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.

A Proposed Regulatory Review Model to Support the South African Health Products Regulatory Authority to Become a More Efficient and Effective Agency.

BACKGROUND: National regulatory agencies of various sizes and maturity levels, including the South African Health Products Regulatory Authority (SAHPRA), have had to revise systems and re-engineer processes in order to adapt to the new regulatory environment and increase the effectiveness of regulatory operations. This study aimed to develop a new regulatory review model for improved regulatory performance, underpinned by the parameters of the World Health Organization Global Benchmarking Tool (WHO GBT) that support strengthening of regulatory systems. METHODS: A new enhanced model for regulatory review, was developed based on the key recommendations from 6 studies, previously conducted by the authors, that were identified as fundamental elements in enhancing regulatory performance. The elements selected to define the new regulatory review model were endorsed through the integration of the parameters of the WHO GBT that, when embedded within regulatory systems, support enhanced regulatory performance. RESULTS: Opportunities for improvement in regulatory performance were identified and include quality measures; monitoring and evaluating review times; a risk-based evaluation; transparency and communication; and training and education. An improved model for the South African regulatory review and benefit-risk (BR) assessment supported by quality decision-making was proposed as well as recommendations for the application of risk-stratification strategies, strengthening of reliance networks, reinforcing good regulatory practices (GRPs) and enhancing transparency. CONCLUSION: If implemented the proposed improved regulatory model may pave the way towards more efficient and transparent, streamlined review processes, coupled with increased consistency, evidence-based decision-making practices, reduced timelines and improved patients' access to new medicines in South Africa.

Can Standardisation of the Public Assessment Report Improve Benefit-Risk Communication?

BACKGROUND: National regulatory authorities (NRAs) make the decision to register a medicine based on an assessment of its benefits and risks and publicly available assessment reports are used as a tool to communicate the basis for the decision. The Universal Methodology for Benefit-Risk Assessment (UMBRA) has also been used to effectively communicate the basis of regulatory decisions. Many NRAs in emerging markets place reliance on the public assessment reports (PARs) of reference agencies to inform about their own regulatory decisions. However, PAR users often criticise the redacted nature of PARs and may be challenged in identifying key benefits and risks, value judgements, and benefit-risk (BR) trade-offs. METHODS: PARs for ertugliflozin l-pyroglutamic acid, erenumab, and durvalumab published by regulatory bodies in Australia, Europe, Canada, and the United States were compared with the validated UMBRA Benefit-Risk Template to evaluate the BR decision documentation. Published validation of UMBRA included report of a consortium of four regulatory authorities in Australia, Canada, Switzerland, and Singapore indicating that their clinical assessment templates were modified to align with the UMBRA approach. A focus group discussed the use of PARs as potential knowledge management tools for stakeholder understanding of regulatory decision making. The South African Health Product Regulatory Authority (SAHPRA) approach to document and communicate the BR decisions was evaluated. RESULTS: Results indicate key elements to include in the PARs including regulatory history, an effects table and a record of the strengths and uncertainties for each benefit and risk. Focus group participants agreed that a harmonised PAR template would support improved regulatory decision-making transparency. SAHPRA communication of BR decisions could be improved through the use of the UMBRA BR Template as a guidance for BR assessment and the basis of the South Africa public assessment report format. CONCLUSION: SAHPRA's use of a structured template that supports transparent and quality decision making could have a major impact in ensuring consistency in the BR assessment of new medicines. The implementation of this effective approach for communicating BR decisions will advance agency goals of being a trusted, responsive, accountable regulatory body in which all healthcare stakeholders may rely on with confidence.

Evaluation of the Performance of the South Africa Regulatory Agency: Recommendations for Improved Patients' Access to Medicines.

BACKGROUND: Timely access to new medicines may be addressed through strengthening of registration efficiencies and timelines by establishing and refining value-added registration processes, resources, and systems. The aims of this study were to evaluate the timelines of the milestones of the South African review process and the overall approval process for new active substances (NASs) in 2015-2018 and to provide recommendations for improved patients' access to new medicines through timely registration. METHODS: Data identifying the milestones and overall approval times for NASs registered by the South African Agency during 2015-2018 were collected and analyzed. RESULTS: The most NASs (42) were approved in 2017 and the least (15) in 2018. The shortest median approval time (1218 calendar days) was achieved in 2015 and the longest (2124 days), in 2018. All applications were reviewed using the full review process, and 16/99 (16%) were assigned priority status and were reviewed and approved through the fast track review. CONCLUSIONS: While the extensive delays in NASs approvals in South Africa may be attributed to inefficient operational processes, resource constraints, and as an increased number of applications for registration, the newly established South African Heath Products Regulatory Agency has re-engineered and streamlined its regulatory review process, which has been piloted and will be enhanced prior to final implementation. Among recommendations for improvement, SAHPRA should consider measurement and monitoring of milestones, facilitated regulatory pathways, implementing a reliance strategy, and a quality management system.

