues.

The process of developing recommendations for a new product or intervention would trigger a shift from the research and pilot introductory phase to a programmatic phase with more widespread use. It would motivate decisions about new product introduction, and support evidence-based policy and practice in individual countries. These recommendations could also facilitate and accelerate programme scale-up in key countries, and would be critical for existing and new donors (that had not supported research and product development but may support product introduction and scale-up). Finally, the recommendations would draw attention to new products and interventions and inform communication, advocacy and education, as well as encourage interest and acceptance among clinicians, users and the public.

Drawing on recent experience with HPV vaccines and male circumcision, participants made a number of observations related to the WHO recommendations. First, the consultative process should start as soon as evidence becomes available. In the case of male circumcision, the evidence from the first trial to release results was impressive and consistent with prior observational studies. A significant amount of work to prepare for access to the procedure was initiated prior to the results of the second and third trials being announced. When the data-safety monitoring board of the remaining two trials recommended public release of the data, planning for the WHO/UNAIDS consultation to examine the implications for policy and programming started before the full trial data were published. The consultation took place within 10 days of publication of the results. It is unlikely that the novel product PRO 2000 could have such a rapid review, even if the two trials were consistent and showed no safety concerns.

One participant queried the relationship between regulatory review and the WHO process. While WHO recommendations are not formally linked to regulatory review, the processes are complementary: review by national regulatory authorities is, by definition, a national process, while WHO is charged with making recommendations that are about public-health benefits over a wide range of countries and settings.

There was some concern as to whether a WHO recommendation on PRO 2000 might make countries feel “pressured” to grant regulatory approval. Based on other experiences, the review process is both

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informed by and informs country processes based on their own priorities. Key considerations for PRO 2000 will be the level of effectiveness, acceptability, cost and potential public-health impact in different settings.

Implications for other prevention trials

The implication of new prevention technologies for ongoing or future HIV-prevention trials is a growing area of debate across the prevention research field. Integrating any new technology into the prevention package offered to trial participants could have significant implications for the trial size and duration necessary to reach a given number of endpoints. Depending on the product’s particular mechanism of action, it may not be possible to separate out the effect of the test product (for example, providing a vaginal product in a trial of another vaginal product, or an ARV-based prevention method in a trial of another ARV-based method). The Global Campaign for Microbicides, UNAIDS and the USA Centers for Disease Control and Prevention recently hosted a consultation in Uganda on this topic, where participants reached some general areas of agreement and identified other areas where further debate is needed.

In general, participants in the London meeting felt that, given the unknown outcome of the MDP trial, the relatively long time horizon before a regulatory dossier could be submitted and reviewed, and the currently limited supply of PRO 2000, this would probably not be a major issue for currently ongoing trials or those soon to start. The HIV-prevention research field needs to continue to debate and address the issue of the standards of prevention in HIV-prevention trials and how these should evolve as new prevention technologies become available. It was noted that regulatory approval of a product was a necessary step in the process, yet many additional steps were required before a product became reliably available in trial communities. Whether or not a new or ongoing trial was able to provide PRO 2000 to trial participants, either as standard of care or as comparator, clear explanations on the different elements of the HIV-prevention package need to be included in the trial protocol and in communications to trial communities.

Strategic communications and messaging

Regardless of the results of the MDP 301 trial, it will be very important for the microbicide field and HIV-prevention research overall to work out ways to convey clear and accurate messages about what the results mean for PRO 2000, microbicides and HIV-prevention research. In the past, trial results and their implications have sometimes been misinterpreted, misreported or exaggerated. Messages need to be crafted with and for a range of different audiences. These efforts will be coordinated among the MDP, the MRC and the collaborating institutions working directly on the MDP 301 trial, as well as other key actors in the microbicide and wider HIV-prevention fields. It will be important to balance clear and consistent messaging with what will probably be a range of views – within and outside the microbicide field – about what the MDP trial results mean for PRO 2000 and the microbicide field overall.

Messages need to be developed for a number of different scenarios. These include, but are not limited to:

a significant result that confirms the findings of the HPTN 035 trial; a significant result that indicates a higher level of effectiveness; or a result that indicates less overall effectiveness than HPTN 035. Several people suggested that work should start soon to inform and prepare different audiences, particularly key policy-makers and science journalists, to understand the trial results and their implications. Topics could include, for example: the different possible scenarios for the trial results; partial effectiveness and the implications for the level of protection afforded at individual and population levels; and the likely timeframe for availability of PRO 2000 if the results warrant further investment and development.

