Transparency practices at the FDA: A barrier to global health.

Data sharing among regulators must be "business as usual".

Use of RWE to Inform Regulatory, Public Health Policy, and Intervention Priorities for the Developing World.

For low- and middle-income countries (LMICs) to benefit from real-world evidence (RWE)/real-world data (RWD) in both product registration ("regulatory") decision making and in product utilization policy ("policy") decision making, they need to overcome several challenges. They need to deploy more electronic health records systems (EHRs), adjust for confounder variables, build trust between stakeholders, and create laws and regulations for local generation of data that are assented for secondary use. The role of procurers and their use of RWE/RWD in the LMIC context likewise is in a state of ongoing development. Procurers of health products are strong players currently in the "access" chain as LMICs continue to work on strengthening governmental health technology assessment (HTA) bodies. Procurers' use of RWE is presently at an early stage and is mostly indirect, leveraging RWE results that are produced by researchers in high-income countries (HICs), often under considerably different regulatory and policy objectives and constraints compared to LMICs' epidemiology and priorities. Pending wider deployment of EHRs and other RWE sources, stakeholders must realize that populations from HIC RWE (i) can be devised to closely resemble phenotypic patterns in LMIC populations and (ii) can be analyzed to align with LMICs' unmet needs.

The case for an HIV cure and how to get there.

In light of the increasing global burden of new HIV infections, growing financial requirements, and shifting funding landscape, the global health community must accelerate the development and delivery of an HIV cure to complement existing prevention modalities. An effective curative intervention could prevent new infections, overcome the limitations of antiretroviral treatment, combat stigma and discrimination, and provide a sustainable financial solution for pandemic control. We propose steps to plan for an HIV cure now, including defining a target product profile and establishing the HIV Cure Africa Acceleration Partnership (HCAAP), a multidisciplinary public-private partnership that will catalyse and promote HIV cure research through diverse stakeholder engagement. HCAAP will convene stakeholders, including people living with HIV, at an early stage to accelerate the design, social acceptability, and rapid adoption of HIV-cure products.

Navigating facilitated regulatory pathways during a disease X pandemic.

In 2018, the Bill and Melinda Gates Foundation convened over thirty subject matter experts in clinical development, manufacturing, and regulatory assessment to determine how the development and approval of medical countermeasures could be accelerated in the event of Disease X. Disease X is the result of a presently unknown pathogen with epidemic or pandemic potential. A key opportunity to accelerate the scientific assessment and regulatory approval of medical countermeasures exists within efficient navigation of facilitated regulatory pathways. It was identified that not all stakeholders will be able to skillfully navigate the facilitated pathways offered by the various regulatory agencies during a public health emergency. To democratize this knowledge, we have written an overview of the facilitated approaches which have been developed and refined by Stringent Regulatory Authorities and the World Health Organization for the primary assessment of medical products. We discuss the conditions necessary for use of these approaches, scenarios in which certain pathways may be applicable, and the pros and cons of these approaches. We also address opportunities available to developers in, or developers who wish to access, low-income countries that may have nascent regulatory frameworks.

Eight years of the East African Community Medicines Regulatory Harmonization initiative: Implementation, progress, and lessons learned.

Jane H. Mashingia and colleagues reveal the progress made to date for the East African Community Medicines Regulatory Harmonization initiative.

Coming together to improve access to medicines: The genesis of the East African Community's Medicines Regulatory Harmonization initiative.

Hiiti Sillo and colleagues reveal how the East African Community's Medicines Regulatory Harmonization initiative improves access to important medicines in Africa.

Scientific considerations for global drug development.

Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Integrating pharmaceutical systems strengthening in the current global health scenario: three 'uncomfortable truths'.

The response to emergency public health challenges such as HIV, TB, and malaria has been successful in mobilising resources and scaling up treatment for communicable diseases. However, many of the remaining challenges in improving access to and appropriate use of medicines and services require pharmaceutical systems strengthening. Incorporating pharmaceutical systems strengthening into global health programmes requires recognition of a few 'truths'. Systems strengthening is a lengthy and resource-intensive process that requires sustained engagement, which may not align with the short time frame for achieving targets in vertical-oriented programmes. Further, there is a lack of clarity on what key metrics associated with population and patient level outcomes should be tracked for systems strengthening interventions. This can hinder advocacy and communication with decision makers regarding health systems investments. Moving forward, it is important to find ways to balance the inherent tensions between the short-term focus on the efficiency of vertical programmes and broader, longer-term health and development objectives. Global health programme design should also shift away from a narrow view of medicines primarily as an input commodity to a more comprehensive view that recognizes the various structures and processes and their interactions within the broader health system that help ensure access to and appropriate use of medicines and related services.

Pandemic Best Regulatory Practices: An Urgent Need in the COVID-19 Pandemic.

