Concept and research

During the concept and research phase, the developer investigates the business opportunity for the potential diagnostic product and evaluates whether there is any merit in pursuing it. One of the first steps in the process is to clearly define the need for a diagnostic tool by understanding the healthcare problem: the extent of the diagnostic gap and the limitations of existing diagnostic procedures, the context in which this problem occurs, the various factors affecting it and the estimated impact of the proposed diagnostic tool.11 Estimating the impact of diagnostics, however, becomes challenging in the absence of robust data on the disease burden, patient accessibility to healthcare facilities, the characteristics of these facilities and current and future treatment practices.4 5 12

The TB community has addressed this gap by providing a website that directs developers to online resources on the TB disease burden and treatment landscape and pipeline (see more at http://www.tbfaqs.org). Modelling studies such as the Nature series commissioned by the Bill and Melinda Gates Foundation used multiple data sources and made key assumptions in order to define the health impact of improved access to TB, pneumonia and HIV diagnostics.2 12 As demonstrated in the particular case of TB, collective effort to interview and gather input from multiple stakeholders, including patients, clinicians, experts from national TB programme and researchers, is important in developing a better understanding of the diagnostic need.13 Once the need is defined and a product concept to meet the need is created, the developer selects the technology(ies) that will be incorporated into the product. Demonstrating initial feasibility of the technology(ies) and proof of concept is a key decision criterion to move to the next phase of development.

Market activities focus on evaluating whether there is a commercial opportunity to meet the need. The importance of identifying and understanding all key stakeholder goals and preferences cannot be overemphasised. Developers often need to engage a diverse and complex network of stakeholders in multiple global and national entities (table 2).11 14 15 Given that those who might have the authority to decide whether to adopt a product are not necessarily those who purchase or use the product,5 input from all actors is critical from very early in the development process and throughout all phases. A comprehensive stakeholder analysis sets the stage for other activities, such as further understanding and defining user needs and product value propositions from different perspectives or developing policy and advocacy engagement strategies. Initial communication with WHO programme offices or national country programmes is required to identify whether there is a need for a policy change or to monitor potential policy changes that might impact how and whether to move forward with development.16

Market research is conducted to better understand the projected growth, size and share of the market(s) in which the product will be sold, how the product will be distributed to the end user, customer needs and preferences and the product’s competitive advantage.7 8 These activities inform others, such as development of the marketing plan, user-requirements document and the business case. The business case provides evidence to justify the need for the new diagnostic product and why pursuing its development will be a viable business opportunity. Developers also prepare a financial model that provides details around the initial investment cost, projected sales, payback period and breakeven point and other investment performance considerations, such as whether the efforts of developers, are likely to yield an acceptable return on investment. Typically, the business case and financial model are updated throughout the development process as more information becomes available and the decision to continue with development is re-evaluated at the end of each development phase.

Product feasibility, definition and planning

Once the decision to initiate the business opportunity is approved, the developer further defines product requirements and specifications, evaluates the feasibility of meeting these requirements and identifies and mitigates technical and commercial risks to development. Customer needs and preferences that are identified during the concept and research phase are finalised as part of the user-requirements document and translated into product requirements (also known in global health as the target product profile or TPP). The TPP specifies the use case, that is, the context in which the diagnostics will be used (target population, desired specimen type, intended use of the test in clinical decision making and healthcare level where the test will be used), and covers the key performance and operational characteristics of the product to meet the needs of the use case (eg, expected sensitivity and specificity, turnaround time for test results, throughput and physical infrastructure requirements).17