Implementation of a Framework for an Abridged Review Using Good Reliance Practices: Optimising the Medicine Regulatory Review Process in South Africa.

BACKGROUND: This study sought to identify criteria and current practices for implementing an abridged review process and understanding barriers and enablers in utilizing reliance models and to offer recommendations for the implementation of an abridged review process in South Africa based on good reliance practices (GRelP). METHODS: A questionnaire was completed by six national regulatory authorities (NRAs) to determine criteria and current practices for implementing an abridged review process. In addition, two focus group discussions were conducted on the practical implementation of an abridged review process based on GRelP. RESULTS: Participating NRAs indicated that reliance would be placed on one reference agency. Applications submitted to NRAs for an abridged review had to be identical to those submitted to the reference agency. Unredacted reference agency assessment reports would be required to facilitate the abridged review process. A full technical dossier would also be required, but only parts would be assessed during the abridged review. Focus groups indicated that abridged review elements had been identified and should be considered in implementing GRelP. CONCLUSIONS: NRAs strive to improve regulatory performance and accelerate approval times; however, many continue to face challenges due to resource constraints. Increasing workloads, advancing technologies, and limited expertise require NRAs to leverage regulatory convergence initiatives, collaborative registration procedures, and functional regional, continental and international networks to fulfil regulatory mandates. Recommendations for the implementation of an abridged review process and a framework for GRelP have been made with a view to optimise regulatory review processes in South Africa.

The South African Medicines Control Council: Comparison of Its Registration Process With Australia, Canada, Singapore, and Switzerland.

Introduction: Comparisons between regulatory authorities of similar size and regulatory characteristics facilitate value-added benchmarking and provide insight into regulatory performance. Such comparisons highlight areas for improvement as authorities move toward achieving their regulatory goals and stakeholders' demands. The aims of this study were to compare the registration process and the regulatory review model of the South African Medicines Control Council (MCC) to that of four other similar-sized regulatory authorities and to identify areas for improvement that may inform recommendations to the South African Health Products Regulatory Authority (SAHPRA) as it looks to re-engineer and enhance the registration process in South Africa. Methods: A questionnaire describing the organisational structure, the registration process, good review and decision-making practices of the MCC was completed by the author (AK) for the purpose of this study and validated by the Registrar of the MCC. Similar questionnaires were also completed and validated by Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada, Singapore's Health Science Authority (HSA) and Switzerland's Swissmedic. Results: A comparison of the MCC regulatory process with the four comparative agencies indicated that they all have similar requirements and employ a full-review model although the timelines for the MCC were considerably longer. However, similar quality measures were implemented by all authorities as part of their good review practices (GRevP) including prioritising transparency, communication, continuous improvement initiatives and training. Conclusion: Comparisons made through this study provided insight into the areas of the MCC registration process that may be improved and have informed recommendations to SAHPRA including the implementation of facilitated regulatory pathways, definition of targets for key milestones in regulatory review and formal implementation and monitoring of GRevP. In order to build quality into the review process the application of a standardised template for the clinical assessment of medicines such as the Universal Methodology for Benefit-Risk Assessment (UMBRA) could be considered as well as enhancing transparency and communication through the application of an electronic management system and the development of publicly available summaries for the basis of approval.

The South African Regulatory System: Past, Present, and Future.

The drive for improved regulatory systems and the establishment of a more effective regulatory framework in South Africa has been evident for the past two decades but despite political intentions and legislative revisions success has been limited to date. Efforts to address the increasing volume of applications that have been received have to date failed and resources have been stretched to capacity resulting in the development of a significant backlog and extended timelines for product registration. The promulgation of the recently amended Medicines and Related Substance Act of 1965 triggered the establishment of the South African Health Products Regulatory Authority (SAHPRA) as a separate juristic person outside of the National Department of Health to replace the former medicine regulatory authority the Medicines Control Council (MCC). The aim of this review is to provide the historical context supporting the new regulatory environment in South Africa and the transition from the MCC to SAHPRA. Key recommendations to SAHPRA to ensure the full potential of the new regulatory environment in South Africa include: establishing a quality management system to safeguard accountability, consistency and transparency and to streamline the implementation of good review practices including quality decision-making practices and benefit-risk assessment; the measurement and monitoring of regulatory performance, targets for overall approval time and key review milestones to instill a culture of accurate metrics collection and measurement of key performance indicators and their continuous improvement and the employment of a risk-based approach to the evaluation of medical products and codify the use of facilitated regulatory pathways in policy and culture. The application of a risk-based approach to regulatory review commensurate with a product's risk to patients will facilitate the application of increased resources for pharmacovigilance activities and to support the reliance and recognition of reference agencies.

A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis.

Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 - 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB.