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The PDP Access Group commissioned, with the support of the Netherlands Directorate-General for International Cooperation (DGIS), a series of discussion papers on topics relevant to the complex set of issues that affect access to new health products in low and middle income countries. These papers were conceived primarily to guide the work of the PDPs, and to provide some thinking about the different options available for PDPs and their partners.

Access Timelines

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The Product Development Partnership (PDP) Access Steering Committee commissioned this paper to explore the optimal timing and sequencing of access-related activities for drugs and vaccines, the underlying rationale for this sequencing, and the dependencies between activities.  The paper accompanies two generic Gantt charts—one for drugs and one for vaccines—that capture the timing and sequencing of access activities. Semi-structured telephone interviews were conducted with sixteen respondents in donor organizations, pharmaceutical companies with experience of drug and vaccine development and commercialization in low- and middle-income countries (LMICs), and PDPs working on drug and vaccine projects.

The time period prior to stringent regulatory authority (SRA) or twinned product approval is referred to as “upstream” within the paper.  The earliest access activities, which begin prior to Phase 2b trials, usually between nine and ten years prior to product approval by an SRA, are conducted to establish the disease context, the intellectual property context, and the key relationships with regulators and key opinion leaders that will be required throughout the following years.  The second phase of upstream activities runs from between nine and six years prior to SRA product approval and occurs in parallel with Phase 2b clinical studies.  These activities focus on gaining a better understanding of the value proposition of the new intervention and establishing draft strategies in areas such as regulatory affairs, manufacturing, and financing.   In the period between six and three years prior to SRA product approval, around the same time that Phase 3 studies are being carried out, there are four groups of access activities for PDP consideration, which focus on building a stronger constituency of support at the global and national level and at financing agencies.  Market and stakeholder studies can also continue during this time and be used as part of the relationship-building approach.  In the final upstream time period from three years prior to SRA product approval, the PDP provides necessary support to manufacturing partners to ensure that the product will be ready for shipment by the time of launch in the first wave of countries.  In addition, PDPs and their partners will engage in various financing activities, file an SRA regulatory package, and establish and/or refine an evidence package for both country decision makers and WHO.

In the downstream period, which refers to the time after a product receives approval from an SRA or via a twinned regulatory filing, the PDP’s role becomes less active and one of supporting, informing, and building capacity for existing country-level decision-making and implementation processes.  PDPs and their partners file WHO prequalification and endemic country dossiers, provide support to country policy review and pilot/demonstration studies, and support the conduct of monitoring and evaluation activities.

These timelines reveal a progression from initial scoping of value proposition and strategy, through early engagement and collection of evidence, to an intensification of engagement and assembly of evidence into formal packages to support global and country decision making, and finally to more variable involvement in roll-out and surveillance activities. This discussion paper highlights those activities identified by stakeholders as taking longer than anticipated (including manufacturing,
registration, adoption, and financing issues) and causing delays (including inaccurate demand forecasts, failure to anticipate post-marketing commitments, and inability to obtain intellectual property clearance). The paper also points to some key tactics that, if implemented appropriately and in a timely manner, have the potential to accelerate access timelines (such as early country studies, financing scoping, and consultations with regulators). These considerations, plus the sample timelines, may be used by PDPs and their partners to plan access activities in a way that minimizes delays and maximizes
impact.

Access Costing

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The purpose of the costing analysis was to explore the structure, nature, and size of the costs associated with access to new tools following marketing authorization. See full paper for details.

Access Metrics

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Product Development Partnerships (PDPs) are often challenged to ensure that target populations can access products once developed. Ensuring that products reach end-users requires PDPs to develop, manage and track a wide range of activities and information. Having a clear set of indicators that measure progress along the way from R&D to end-user will be useful for PDP project management and performance enhancement.

A set of commonly used metrics for PDPs to track progress toward access goals is currently lacking. The main challenge in developing these metrics is that a ‘one size, fits all’ approach may not meet the needs of the range of PDPs that have different time lines and very different types of products, among other factors. This Discussion Paper develops a framework for thinking about access metrics from pre-licensure to post-licensure phases related to availability, acceptability, affordability, and adoption of new products.