Given that elements such as manufacturability, cost, distribution and product support greatly affect success, it is vital at this stage to consult delivery stakeholders (manufacturers if different from developer, procurers and distributors) to create realistic TPPs that are well aligned with the real implementation and scale-up needs.6 For example, challenges around affordability might require developers to explore technologies and formats with very low manufacturing costs in order to deliver the required product performance at significantly lower prices. In order to encourage and facilitate the development of diagnostics suitable for LMICs, the WHO and international non-governmental organisations (NGOs) such as the Foundation for Innovative New Diagnostics (FIND) and PATH (formerly the Program in Applied Technology and Health) have increasingly been involved in the development and publication of diagnostics TPPs.18 19 The International Diagnostics Center has published several TPPs for HIV diagnostics on their website (http://www.idc-dx.org/themes/development-and-evaluation/target-product-profiles), and more recently, Médecins Sans Frontières (MSF), FIND and WHO have worked closely with end users through a consensus effort to develop a TPP for a multi-analyte platform to diagnose febrile illness (http://www.who.int/medicines/TPP_intro_20171122_forDistribution.pdf).

During this phase, the developer also prepares clinical and regulatory, manufacturing and marketing and sales plans to meet development and implementation milestones. The marketing and sales plan addresses the target countries or geographies in which the product will be rolled out; develops sales and distribution strategies, including customer-service options (eg, user training, external quality-assurance programmes, installation and maintenance of instrumentation, calibration and repair)14 and defines the overall marketing strategy including advocacy and stakeholder engagement plans.

Various factors influence how a product is brought to market, such as available funding, market size, probability of success, infrastructure, policy guidelines and willingness of countries to adopt the product; there is no one-size-fits-all sales and distribution strategy. Products might be sold directly to governments, global funders or procurers (eg, the Global Fund to Fight AIDS, Tuberculosis and Malaria, commonly referred to as the “Global Fund”) or to NGOs that manage a network of health facilities. In formulating the roll out, sales and distribution and marketing plans, it is particularly useful to develop partnerships with key opinion leaders and implementers in countries that might be early adopters of the product. A comprehensive community engagement plan covering communication strategies with global and national policy makers, procurers and funders can aid in better defining in-country implementation strategies, translating policy into practice and assuring financial support.20 21

The initial intellectual property (IP) review can help identify third-party patent rights that might hinder commercialisation opportunities. Mitigation strategies might involve altering design requirements or looking into licensing agreement options.7 In certain cases for which the developer receives funding for development, funders might stipulate that this type of IP information, including the developer’s patent rights, are shared and managed by the funder. This ensures global access to the diagnostic product—broad accessibility of the product to target populations on appropriate price terms and in a timely manner. In such cases, developers might work together with a funder to define a global access plan in order to address factors such as IP, royalties and pricing structures that prevent access to products.22 23 The Bill and Melinda Gates Foundation is one example of a funder that works closely with developers to create global access strategies (http://globalaccess.gatesfoundation.org).

Design development and transfer to manufacturing

Formal development begins after product requirements are defined, technical feasibility is demonstrated, and high-level development and commercialisation plans are formulated by all constituents and stakeholders in the process. The goal of the development phase is to develop the final product, assure its manufacturability and lock in the design so that it is ready to be tested in the hands of the intended user. Implementation activities focus on updating and executing the marketing and sales and global access plans, while paying attention to launch requirements with long lag times.

During this phase, all components of the diagnostic product (eg, hardware, software, reagents, controls and other consumables) are finalised following the standard diagnostics product design optimisation and development process and then transferred to manufacturing. During the design process, the developer identifies an optimal product design that closely meets the desired performance specifications. End users and other stakeholders can provide valuable feedback on the prototype instrument in order to refine its design.6 24 In some cases, the relative importance of different features may need to be reassessed and used to make decisions on product design priorities.

Once the product components are fully optimised and developed, they are integrated into the overall system and formally tested during the verification process to assure that technical risks are mitigated and that performance requirements are met according to pre-established specifications. Also, during this stage, manufacturing and quality control documents and procedures for all components of the system are developed so that they can be produced in a pilot plant and/or manufacturing site, and their performance is verified to assure manufacturing consistency that meets all product requirements.

Validation, regulatory approvals and first launch

As the product enters the validation and regulatory approvals phase, the developer conducts multiple activities required for product launch: (1) conducting clinical validation studies and preparing submissions for regulatory approval; (2) aligning the product offering with the policies, guidelines and mechanisms of WHO, the country and the procurement agency and (3) executing the marketing and sales plan.