As large numbers of candidate drugs and vaccines for potential use in the coronavirus disease 2019 (COVID-19) pandemic are being investigated, medicine regulators globally must now make urgent, informed, contextually risk-1based decisions regarding clinical trials and marketing authorizations. They must do this with the flexibility demanded by the pandemic while maintaining their core risk assessment and public safety functions. We lay out the critical role of regulators in the current crisis and offer eight "pandemic best regulatory practices." These should support both the regulatory public heath imperative and assure timely patient access to effective, safe, quality products worldwide during this emergency-thus contributing to ending this pandemic as quickly, effectively, and safely as possible.

Recognizing that Evidence is Made, not Born.

Therapeutic product development, licensing and reimbursement may seem a well-oiled machine, but continuing high attrition rates, regulatory refusals, and patients' access issues suggest otherwise; despite serious efforts, gaps persist between stakeholders' stated evidence requirements and actual evidence supplied. Evidentiary deficiencies and/or human tendencies resulting in avoidable inefficiencies might be further reduced with fresh institutional cultures/mindsets, combined with a context-adaptable practices framework that integrates emerging innovations. Here, Structured Evidence Planning, Production, and Evaluation (SEPPE) posits that evidence be treated as something produced, much like other manufactured goods, for which "built-in quality" (i.e., "people" and "process") approaches have been successfully implemented globally. Incorporating proactive, iterative feedback-and-adjust loops involving key decision-makers at critical points could curtail avoidable evidence quality and decision hazards-pulling needed therapeutic products with high quality evidence of beneficial performance through to approvals. Critical for success, however, is dedicated, long-term commitment to systemic transformation.

Expanding global access to essential medicines: investment priorities for sustainably strengthening medical product regulatory systems.

Access to quality-assured medical products improves health and save lives. However, one third of the world's population lacks timely access to quality-assured medicines while estimates indicate that at least 10% of medicine in low- and middle-income countries (LMICs) are substandard or falsified (SF), costing approximately US$ 31 billion annually. National regulatory authorities are the key government institutions that promote access to quality-assured medicines and combat SF medical products but despite progress, regulatory capacity in LMICs is still insufficient. Continued and increased investment in regulatory system strengthening (RSS) is needed. We have therefore reviewed existing global normative documents and resources and engaged with our networks of global partners and stakeholders to identify three critical challenges being faced by NRAs in LMICs that are limiting access to medical products and impeding detection of and response to SF medicines. The challenges are; implementing value-added regulatory practices that best utilize available resources, a lack of timely access to new, quality medical products, and limited evidence-based data to support post-marketing regulatory actions. To address these challenges, we have identified seven focused strategies; advancing and leveraging convergence and reliance initiatives, institutionalizing sustainability, utilizing risk-based approaches for resource allocation, strengthening registration efficiency and timeliness, strengthening inspection capacity and effectiveness, developing and implementing risk-based post-marketing quality surveillance systems, and strengthening regulatory management of manufacturing variations. These proposed solutions are underpinned by 13 focused recommendations, which we believe, if financed, technically supported and implemented, will lead to stronger health system and as a consequence, positive health outcomes.

The cost of entry: An analysis of pharmaceutical registration fees in low-, middle-, and high-income countries.

BACKGROUND: Advances in pharmaceuticals offer improved health outcomes for a wide range of illnesses, yet medicines are often inaccessible for many patients worldwide. One potential barrier to making medicines available to all is the cost of product registration, the fees for regulatory review and licensing for the sale of medicines beyond the cost of clinical trials, if needed. METHODS AND FINDINGS: We performed a cross-sectional analysis of pharmaceutical registration fees in low-, middle-, and high-income countries. We collected data on market authorization fees for new chemical entities and for generic drugs in 95 countries. We calculated measures of registration fee size relative to population, gross domestic product (GDP), and total health spending in each country. Each of the 95 countries had a fee for registering new chemical entities. On average, the ratio of registration fees to GDP was highest in Europe and North America and lowest in South and Central America. Across individual countries, the level of registration fees was positively correlated with GDP and total health spending, with relatively few outliers. DISCUSSION: We find that, generally speaking, the regulatory fees charged by medicines regulatory authorities are roughly proportional to the market size in their jurisdictions. The data therefore do not support the hypothesis that regulatory fees are a barrier to market entry in most countries.

Optimized Medical Product Regulation in Mexico: A Win-Win for Public and Economic Health.

BACKGROUND: Medicines regulators, while performing a vital public health activity, are often perceived as both negative cost centers for governments and as impediments to innovation and economic development. The Mexican government recently undertook a regulatory optimization program focused on transforming the Mexican medicines regulatory pathway into one that is efficient, value-added, aligned with international norms, resource accountable, and one that protects and promotes public health, while also facilitating economic development. METHODS: To facilitate the implementation of a new national access to medicines policy, the national government and the Mexican medicines regulatory agency instituted a multifaceted series of regulatory and legal reforms, which are described in this paper. These reforms encompassed multiple aspects of the regulatory oversight of medicines: administrative processes, clinical trials oversight, reliance on market authorization information and reports (ie, "work products") of other trusted regulators, and validation of activities by both Pan American Health Organization (PAHO) and WHO. FINDINGS: These reforms have resulted in a marked positive impact on the availability of safe, effective, quality medicines at lower costs for Mexicans, both in the private and public sectors, while simultaneously facilitating expansion of the Mexican pharmaceutical industry. INTERPRETATION: The regulatory optimization approach undertaken by Mexico could be a useful model for other countries that are trying to provide appropriate public health protection to their citizens, facilitate access to needed quality medicines, and encourage local economic development.