There will probably be different interpretations of the trial results and their implications, and several participants noted that this is not only inevitable but desirable. In general, participants agreed that messages should be complementary and consistent in the short term, with MDP managing messaging for the trial communities and countries, as well as information specifically about the MDP trial in the

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international press. Other actors in the field could work with MDP, and the Microbicides Media and Communications Initiative (MMCI) offered to serve as a resource for sharing materials, arranging conference calls, and other activities in support of global communications.

Scientists

It will be important to develop a clear strategy for engaging the broader scientific community and to make and convey decisions and reasoning about interpreting the trial results in a manner that is as transparent and clear as possible. Several people noted that the critical article published in Science in 2008¹ was a setback for the field, and that it is important to convey the way the field is evolving and changing.

The Microbicide Research Working Group may be well positioned to work with scientists, since its members work across a number of related fields.

Policy-makers

Policy-makers also need to be prepared to understand the trial results so they can make informed decisions about the implications for PRO 2000 and other microbicide and prevention trials, and present accurate information when asked to comment in the press. Several meeting participants urged that key policy-makers need to be engaged now, while others were concerned that it would be difficult to engage policy-makers before the trial results were available.

Trial communities

Institutions collaborating on the MDP 301 trial will manage the dissemination of trial results to policy- makers, the press and communities in the trial countries. Institutions collaborating on the HPTN 035 trial will do the same in those trial sites. A critical element of this process will be to manage expectations around the timeframe for product availability in the trial sites. There is some possibility that PRO 2000 could be made available to trial participants or communities under a research designation, either through additional clinical studies or through pre-introductory studies and operations research. However, these studies have not been developed and it was not clear how much product would be available for these or other research efforts. The MDP and MTN networks should work with donors and the product sponsor to clarify, as soon as possible, plans – if any – to make product available to the trial participants and communities, so that any plans can be made clear when the results of the MDP 301 trial are announced.

Next steps

During the last part of the meeting, participants identified and prioritized action items and next steps, including, when possible, which agency would be responsible for following up, potential funding sources, and the timeframe. These were refined and distributed to participants shortly after the meeting (see chart and timeline in Appendix 1 and 2). WHO was requested to play a coordinating role in tracking, monitoring and facilitating these follow-up activities.

Overall, the meeting was important in laying out the many possible scenarios and the uncertainties around PRO 2000 in anticipation of the results of the MDP 301 trial. It helped identify next steps for the field, and gave participants a more complete and realistic understanding of the efforts that are needed around the release of the trial results, as well as the many steps and commitments that will be needed to deliver PRO 2000 – or any product – to the people and communities that urgently need it.

1 Grant et al. Whither or wither microbicides? Science, 2008, 321:532–534.

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Ac tiv ity Or ga ni za tio n l ea d Ti m in g Fu nd in g Co m m en ts Pr od uc t o w ner sh ip a nd l ic ens in g

Discussions re: ownership and licensing arrangements Endo, UK MRC and others Immediate Decision on ownership Endo, UK MRC and others “Next few months” N/AClarity on this issue is critical for planning and action by other players Determine development plan or licensing arrangementsEndo, UK MRC and others N/A Articulate and address key questions for MDP301 TRC to consider in recommendations to MRC about further product development

MDP, WHO, others? Immediate Led by MDP but broadened to consider public health and implementation issues. Prepare in case license reverts to MRC

Po lic y a nd p ro gr am m es

Engage donors IPM at donor’s meeting DFID through PDP group DFID and NIH June 2009 Ongoing Set date now for meeting after results announced; ongoing

N/AScenarios re: MDP and PRO 2000 and implications for donor investment and for field Demand forecasting and projected costs for activities are important to inform this Define evidence base needed for WHO guidelines WHO Immediate Needed to prepare for WHO guidelines and plan for additional information required Develop WHO guidelines WHOQ3 2010→For release and implementation after licensure Dialogue on partial efficacy, levels of effectiveness WHO and others Q4 2009 or Q1 2010Implications for policy decisions on whether further development of PRO 2000 will be warranted Develop plans for pre-introductory studies/ongoing access for trial participants and communities MDP, MTN plus groups experienced in implementation research

Q3 and Q4 2009 (so plans and timeframe are clear when results are announced) Can meet joint goals of answering critical research questions and ongoing access under research designation in trial populations and communities. Depends in part on product availability

Ap pe nd ix 1 : Co nt in ge nc y p la nn in g l is t f or P RO 2 00 0 a cce ss

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Ac tiv ity Or ga ni za tio n l ea d Ti m in g Fu nd in g Co m m en ts

Policy and programmes continued Communicate with policy-makers and community leaders in trial countries to understand the implications of trial results, timeline and product availability

