4.1. Primary Indications for MPT Drug-Drug and Drug-Device Combinations
Across working groups and respondents to different data-gathering approaches, consensus emerged that the most critical parameter in the construction of an MPT Target Product Profile was the combination of indications to be met by a given product, that is, contraception, HIV prevention, and/or prevention of non-HIV-STIs. Overall, the combination of HIV prevention and contraception was assigned the highest priority, followed closely by HIV + HSV. Non-HIV STIs were variously prioritized in terms of relevance for HIV transmission, technical feasibility, epidemiological burden, and effectiveness of available treatments.
Variability among informant populations did produce noteworthy differences in rankings. Comparison of findings from the surveys among US and African reproductive health care providers () found that 66 percent of African providers ranked unintended pregnancy + HIV as of highest priority, while the same percentage of US providers ranked unintended pregnancy + non-HIV STIs as the highest-priority target indication. HPV was ranked as the highest-priority non-HIV STI by both survey populations (75 percent and 68 percent of African and US providers, resp.). While response volumes from China and India were not high, the combination of contraception + non-HIV STIs appeared to command the most interest as MPT candidates for those markets.
4.2. TPP Parameters for Prioritizing MPT Development
The consensus Target Product Profile for MPTs comprised a defined set of parameters with associated “preferred” and “minimally acceptable” criteria that formed the architecture for determining what must matter most for MPT development once the highest-priority indication has been determined. Those assigned priority through the methods described in the preceding section appear above in . Several of these attributes received intense scrutiny and thus merit additional comment.
TPP parameters for prioritizing MPT development.
Dosage Forms. Given broad consensus that a crucial arbiter of efficacy for any MPT will be adherence to correct product use, it was not surprising that sustained-release devices, importantly intravaginal rings (IVR), were identified as the highest-priority dosage form. The rationale for IVR as a preferred delivery system was that such technologies, which could be user-inserted and designed for at least 30 days of efficacy, offered potential for greater adherence compared to other user-administered systems. IVRs are reversible, may impose less of a burden on health systems and, depending on drug activity, might also mitigate some of the side effects associated with oral administration and correspondingly greater systemic exposure. Again, however, there was variation across survey populations. US providers preferred oral dosage forms, while African providers leaned toward a “suite” of several dosage forms as offering greater potential for acceptability and use, and ranked injection and sustained-release devices slightly higher than others.
Efficacy Targets. There was consensus that MPT components for HIV prevention should meet a minimum requirement of 40–50% reduction in risk, preferably at least 80% with perfect use and 60% with typical use. Contraceptive MPT components should be no less effective than currently available products and an efficacy minimum of at least 40% was the target for prevention of non-HIV STIs.
Product Attributes. Most specific attributes were identified within the context of safety, efficacy, and other factors, with a relatively long shelf life (36 months) and storage at high temperature (40°C) as the most consistently-supported priorities.
Side Effects. The general view was that these would need to be assessed in the context of the overall safety and anticipated efficacy of the MPT under consideration, but should be “no worse than individual indication products,” for example, currently available contraceptives.
Other Parameters. Another group of “non-TPP parameters” emerged in the research and review process as issues requiring further discussion with respect to their importance for different potential user populations. Those were research entity, resupply infrastructure, access to testing/monitoring, cold chain storage (if needed), time to development for compounds, potential drug interactions, mechanism of action established in other products (e.g.,Truvada, NuvaRing), novelty of mechanism of action and enhancement of pipeline diversity, pipeline redundancy, potential for drug resistance, potential for discreet use, influence on sexual experience, incidence/prevalence in target population and overall burden of disease, and few or no existing or readily available treatment options.
4.3. Multipurpose Reproductive Health (RH) Vaccine Working Group
The Multipurpose RH Vaccine Working Group's “Request for Concepts” elicited 13 submissions and/or comments, almost all based on active immunization () and responsive to the Target Product Profile developed by this group (). Two additional concepts were based on passive immunization [59
] and adenovirus vectored antibodies [60
] and one submission was focused on product development strategies. In general, it was recognized that advances in mucosal vaccinology were crucial to advancement of these concepts [62
Multipurpose RH Vaccine Working Group: active immunization concepts.
