Regional regulatory harmonisation initiatives: Their potential contribution to the newly established African Medicines Agency.

BACKGROUND: Key regulatory entities can serve as building blocks for the African Medicines Agency (AMA). The aim of this study is to demonstrate how the regional medicines regulatory harmonisation programmes could contribute to AMA's effectiveness and efficiency. METHODS: A literature search was conducted using key words to identify publications about the AMA, African Medicines Regulatory Harmonisation (AMRH) and East African Community Medicines Regulatory Harmonisation programmes (EAC-MRH) from 2009 to 2023. The EAC-MRH programme experience was used to highlight the benefits and challenges of African regulatory harmonisation. RESULTS: As the foundation for the AMA, the AMRH has established structures and workstreams to support its operationalisation, including 10 Technical Committees (TCs) and 5 Regional Economic Committees (RECs). Lessons learned from the EAC-MRH 10-year experience are being used to scale up regulatory harmonisation and could be of value to AMA harmonisation experience. CONCLUSIONS: As of June 2023, 35 of 55 countries have either signed and/or ratified the AMA Treaty, whilst 20 have neither signed nor ratified it. An effective AMA will need strong National Medicines Regulatory Authorities as well as Regional programmes and it is imperative for more well-resourced countries to ratify the treaty to ensure access to essential medical products and technologies for the African people.

Regulatory performance of the East African Community joint assessment procedure: The way forward for regulatory systems strengthening.

BACKGROUND: Seven national medicines regulatory authorities in the East African Community (EAC) have embraced regulatory reliance, harmonization and work sharing through the EAC Medicines Regulatory Harmonization programme. Measuring the performance of regulatory systems provides key baseline information to build on regulatory system-strengthening strategies. Therefore, the aim of the study was to evaluate the regulatory performance of the EAC joint scientific assessment of applications approved between 2018 and 2021. METHODS: Utilising a data metrics tool, information was collected reflecting timelines for various milestones including submission to screening, scientific assessment and communication of regional recommendations for biologicals and pharmaceuticals that received a positive regional recommendation for product registration from 2018 to 2021. RESULTS: Several challenges as well as possible solutions were identified, including median overall approval times exceeding the EAC 465-day target and median times to issue marketing authorisation following EAC joint assessment recommendation that far exceeded the 116-day target. Recommendations included establishment of an integrated information management system and automation of the capture of regulatory timelines through the EAC metric tool. CONCLUSIONS: Despite initiative progress, work is required to improve the EAC joint regulatory procedure to achieve regulatory systems-strengthening and ensure patients' timely access to safe, efficacious and quality medicines.

Weekend Carotid Endarterectomies are Not Associated with a Greater Risk of Stroke and/or Death in Australia and New Zealand.

BACKGROUND: Data from multiple surgical studies and settings have reported an increase in adverse events in patients admitted or treated on weekends. The aim of this study was to investigate short-term outcomes for patients undergoing carotid endarterectomy (CEA) in Australia and New Zealand based on the day of surgery. METHODS: This is a retrospective observational cohort study. Analysis of 7,857 CEAs recorded for more than 4 years in the Australasian Vascular Audit database was performed. Multivariate logistic regression was used to compare the following outcomes between CEAs performed during the week and on the weekend: (1) in-hospital stroke and/or death; (2) other postoperative complications; and (3) shorter (2 days or less) length of stay (LOS). RESULTS: A total of 7,857 CEAs were recorded, with significantly more procedures performed during the week (n = 7,333, P < 0.001). There was no statistically significant difference in the frequency of stroke and/or death or other complications between CEAs performed during the week or on the weekend (P = 0.294 and P = 0.806, respectively). However, there was a significant difference in LOS for procedures performed during the weekend, with more of these patients being discharged within 2 days compared with procedures performed during the week (56.8% vs. 51.5%; P = 0.003). Multivariable logistic regression found no effect of day of the week on the odds of postoperative stroke and/or death (P = 0.685). Day of surgery was also not associated with greater odds of other complications (P = 0.925). However, CEAs performed by nonconsultants had significantly lower adjusted odds of other complications (3.1% vs. 4.1%; P = 0.033). The adjusted odds of having a shorter LOS were significantly greater for operations taking place on the weekend (P = 0.003). CONCLUSIONS: In Australia and New Zealand, there appears to be no disadvantage to performing CEA on the weekend, in terms of stroke and/or death. Level of experience of the primary operator does not affect rates of stroke and/or death after CEA. Weekend CEA is associated with a shorter hospital LOS.