MDP, MTN with WHO, others? Q3, Q4 2009 Focus in trial countries Implement pre-introductory studies/ongoing access for trial populations and communitiesTBDCan meet joint goals of answering critical research questions and ongoing access under research designation in trial populations and communities. Depends on product availability Additional work on implications of PRO 2000 on standards of prevention, and use as comparator in microbicide and other HIV-prevention trials

WHO/UNAIDS Q3, Q4 2009

Re gu la to ry

Clarify potential regulatory scenarios Endo or licence holder Immediate Determine if review to be done first in FDA, MCC, EMA, EMA via Article 58, or a combination of NRAs Determine implications of different regulatory scenarios for programmes – donor funding, etc. TBDQ3 2009 Meet with FDA and/or other regulatory authoritiesEndo or licence holderQ1 2010 Clarify other studies/data to be included in regulatory dossierEndo or licence holderQ1 2010 Prepare regulatory dossier Endo or licence holderQ1 2010 to Q4 2011Timing is dependent on whether additional studies are needed

M an uf ac tu rin g a nd p ro ce ss d ev el op m en t

Validated, scaled-up commercial process needed for regulatory submissionEndo or licence holder18–24 monthsOn critical path for regulatory submission Identify manufacturing capacity and costs for additional studies (clinical, bridging, pre-introductory)

Endo, CONRAD, IPM, other?

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Ac tiv ity Or ga ni za tio n l ea d Ti m in g Fu nd in g Co m m en ts

Determine how much PRO 2000 is currently available for additional studies and the time/cost to produce more

Endo Q3–4 2009N/ACritical for planning, prioritizing and costing additional research

Dem an d p ro je ct io ns

Demand projections for additional clinical and pre- introductory studies MDP Q3 2009→To determine priorities to use available product and potential and cost to produce additional supplies Demand projections for introduction and scale-up TBD Q2 2010Needed to calculate for manufacturing needs and potential donor investment

Ca rc in og en ic ity s tu dy

Develop strategy, plan, protocol for carcinogenicity study NIAID and group to be contracted Immediate Possible NIH Conduct carcinogenicity study NIAID to contract?Q1 2010 to Q4 2011Possible NIH; needs to be prioritized by MTN, reviewed, etc.

As determined by regulatory requirements and results of MDP 301

Ad di tio na l c lin ica l s tu di es

Rectal safety study in men and women UK MRC Q1 2010 Available Ready to go (protocol written, sites identified, funding, product) but waiting on MDP 301 results Safety in pregnancy MTN?Necessary for regulatory review? Safety in adolescents Necessary for regulatory review? Safety – 2%, high-frequency use Depends on outcome of MDP 301; is high- frequency use proxy for higher concentration? Additional safety studies TBD TBD depending on results of MDP 301 and opinion of regulatory authorities

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Ac tiv ity Or ga ni za tio n l ea d Ti m in g Fu nd in g Co m m en ts

Additional clinical studies continued Study of user-filled paper applicatorPATHQ4 2010 (protocol and site ready) USAID; additional funds needed for packaging, labelling and testing

Study being conducted with tenofovir in 2009/2010; can be repeated with PRO 2000 in 2010 or 2011 pending product availability and funding Study with reusable (or other) applicatorCONRAD Critical to reduce cost; long-term stability data would be needed

M od el lin g

Finalize distribution scenarios to model linked to MDPLSHTM MDP and WHO funds Analyses to develop estimates of imputed efficacy and associated range of uncertainty; role of modelling in helping convey what results represent

LSHTM and others?Q3 2009→MDP and WHO fundse.g. overall impact from a combination of levels of condom use Develop range of unit costs to be used in first-round cost-effectiveness analyses for donorsLSHTM with EndoQ3 2009 to Q3 2010MDP and WHO funds Impact projections focused on established epidemic and general distribution; programme targets LSHTM with others?Q3 2009 to Q3 2010MDP and WHO funds Develop impact model aimed at policymakers (following MC Decision Makers’ Programme Planning Tool example)

UNAIDS2010 or laterWHO and UNAIDS

Coo rd in at io n

Complete timeline with costing for activities Alliance Q3 2009 For review by meeting participants Develop detailed timeline and list of action items for Q3 and Q4 2009 before MDP 301 results Alliance and WHOASAP Completed; updating ongoing Monitor and coordinate activities WHO Ongoing

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Ac tiv ity Or ga ni za tio n l ea d Ti m in g Fu nd in g Co m m en ts St ra te gi c co m m un ica tio ns