Reproductive Health Consensus Target Product Profile for MPT Vaccines.
4.4. Understanding Regional Needs and Priorities for MPT Development
The information that has accumulated with respect to regional priorities for MPTs has accelerated in volume, coverage and, with the refinement of the Target Product Profiles, its relevance to MPT development writ large. The January 2012 Global Forum on MPTs hosted by the Wellcome Trust was explicitly designed to elicit international multisectoral input into the draft TPPs, extend consideration of the critical path for regulatory approval of MPTs beyond the perspectives of the USFDA to include the views of representatives from other regulatory authorities; encourage a global perspective and international support for this Initiative and seek consensus on next steps, and identify the types of target populations in specific geographic regions most likely to benefit from MPTs. summarizes the extensive output of that vital consultation and background material provided by its participants.
4.4.1. The MPT Pipeline
Extensive research by the Scientific Agenda Working Group (SAWG) and colleagues also recently generated the first comprehensive list of all known potential MPT candidate products and components, concepts, relevant technology platforms, and delivery systems responsive to the major MPT indications. The drug candidates in this listing were then subcategorized by mechanism of action, chemical class; product candidates were organized according to dosage form and stage of development. In addition to yielding a summary set of MPT product priorities, this review and analysis process revealed certain imbalances in the R&D efforts being invested in different MPT product and component types.
4.4.2. Pipeline Prioritization and Gap Identification
Priorities. The exercise to prioritize MPT candidate drugs and products identified specific active pharmaceutical ingredients (API) and product configurations appropriate for timely and effective development of MPT products. In light of the priority indications of HIV and pregnancy prevention, MPTs that involve small organic molecule antiretroviral (ARV) agents and hormonal contraceptives were prioritized. The lack of candidate STI prevention options did not allow for specific prioritization for this indication (see in what follows). Further, it was recognized that a suite of MPT product configurations would be necessary to achieve maximum public health impact. Specifically, vaginal rings, long acting injectables, and alternative on-demand formulations are all defined as priority configurations for MPT products.
A range of gaps were identified in the course of the prioritization exercise. Specifically, it was noted in the following:
- There is a lack of alternatives to reverse transcriptase inhibitor (RTI) antiretrovirals (ARV) for the HIV indication.
- Sufficient understanding of the potential relationship between specific forms of hormonal contraception (e.g., injectable DMPA) and increased risk of HIV transmission is lacking.
- Viable, pathogen-specific options for the non-HIV STI indication for potential MPTs are unavailable.
- There are insufficient data on acceptability, use, and uptake of intravaginal rings.
- Too few options for long-acting injectable delivery modalities are in development.
- Insufficient knowledge about the safety of intermittent use of ARVs and other anti-infectives is a risk for on-demand product options in general.
- Limited non-hormonal-contraception and STI-prevention options exist.
- Definitive social-behavioral science to support all product options is limited.
The analysis also generated a short list of early-stage development candidate categories meriting pursuit for possible longer-term development:
- STI-specific APIs;
- non-ARV-based HIV prevention;
- lactobacillus-based products;
- nonhormonal contraceptives;
- novel on-demand product configurations.
The product prioritization exercise also generated a set of “process priorities,” the absence of which could hinder the MPT effort in the longer term. The key process priority is the need for coordination across donor investments, sponsor development, and program management. This, in general, has been seen as desirable but often absent; however, current resource limitations and the complexities around MPTs dictate the urgency of
- consensus on priority products, gaps, and development strategies,
- a coordinated approach to identify single-lead products for each priority MPT product type,
- pooling of capacity, capability, expertise, and other resources between viable development entities interested in MPT products,
- coordinated investment and collaborative/partnered development management,
- early and proactive engagement of regulatory authorities, supported by TPP templates specific to product types.