Nellix Endobag rupture associated with a fatal outcome.

Endovascular treatment of a type IA endoleak was conducted using a Nellix chimney graft technique for an expanding abdominal aortic aneurysm in an 84-year-old man. During the procedure, a polymer leak occurred from one of the endobags. Postoperatively, the patient developed hemodynamic instability and a swollen leg on the side of the leaking endobag, resulting in a fatal outcome.

Health Technology Assessment (HTA) Case Studies: Factors Influencing Divergent HTA Reimbursement Recommendations in Australia, Canada, England, and Scotland.

OBJECTIVES: To evaluate the national regulatory, health technology assessment (HTA), and reimbursement pathways for public health care in Australia, Canada, England, and Scotland, to compare initial Canadian national HTA recommendations with the initial decisions of the other HTA agencies, and to identify factors for differing national HTA recommendations between the four HTA agencies. METHODS: Information from the public domain was used to develop a regulatory process map for each jurisdiction and to compare the HTA agencies' reimbursement recommendations. Medicines that were reviewed by all four agencies and received a negative recommendation from only one agency were selected as case studies. RESULTS: All four countries have a national HTA agency. Their reimbursement recommendations are guided by both clinical efficacy and cost-effectiveness, and the necessity for patient input. Their activities, however, vary because of different mandates and their unique political, social, and population needs. All have an implicit or explicit quality-adjusted life-year threshold. The seven divergent case studies demonstrate examples in which new medicine-indication pairs have been rejected because of uncertainties surrounding a range of factors including cost-effectiveness, comparator choice, clinical benefit, safety, trial design, and submission timing. CONCLUSIONS: The four HTA agencies selected for inclusion in this study share common factors, including a focus on clinical efficacy and cost-effectiveness in their decision-making processes. The differences in recommendations could be considered to be due to an individual agency's approach to risk perception, and the comparator choice used in clinical and cost-effectiveness studies.

Mortality outcomes of ruptured abdominal aortic aneurysms and rural presentation.

OBJECTIVES: Centralisation of vascular surgery services has coincided with a move towards endovascular repair of ruptured abdominal aortic aneurysms with the goal to improve patient outcomes. The aim of this study was to assess the effect of rural presentation and transfer times on survival from ruptured abdominal aortic aneurysm. DESIGN: A retrospective review. MATERIALS: All patients presenting with ruptured abdominal aortic aneurysm to public hospitals in Tasmania between July 2006 and April 2013. METHODS: Demographic data, Glasgow aneurysm score, Hardman index, transfer times, operative technique and 30-day mortality were collected from medical records. RESULTS: Over the study period 127 patients presented to public hospitals in Tasmania with ruptured abdominal aortic aneurysm. A total of 27 presented to north west hospitals where no vascular surgery service is provided (NWRH), 23 to a northern hospital where an intermittent vascular surgery service is provided (LGH) and 77 to the state tertiary vascular surgery service (RHH). Of these, 4 (14.8%) died at NWRH, 6 (26.1%) died at LGH and 43 (55.8%) died at RHH without operation. Of the 35 patients transferred from NWRH and LGH to RHH, 5 died without operation. Median time from presentation to theatre at RHH if transferred from NWRH was 6.25 hours, from the LGH 4.75 hours, compared to 2.75 hours when presenting directly to RHH. Open repair was performed in 41 patients and endovascular repair in 23 patients. Overall 30-day mortality in those treated at RHH was 26.6% (39.0% for open repair, 4.3% for endovascular repair). Mortality for intended operative patients initially presenting to non-RHH hospitals was 33.3% vs. 32.3% for those initially presenting to RHH. p Value 0.93. CONCLUSION: There was no clinical or statistical disadvantage to rural presentation and transfer for patients presenting with ruptured abdominal aortic aneurysm in Tasmania. Endovascular repair has a role despite long transfer times.