Scientific community MRWG (NIH) with others Q3 and Q4 2009 N/AOutreach to scientific community outside of microbicides re: trial results and implications for microbicide field Communications plan and messaging around MDP results MDP Q3 and Q4 2009 Develop and implement communications plan around trial results in trial communities, countries and internationally, including plans for availability in trial communities Communications plan and messaging around MDP results (implications for field)MMCI with others Q3 and Q4 2009 Available through core funding

Develop and coordinate messaging around implications of MDP 301 results for field Impact on other trials: distribute points of agreement from GCM/UNAIDS/CDC meeting GCM, CDC, UNAIDS Immediate N/AClear recommendations that existing trial designs should not be altered and placebo- controlled trials should continue Impact on other trials: continue debate and consensus-building around ethical and practical implications

UNAIDS/WHO with GCM, CDCOngoing Community education around partial efficacy and implications in trial sites and other settings MTN, MDP, GCM, AVAC, AMAG Ongoing, continueKey for users and others to understand partial efficacy (rather than the dichotomy presented around trials that a product will “work” or “not work” to prevent HIV) Develop and disseminate clear messages about timing, product availability, regulatory review, trial results only around male to female transmission, etc., to manage expectations

TBDImmediate and ongoingNeed to make clear that even in the best-case scenario, product will not be available for several years; regulatory dossier will take 2 years at least to submit, and manufacturing scale-up, etc. need to be considered. The evidence base is only for safety and efficacy in male-to-female transmission Acronyms and abbreviations on page 20

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Ac ro ny m s a nd a bb re vi at io ns

ASAPas soon as possible AVACAIDS Vaccine Advocacy Coalition CDC Centers for Disease Control and Prevention (USA) DFIDDepartment for International Development (UK) EMA European Medicines Agency FDA Food and Drug Administration TBD to be decided GCMGlobal Campaign for Microbicides IPMInternational Partnership for Microbicides LSHTMLondon School of Hygiene and Tropical Medicine MCCMCC MDPMicrobicides Development Programme (of the UK MRC) MMCIMicrobicides Media and Communications Initiative MRCMedical Research Council (UK) MRWGMicrobicide Research Working Group (NIH) MTNMicrobicide Trials Network N/Anot available NIAIDNational Institute for Allergy and Infectious Diseases NIH National Institutes of Health NRAnational regulatory authorities PDPProduct Development Partnership TRCTechnical Review Committee (for MDP 301 trial of PRO 2000) UNAIDSJoint United Nations Programme on AIDS USAIDUnited States Agency for International Development WHOWorld Health Organization

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Organized discussions with donors and scientific community Decision re need for carcinogenicity study; if needed immediately develop protocol and implement (>US$2m)

Optimizing manufacturing processes, scale-up; validation/preparation of registration batches

Dossier evaluation/ decision

Regulatory dossier preparation and submission (US$1m)

Develop communication strategies, messages, dissemination

Define evidence base required for WHO guidelines Rectal safety study

Decisions on need for other studies/data for inclusion indossier Demand projections for introduction and scale-up Alternative applicator preparation (start flexible) Additional pre-introductory and operations research studies Additional studies for label expansion MDP results

Decision re: ownership/ licensing/development plans Plans for pre-introductory studies/ongoing access for trial participants, communities

Develop WHO guidelines Protocol development Implementation Protocol design and implementation

Ap pe nd ix 2 : T im el ine f or P RO 2 00 0 a cce ss

IMMEDIATE ACTIONS NEEDED • Decisions re: ownership • Determine development plans/licensing arrangements • Clarify potential regulatory scenarios • Discussions with donors and scientific community • Dialogue on partial efficacy, levels of effectiveness • Key questions for MDP Technical Review Committee to consider • Communications strategies and message development • Demand projections for additional clinical and pre-introductory studies • Costing estimates for all activities • Define evidence base needed for WHO guidelines • Modelling activities

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Salim Abdool Karim

Deputy Vice Chancellor (Research and Development) Nelson R Mandela School of Medicine; University of Natal Durban, South Africa

Elizabeth Abu-Haydar Program Officer Technology Solutions

Program for Appropriate Technologies in Health (PATH) Seattle, Washington, USA

Eniko Akom Senior researcher

Population Services International Washington DC, USA

Deborah Baron

Microbicide Media Communications Initiative (MMCI) Johannesburg, South Africa

Michael Berntgen

Pre-authorization Evaluation of Medicines for Human Use European Medicines Agency (EMA)

London, United Kingdom Roberta Black

Division of AIDS

National Institutes of Health Bethesda, MD, USA Gina Brown

National Institutes of Health Office of AIDS Research Rockville, USA Michael Chirenje