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization.

BACKGROUND: The United Nations Millennium Development Goals galvanized global efforts to alleviate suffering of the world's poorest people through unprecedented public-private partnerships. Donor aid agencies have demonstrably saved millions of lives that might otherwise have been lost to disease through increased access to quality-assured vaccines and medicines. Yet, the introduction of these health interventions in low- and middle-income countries (LMICs) continues to face a time lag due to factors which remain poorly understood. METHODS AND FINDINGS: A recurring theme from our partnership engagements was that an optimized regulatory process would contribute to improved access to quality health products. Therefore, we investigated the current system for medicine and vaccine registration in LMICs as part of our comprehensive regulatory strategy. Here, we report a fact base of the registration timelines for vaccines and drugs used to treat certain communicable diseases in LMICs. We worked with a broad set of stakeholders, including the World Health Organization's prequalification team, national regulatory authorities, manufacturers, procurers, and other experts, and collected data on the timelines between first submission and last approval of applications for product registration sub-Saharan Africa. We focused on countries with the highest burden of communicable disease and the greatest need for the products studied. The data showed a typical lag of 4 to 7 years between the first regulatory submission which was usually to a regulatory agency in a high-income country, and the final approval in Sub-Saharan Africa. Two of the three typical registration steps which products undergo before delivery in the countries involve lengthy timelines. Failure to leverage or rely on the findings from reviews already performed by competent regulatory authorities, disparate requirements for product approval by the countries, and lengthy timelines by manufacturers to respond to regulatory queries were key underlying factors for the delays. CONCLUSIONS: We propose a series of measures which we developed in close collaboration with key stakeholders that could be taken to reduce registration time and to make safe, effective medicines more quickly available in countries where they are most needed. Many of these recommendations are being implemented by the responsible stakeholders, including the WHO prequalification team and the national regulatory authorities in Sub-Saharan Africa. Those efforts will be the focus of subsequent publications by the pertinent groups.

Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities.

OBJECTIVES: We assessed the characteristics of currently implemented expedited (facilitated) regulatory pathways (FRPs) used by national regulatory authorities (NRAs) in emerging economies to speed access to important new medicines. METHODS: We identified NRAs with FRPs through Thomson Reuters Cortellis Regulatory Intelligence and through agency Websites. We developed a list of 27 FRP characteristics. We categorised characteristics as procedural or substantive and based them on five sequential regulatory activities. FINDINGS: We assessed 29 countries with 33 FRPs. The regions with the characteristics described most extensively by their FRPs were the Middle East/North Africa and Eastern Europe. The Sub-Saharan African region included the FRPs that were least specific in describing characteristics. Overall, FRPs presented at least twice as many procedural as substantive characteristics. CONCLUSIONS: We observed diversity by region in FRP characteristics, suggesting a role for further engagement with emerging NRAs in their design and implementation. Common processes could advance regulatory alignment initiatives and help the WHO inform the development of novel, globally aligned accelerated development and regulatory pathways for products that fulfil serious unmet public health needs.Journal of Public Health Policy advance online publication, 10 March 2016; doi:10.1057/jphp.2016.8.

Medicines Adaptive Pathways to Patients (MAPPs): A Story of International Collaboration Leading to Implementation.

After nearly a decade of discussion, analysis, and development, the Medicines Adaptive Pathways to Patients (MAPPs) initiative is beginning to see acceptance from regulators, industry, patients, and payers, with the first live pilot project initiated under the guidance of the European Medicines Agency in 2014. Although it is a significant achievement to see the first asset being placed into human trials under an adaptive pathway, there is much to be learned regarding the multinational and multi-stakeholder effort that has driven the growing acceptance of MAPPs as a methodology and concept, as well as the need for continued and increasing international collaboration to foster the wider adoption of MAPPs. Changes in available science and technology, as well as a number of challenges in the current system, outlined in this paper, are transforming approaches to medicines development and approval. It is these challenges that have led directly to the groundbreaking MAPPs collaboration between the Massachusetts Institute of Technology Center for Biomedical Innovation's New Drug Development Paradigms Initiative, the EMA, patient, payer and health technology assessment groups, the European Federation of Pharmaceutical Industries and Associations, and the Innovative Medicines Initiative-a European public-private partnership. This article examines the development of MAPPs, from inception of the concept, to the establishment of this trans-Atlantic initiative, and examines challenges for the future.