A set of 26 core and 12 additional indicators are identified based on consultation with 15 PDP staff regarding their major milestones, supplemented by other indicators gleaned from the literature, and discussion with six donor organizations. More than half of the core indicators measure achievements relative to planned activities. The remaining indicators are designed to measure discrete outputs of access-related activities. Next steps include tailoring the indicators to individual PDPs and products, and piloting the use of the indicators for internal management and dialogue with funding agencies.

Pharmacovigilance

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The authors conducted an assessment of pharmacovigilance (PV) strategies on behalf of the Product Development Partnership (PDP) Access Steering Group. The assessment was based on interviews with 13 PDPs, 13 regulatory authorities (NRAs), and 7 technical and stakeholder agencies.

This assessment applies the broader definition of PV which includes activities related to safety monitoring of therapeutics and vaccines during clinical development and post-product launch—a complete life cycle approach. In order to assess the safety of products during all stages, NRAs require Development Risk Management Plans (DRMPs) as part of the Clinical Development Plans at the outset of clinical trials (CTs), and these evolve to Risk Management Plans (RMPs). As the product moves from the early development stage to clinical development and finally to the market, the knowledge regarding the safety profile of the product also increases proportionately.

Once the product is marketed, PV covers a range of activities including passive surveillance, stimulated reporting, active surveillance, comparative observational studies and targeted clinical trials. In several developing countries with rudimentary or emerging PV capacity, mostly passive surveillance systems exist. Developed countries use a mix of PV strategies to ensure the drugs and vaccines have a favorable benefit-risk profile.

Most PDPs have PV capacity during CTs, although the extent of their involvement in PV activities varies depending on the phase of development of the product and the entity conducting product development (i.e. the PDP or a commercial partner). These PV activities during CTs are important for setting the stage for post-marketing surveillance (PMS) and for exploring the possibility of building PV capacity in countries targeted for product introduction.

PMS largely depends on the strength and capacity of the overseeing NRA to guide and enforce PV activities–the tendency for PDP manufacturing partners is to do less if this activity is not mandated. Activities for PMS are just beginning, except in those PDPs which have products progressing to Phase 3 or are already authorized. These PDPs are developing multiple strategies to address product safety concerns, such as planning and implementing phase 4 studies, sentinel and cohort event monitoring studies.

Some PDPs are thinking about PV more broadly, and in addition to building the capacity of their own staff, these PDPs are planning/helping to build the capacity of PV for NRAs in countries where products will be marketed.

Those PDPs with products earlier in the pipeline have generally not given much consideration to PMS, and are not yet poised to move to the next step; in fact, many felt that PMS strategies were the sole responsibility of the MAH. Even if PDPs are prepared to embark on PMS, funding for these activities is limited.

To improve PDP performance in PV and to gain synergies, some specific actions are recommended, including: clearer definition of roles and responsibilities of PDPs throughout the PV life cycle; provision of a handbook which outlines PV regulatory capacities of target countries; tabulation of basic biological markers in specific developing country populations to facilitate evaluation of adverse events; exploration of strategies for centralized sharing among PDPs, such as electronic reporting, capacity building, and trial sites.

Manufacturing and Supply

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The Access Steering Committee of the Product Development Partnerships (PDPs) commissioned this paper on “PDP Manufacturing and Supply Strategies.” This paper discusses the approaches that PDPs currently use to ensure the secure manufacturing and supply (M&S) of quality products at an affordable price, once their products have received regulatory approval.

Eleven PDPs were interviewed in preparing this paper, working on a range of vaccine, medicine, microbicide and diagnostic products. Three key stakeholders were also interviewed. M&S strategies and approaches vary widely among the PDPs interviewed, mostly by:

  • stage of product development;
  • organizational experience with previous product approvals and launches;
  • marketplace readiness for innovative products; and
  • technologies used for manufacturing.

Establishing low-cost, high-quality, sustainable supply is the goal of all concerned. PDPs, focusing on product development programs, can be challenged with evaluating and selecting manufacturing and supply partners for access activities, and must also anticipate manufacturing planning early in their development processes, often before a competent manufacturing partner has been found.