Department of Obstetrics and Gynaecology College of Health Sciences

University of Zimbabwe Harare, Zimbabwe Sheila Clapp

Family Health International Durham, NC, USA Lee Claypool

Research, Technology and Utilization Division Office of Population and Reproductive Health Bureau for Global Health

US Agency for International Development Washington, DC USA

Anne Coletti

Family Health International Durham, NC, USA Diana Dunstan

Chair EDCTP General Assembly The Hague, The Netherlands Anna Forbes

Deputy Director

Global Campaign for Microbicides Washington DC, USA

Appendix 3: List of participants

Henry Gabelnick Executive Director CONRAD Arlington, VA, USA Polly Harrison Director

Alliance for Microbicide Development Silver Spring, MD, USA

Lori Heise Senior Associate

Global Violence and Health Centre

London School of Hygiene and Tropical Medicine London, United Kingdom

Shabbar Jaffar

European and Developing Countries Clinical Trials Partnership and Reader in Infectious Disease Epidemiology

London School of Hygiene and Tropical Medicine London, United Kingdom

Sheena McCormack

Reader in Clinical Epidemiology Senior Clinical Epidemiologist MRC Clinical Trials Unit London, United Kingdom Ian McGowan

Professor of Medicine

Magee-Women’s Research Institute University of Pittsburgh School of Medicine Pittsburgh, PA, USA

Rajen Misra

Director, Clinical Evaluation and Trials Cluster Medicines Regulatory Authority

Johannesburg, South Africa Jo Mulligan

Health Adviser DFID Research

UK Department for International Development London, United Kingdom

Richard Mutemwa

Centre for Global Health, Population, Poverty and Policy School of Social Sciences

University of Southampton Southampton, United Kingdom Pamela Norick

Chief of External Relations

International Partnership for Microbicides Silver Spring, MD, USA

Robert Pool

Centre for International Health Hospital Clinic

University of Barcelona Barcelona, Spain

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Albert Profy

Vice President, Preclinical and Pharmaceutical Sciences Endo Pharmaceuticals Solutions, Inc. (formerly Indevus Pharmaceuticals, Inc.)

Lexington, MA, USA Gita Ramjee Director

HIV Prevention Research Unit Medical Research Council Durban, South Africa Barbra Richardson

Research Associate Professor of Biostatistics University of Washington

Joint Associate Member in Public Health Sciences Fred Hutchinson Cancer Research Center Harborview Medical Center

Seattle, WA, USA Renée Ridzon Senior Program Officer

Global Health – Infectious Diseases Development Bill and Melinda Gates Foundation

Seattle, WA, USA Joseph Romano

Chief of Product Development

Zeda Rosenberg Chief Executive Officer

Linly Seyama Johns Hopkins Project Chipatala Avenue Blantyre, Malawi Alan Stone Director, MEDSA Ltd, London, United Kingdom John Townsend

Director, Reproductive Health Population Council

Washington DC, USA Morenike Ukpong

African Microbicides Advocacy Group Department of Child Dental Health Obafemi Awolowo University Ile-Ife, Nigeria

Mitchell Warren Executive Director

AIDS Vaccine Advocacy Coalition (AVAC) New York, NY, USA

Charlotte Watts

Department of Public Health and Policy London School of Hygiene and Tropical Medicine

Joyce Wood

Communications Adviser MDP

London, United Kingdom Sheryl Zwerski Division of AIDS,

National Institutes of Health Bethesda, MD, USA

Secretariat

Tim Farley Scientist

Controlling Sexually Transmitted and Reproductive Tract Infections (STI)

Department of Reproductive Health and Research (RHR) World Health Organization

Geneva, Switzerland Sofia Dambri Assistant to Tim Farley

Controlling Sexually Transmitted and Reproductive Tract Infections (STI)

Department of Reproductive Health and Research (RHR) World Health Organization

Geneva, Switzerland Kim Dickson Medical Officer HIV Department

World Health Organization Geneva, Switzerland Catherine Hankins

Chief Scientific Adviser to UNAIDS and Associate Director;

Department of Evidence, Monitoring and Policy UNAIDS

Geneva, Switzerland Ying-Ru Lo Coordinator

Prevention in the Health Sector World Health Organization

Coordinator Prevention in the Health Sector Department of HIV/AIDS

World Health Organization Geneva, Switzerland Nicolai Lohse Research Officer

Evidence Monitoring and Policy Department Geneva, Switzerland

UNAIDS

Elizabeth Mcgrory WHO Consultant Nyack, NY, USA

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Avenue Appia 20, CH-1211 Geneva 27, Switzerland www.who.int/reproductivehealth

Preparing for access to PRO 2000 microbicide

M e e ti n g r e p o rt M e e tin g re p o rt