Regulatory pathways for diagnostic products targeted for LMICs are complex. The first step involves conducting clinical validation studies to generate the data required for regulatory approval to complement the in-house analytical studies. The clinical studies, conducted at LMIC clinical sites, demonstrate that the final product meets the clinical performance requirements and the requirements of the intended user. Developers selling into HICs initially obtain approval from stringent regulatory authorities (SRAs), as defined by the International Medical Device Regulators Forum (previously the Global Harmonization Taskforce; see http://www.imdrf.org/). Examples of SRAs include the Food and Drug Administration (USA) or the European Commission Directorate General (European Union), which oversees Conformitée Européene (CE) marking certification. SRAs provide regulatory approval of IVDs to be commercialised in their areas of jurisdiction.

The WHO Prequalification of In-Vitro Diagnostics Program (WHO DxPQ) provides global assurance on product quality, safety and performance in LMICs for (1) the UN and other procurement agencies to guide their purchasing decisions and (2) country national regulatory authorities that might not have sufficient capacity to fully evaluate the products and manufacturing sites. The WHO DxPQ process was recently revised; under the new process, products that are approved by an SRA have access to an expedited prequalification route. Presently, not all diagnostic products are assessed by the WHO DxPQ mechanism. For example, in the case of TB, diagnostic products are evaluated and endorsed by the WHO Strategic and Technical Advisory Group for Tuberculosis (STAG-TB).25 26

In order to access LMIC markets, developers will increasingly need to register their products locally. The legal and policy framework and capacity for the regulation of diagnostic products in low-resource settings is still evolving. Regulatory standards and processes vary from country to country, which range from those with no formal system reliant on UN or other approvals to those with a well-resourced SRA. In many countries, local registration is often informed by international approvals, but developers are frequently required to carry out independent product registrations in different countries, often with diagnostic performance evaluations conducted by country-level laboratories. This requires careful planning, since duplicative evaluations and unclear registration requirements can delay or limit product introduction in certain geographies and disincentivise supplying LMIC markets. For example, in the case of Abbott’s PIMA CD4 test (previously Alere PIMA), over 20 independent evaluations were conducted within 3 years of its release.27

Overall, it should be acknowledged that work still needs to be done to better harmonise the regulatory process and to improve the criteria by which the products are evaluated to guarantee that they consistently meet their performance requirements when they are used by the intended users in the intended settings. There have been efforts to improve elements of the process by promoting regulatory harmonisation and collaborative approaches and new efforts are being pursued to expand these approaches;28 the WHO Regulatory Systems Strengthening Program, which is tasked with providing technical support to national regulatory authorities to improve capacity, is one such initiative.

Global and in-country policies and guidelines are also prerequisites for implementation of diagnostic products in the public sector. WHO programme teams develop the global policy recommendations, indicating what types of diagnostic products should be used, by whom (type of health worker), for whom (patient population) and for what (disease indication), based on a systematic review and grading of the evidence.29 The recently released WHO Essential Diagnostics List is also likely to play an increasing role in setting priorities for which test types are procured and implemented at the country level.30 The WHO also develops supporting guidelines, such as diagnostic-testing algorithms, interpretation guidance and patient-management strategies. Similarly, at the country level, national disease programmes make contextually relevant diagnostic policy recommendations and practice guidelines that can be adopted by the clinical community and can inform the implementation plan. Ministries of health, working with implementing and development partners, define the key activities, resources, roles and responsibilities required to prepare the country’s health system for a new product (table 3).31

Although development of a WHO diagnostic policy sometimes precedes and influences a country’s policy-development process, other factors may also play a role. These include local policies and laws that have implications for determining the types of tests that are used at a particular health facility level and by whom; local evidence of diagnostic performance and impact; adoption of intervention by countries that are considered ‘catalysts’ or ‘early adopters’; funding availability; technical capacity and presence of local advocates or champions. Note that in the case of a similar testing method, a new policy might not be needed; tests need only be registered or approved for use. If this is not the case, the manufacturer must work closely with the authorities to confirm that policies are in place to support the product launch.