PDPs have established a wide range of manufacturing and supply models that have been driven by the characteristics of the PDP’s product and the markets they serve. The majority of PDPs do not anticipate playing an active role in the manufacture and supply of their products once they have been approved, as they expect their partners to manage manufacturing and supply responsibilities, together with fulfilling the role of the market authorization holder. Nevertheless PDPs and their manufacturing and supply partners should be fully aligned. Although many PDPs do not want to be deeply involved in planning manufacturing capacity and supply issues, evidence shows that a good understanding of these challenges and the technology involved can be instrumental in ensuring the secure supply of low-cost high-quality products. Some PDPs also play a key role in identifying distribution partners and facilitating entry of their manufacturing partners into public markets.

Licensing and contractual agreements with manufacturing partners offer a mechanism to shape the division of labor between PDPs and partners and ensure the continued supply of low-cost high quality product. These agreements should be proactively evaluated and carefully negotiated. By addressing contentious issues and potential plans for engaging additional manufacturers early, PDPs can develop more stable partnerships.

Matching the not-for-profit development and the for-profit commercial worlds can be easier where commercial partners have the economic depth and the corporate will to support low-cost and low-margin manufacture for the long term. In situations where manufacturing and supply partners may not have the same financial ability and corporate willingness, PDPs have helped negotiate financial incentives to support the establishment of supply chains. This latter case, however, highlights a key finding from the research for this paper: the need for PDPs to plan for the long-term sustainability and security of product supply, beyond the initial launch period.

Manufacturing capacity requirements for new products must be defined early, taking into account the long lead-times typically required to establish new manufacturing facilities and equipment. To accomplish this, the business case for the introduction of the innovation must be based on solid analysis and projections. The relationships between product price, market demand and health resources must be fully understood.

Pricing

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All Product Development Partnerships (PDPs) have as part of their core mission ensuring that the products they develop are affordable and will be accessible to their target populations. Price is usually seen as a surrogate measure for affordability, although the definition of price is important to ensure that the correlation is adequate. Overall PDPs have not developed detailed strategies for pricing and to guide their negotiations with their development partners. This is due to a lack of case histories in setting suitable pricing strategies to guide this process (as most of the projects are still early in the development process). PDPs have historically been reluctant to be too specific in their approach to pricing in order to reassure development partners from the private sector that they are not going to be tied into uneconomic pricing agreements. With a couple of exceptions, pricing has been agreed using the Cost Plus method. PDPs are seen as having increasing leverage with their partners as development progresses and uncertainties about the final product and its cost are reduced. Because of the few products that have made it to the market so far, it has not been possible to develop measures of success by which pricing strategies and methods can be judged. However such measures of success must recognise the two key parameters of ensuring access and sustaining supply. Challenges faced by PDPs over pricing include the development of detailed pricing strategies and their evolution through the development process, partner concerns and education, collection of market intelligence, ensuring sustainable supply, and the role of complementary interventions. PDPs could benefit from collaboration and information sharing on choices of pricing methods, collection of market intelligence, cost calculation methodologies, and auditing of partner’s costs.

Economics and Financing

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Economics and finance issues are important, though often overlooked areas of a strategy to improve access for PDPs. By exploring the economic and financing aspects of a product during the earliest stages of its development, PDPs can improve the chances that an optimal product will be brought to market, demanded by countries and financed by donors.

Affordability is a critical component of economics and financing, driving adoption rates in countries and the likelihood of financing, both from countries and external donors. While pricing is dealt with in a separate paper, in practice, it is part of the economics and financing considerations, namely: (1) Is it worth the expense?; (2) Is it affordable?; and (3) How will countries pay for it?. While PDPs were unanimous in their message that affordability is the first priority, it is in fact intertwined with the effectiveness of the product, and the availability of resources to finance it.

A variety of additional factors will influence the adoption of product in target markets and need to be factored into economic and financing strategies. For middle-income countries, cost-effectiveness is particularly important, as these countries often finance the product domestically. In all markets, product financing is supported by early stage advocacy, demonstration projects and awareness-building with key policy-makers. In the poorest countries, global funding bodies often finance all, or a significant portion, of the purchase, making these partnerships the focus of PDP efforts. Lastly, a number of the activities herein could benefit from PDP collaboration, particularly those working in the same disease area to demonstrate the benefits of multiple interventions.