Factors influencing quality decision-making: regulatory and pharmaceutical industry perspectives.

PURPOSE: Currently, there is no qualified understanding of the influences, behaviours and other factors that impact the decision-making of individuals and organisations involved in the development of new medicines. The aim of this qualitative study was to investigate and identify the important issues that influence quality decision-making. METHODS: Semi-structured interviews were carried out with 29 senior decision-makers from the pharmaceutical industry and regulatory authorities. The study participants were invited to discuss and review their perception of decision-making within their organisation, its role in drug development and the regulatory review and their awareness and use of decision-making techniques and the impact and monitoring of decisions. RESULTS: The analyses (using NVivo 8(©) software) resulted in the identification of 32 major and 97 sub-themes that were consolidated into 19 overarching themes. These included items such as quality and validity of data, time considerations, organisational and cultural influences, analytical and logical approach, qualification and experience, subjective and personal considerations, political influences, precedents for similar previous decisions, understanding of the decision in question, impact analyses, audit trail, education and awareness, individual versus corporate decision-making and frameworks. Relationships between themes were identified. The 19 overarching decision-making themes were integrated into a framework for quality decision-making. CONCLUSION: This study has achieved its aim of exploring decision-making from the perspective of the individual and the organisation working in drug development and the regulatory review and has identified issues and considerations relating to making good quality decisions and allowed for the generation of a framework to aid quality decision-making.

Surviving an abdominal aortic aneurysm type II endoleak rupture without surgical intervention.

We describe a patient who survived a ruptured abdominal aortic aneurysm without any surgical intervention. The patient had previously had endovascular repair of the aneurysm and surveillance of a stable persistent type II endoleak. This case highlights the difficulties surrounding type II endoleak, its natural history, and the ongoing controversies of its management.

On-the-field performance of quintuple-play long-reach OFDM-based WDM-PON optical access networks.

In this paper the on-the-field performance of a WDM-PON optical access providing quintuple-play services using orthogonal frequency division multiplexing (OFDM) modulation is evaluated in a real fiber-to-the-home (FTTH) network deployed by Towercom operator in Bratislava (Slovakia). A bundle of quintuple-play services comprising full-standard OFDM-based signals (LTE, WiMAX, UWB and DVB-T) and an ad-hoc OFDM-GbE signal is transmitted in coexistence per single user. Both downstream and upstream transmission performances are evaluated in different on-the-field long-reach optical link distance configurations. Four wavelength multi-user transmission of quintuple-play OFDM services is demonstrated exceeding 60.8 km reach in standard single mode fiber.

Is there a need for a universal benefit-risk assessment framework for medicines? Regulatory and industry perspectives.

PURPOSE: To explore the current status and need for a universal benefit-risk framework for medicines in regulatory agencies and pharmaceutical companies. METHODS: A questionnaire was developed and sent to 14 mature regulatory agencies and 24 major companies. The data were analysed using descriptive statistics, for a minority of questions preceded by manual grouping of the responses. RESULTS: Overall response rate was 82%, and study participants included key decision makers from agencies and companies. None used a fully quantitative system, most companies preferring a qualitative method. The major reasons for this group not using semi-quantitative or quantitative systems were lack of a universal and scientifically validated framework. The main advantages of a benefit-risk framework were that it provided a systematic standardised approach to decision-making and that it acted as a tool to enhance quality of communication. It was also reported that a framework should be of value to both agencies and companies throughout the life cycle of a product. They believed that it is possible to develop an overarching benefit-risk framework that should involve relevant stakeholders in the development, validation and application of a universal framework. The entire cohort indicated common barriers to implementing a framework were resource limitations, a lack of knowledge and a scientifically validated and acceptable framework. CONCLUSIONS: Stakeholders prefer a semi-quantitative, overarching framework that incorporates a toolbox of different methodologies. A coordinating committee of relevant stakeholders should be formed to guide its development and implementation. Through engaging the stakeholders, these outcomes confirm sentiments and need for developing a universal benefit-risk assessment framework.