There are multiple mechanisms by which diagnostic products can be procured and supplied, and developers will execute a product introduction and a marketing and sales plan based on target markets and procurers. While sale contracts in the private sector typically follow standard commercial rules, public-sector sale and distribution contracts are more complex and depend on the source of funds and the product demand. Public diagnostic procurement activities largely centre on HIV/AIDS, TB and malaria, which have well-established programmes that are mostly funded by national governments, with support from the Global Fund, the US government through the US President’s Emergency Plan for AIDS Relief (PEPFAR) and the US President’s Malaria Initiative (PMI), UN agencies and UNITAID (a global health organisation under WHO that largely funds interventions to address HIV/AIDS, hepatitis, tuberculosis, malaria and reproductive, maternal, newborn and child health).

Governments either obtain funding from local sources or from funders for wide-scale diagnostic public-sector procurement, creating very particular marketing dynamics for these diseases.20 Public-sector procurement usually follows a tender and bidding process that is governed by local legislation and/or funder regulations, if applicable. National procurement authorities are responsible for the procurement, storage and distribution of diagnostic products. Multiple distribution models exist whereby products are directly or indirectly distributed to health facilities, for example, through an intermediary such as district-level hospitals or private contractors.32

The Global Fund primarily awards grants to countries for the procurement of HIV, TB and malaria diagnostics that meet the Global Fund quality requirements (eg, WHO DxPQ, SRA approval or approval from an expert review panel). Depending on the nature of the grant agreement, countries can use their own procurement authorities and systems, select a procurement agent through a competitive process, use procurement agents selected by the Global Fund or participate in the Global Fund’s pooled procurement mechanism. The latter enables countries to benefit from negotiated prices through the bulk order of commodities for multiple grantees.

PEPFAR funds the procurement of HIV diagnostic products for PEPFAR-supported programmes through a pooled mechanism run by contracted procurement agencies. Diagnostics can be procured if they are registered for use in-country, are included in the national guidelines and meet USAID approval criteria—WHO DxPQ, FDA approval or approval by the US Centers for Disease Control and Prevention. Additional site-specific evaluations might also be required.

Post-launch surveillance and stable operations

Following launch of the product in the first country or countries, the developer’s customer service and/or technical-support organisations continuously monitor how the product is performing in the field and provide customer training and support to ensure that the product is performing effectively. The WHO Safety and Vigilance Program tracks reports of product failures and issues notifications to users (http://www.who.int/medicines/regulation/safety-vigilance/en/). The extent of postmarket surveillance for diagnostic products is currently limited but is expected to grow significantly.

Market uptake activities involve the coordinated execution of the developers’ marketing and sales plan according to the countries’ implementation plans (table 3). Integration and coordination of stakeholder activities is important for streamlining the implementation process to support an efficient scale-up. Manufacturing and distribution processes are optimised to improve overall performance from the commercial side. Pilot studies may initially be conducted as an opportunity for countries to evaluate the diagnostic intervention in an operational setting and to adjust the implementation plan as needed prior to scaling up to a larger number of health facilities. The experiences of early adopters and detailed analysis of positive and negative outcomes provide critical insights for the further implementation and scale-up of the product.20

Market uptake activities can often take years before the intervention is routinely integrated into practice. It is therefore critical to keep stakeholders engaged and to rapidly deliver results. This also serves as a useful strategy to attract more funding, given that scale-up and maintenance can be quite costly. Furthermore, ensuring ongoing supply of diagnostic products within the public sector requires routine forecasting and procurement planning by national laboratory departments, as well as innovation in procurement agreements. This is often conducted on an annual basis and in certain circumstances is supported by implementing partners and supply-chain experts. Novel supply-agreement mechanisms in LMICs—such as reagent rentals for instrument-based tests and long-term agreements—to support large-scale procurement of diagnostic products have been developed and implemented by partnerships among developers, implementers and funders. These are designed to mitigate risks for both developers and purchasers, and they require collaboration and partnership.