Regulatory Strategy

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In order to develop more effective strategic pathways for introducing products for global diseases via Product Development Partnerships (PDPs), a number of discussion papers were commissioned to document the strategies currently being used by PDPs,. This document, focused on regulatory strategies, is based on telephone interviews with 10 PDPs, five dealing with medicines (including microbicides), three with vaccines, and one each with diagnostics and pesticides. Telephone and email communications with stakeholders and experts in WHO prequalification were also undertaken. The regulatory strategies in use by the PDPs vary, but for the most part depend on the use of Stringent Regulatory Authorities (SRAs) and/or the WHO prequalification program and recommendations for global use. Alternative approaches that may involve endemic country regulators were viewed with skepticism by a few PDPs, although endorsed by the vaccine PDPs contacted and by at least one medicines PDP. A PDP “wish list” included requests for improvements in the following areas: the comparative quality of regulatory pathways, prequalification, understanding differences among products and their impact on regulation, and capacity building. Stakeholders, including developing country regulatory authorities and donor agencies, identified specific activities for PDPs in the area of capacity building. Finally a list of PDP proposals to maximize regulatory impact was assembled. It included (1) proposals for more efficient sharing of personnel resources and information regarding regulatory requirements, sharing lessons learned in key countries; (2) activities to improve the quality of the regulatory process, such as PDP commitment to certain standards of quality and on-going harmonization efforts; and (3) a shared commitment to capacity building, including support for initiatives that can expedite registration while building capacity.

Country Decision-Making

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When a new health product becomes available, countries have a choice to adopt the product into their national health systems or to pursue an alternate strategy to address the public health problem. Here, we describe the role for product development partnerships (PDPs) in supporting this decision-making process. PDPs are focused on developing new products to respond to health problems prevalent in low and middle income settings. The impact of these products within public sector health systems can only be realized after a country policy process. PDPs may be the organizations most familiar with the evidence which assists decision making, and this generally translates into involvement in international policy development, but PDPs have limited reach into endemic countries. In a few individual countries, there may be more extensive involvement in tracking adoption activities and generating local evidence. This local PDP involvement begins with geographical prioritization based on disease burden, relationships established during clinical trials, PDP in-country resources, and other factors. Strategies adopted by PDPs to establish a presence in endemic countries vary from the opening of country offices to engagement of part-time consultants or with long-term or ad hoc committees. Once a PDP commits to support country decision making, the approaches vary, but include country consultations, regional meetings, formation of regional, product-specific committees, support of in-country advocates, development of decision-making frameworks, provision of technical assistance to aid therapeutic or diagnostic guideline revision, and conduct of stakeholder and Phase 4 studies. To reach large numbers of countries, the formation of partnerships, particularly with WHO, are essential. At this early stage, impact data are limited. But available evidence suggests PDPs can and do play an important catalytic role in their support of country decision making in a number of target countries.

Access Strategy

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This paper discusses the current status of PDP access strategies, select access strategy challenges, and future considerations for improving access strategies. Data were gathered based on discussions with ten PDP access leaders, five PDP donors and four access experts[1], along with a review of access documents submitted by the interviewees. We found that access strategies are extremely variable. Strategies can be stand-alone or integrated into other documents, confidential or public, explicit or not. They may be developed internally, or supported by outside consultants. PDPs largely lack clear definitions of success for their access work, and the accompanying metrics to track their progress. Defining the PDP’s role in supporting post-licensure issues is a critical challenge in access planning. There is a clear tension between donor expectations for PDP involvement at the country-level limited to facilitate uptake of a licensed product, and PDP concerns that gaps in the access architecture will limit the potential impact of their products, possibly justifying a more active role. PDPs see global and country-level advocacy as important for building support for new products, and donors voiced concerns about the timing and intensity of outreach to potentially overburdened ministries of health. Going forward, we suggest that PDPs can more systematically develop their access strategies by differentiating between those access issues that are relevant to the whole portfolio, from those that will vary by product. Defining the portfolio-level issues will enable PDPs to focus their strategy work on the cross-cutting challenges, while creating product-specific plans with product development milestones. There may be opportunities for PDPs to collaborate in the assessment and action associated with some shared post-licensure gaps. Additional research would be needed to more concretely define what those shared activities might be.


[1] With Elizabeth Gardiner (TB Alliance), Florence Camus-Bablon (DNDi) & Don Douglas (PDVI)