Assessment of the effectiveness and efficiency of the economic community of West African States Medicines Regulatory Harmonization initiative by the pharmaceutical industry.

Background: Following the establishment of Economic Community of West African States Medicines Regulatory Harmonization (ECOWAS-MRH) initiative in 2017, it was considered timely to carry out an evaluation of the current status of the initiative's operating model by the pharmaceutical industry users. This study examined the challenges being encountered and identified strategies that would strengthen the ECOWAS-MRH initiative moving forward. Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire was used to collect data from manufacturers who have submitted applications to the joint assessment procedure and had identified recommendations for improving the performance of the ECOWAS-MRH initiative. Results: Ten pharmaceutical manufacturer participants (innovator, generic foreign, generic local) all reported that harmonisation of registration requirements was a major benefit, allowing submission of the same dossier to multiple countries, reducing the application burden and saving time and resources. Additionally, receipt of the same list of questions from several countries enables the compilation of a single response package, resulting in shorter timelines for approvals compared to the individualised country responses. Another benefit of a harmonised registration process was the simultaneous accessibility of medicines in various markets. Key challenges included a lack of centralised submission and tracking, differences in regulatory performance of the national medical regulatory authorities, a lack of detailed information for applicants and a low motivation to use the ECOWAS-MRH route with a preference for other regulatory pathways in the ECOWAS member states. Conclusion: This study identified several approaches to increase the effectiveness of this initiative: the implementation of risk-based approaches such as use of reliance pathways; establishment of a robust information technology systems, building assessor capacity to facilitate processing and monitoring applications; and priority review of ECOWAS-MRH products.

Evaluation of Risk-Based Approaches to the Registration of Medicines: Current Status Among African Regulatory Authorities.

BACKGROUND: Despite the worldwide need for increased access to safe and effective medicines, there is a lack of innovative medicines in many low- to middle-income countries. On the African continent, this is partly due to capacity limitations of National Regulatory Authorities (NRAs). One important approach to address this issue is work sharing and regulatory reliance. Therefore, the aim of this study of regulatory authorities on the African continent was to identify which risk-based approaches are being used as well as their foreseen role in the future. METHODS: The study employed a questionnaire to identify which risk-based models are used for the regulatory approval of medicines and to determine which frameworks are in place to enable a risk-based approach, as well as to provide insight into the future direction for risk-based models. The questionnaire was sent electronically to 26 NRAs in the African Continent. RESULTS: Twenty-one authorities (80%) completed the questionnaire. Work sharing was the most commonly used model, followed closely by unilaterial reliance, information sharing, and collaborative review. These methods were perceived to be an effective and efficient use of resources, enabling faster medicine availability for patients. The unilateral reliance approach by the authorities included abridged (85%), verification (70%) and recognition (50%) models for a range of products. However, challenges included a lack of guidelines to undertake a reliance review together with resource constraints, while access to assessment reports was the most common barrier to using a unilateral reliance model. CONCLUSIONS: Many authorities in Africa have adopted a risk-based approach to medicines registration and created work sharing, unilateral reliance pathways and regionalisation models to facilitate the availability of medicines. The authorities believe that in future, assessment routes should move from stand-alone reviews to risk-based models. However, this study indicated that there would be challenges to implement this approach in practice, which would include improving resource capacity and the number of expert reviewers as well as implementing electronic tracking systems.

Evaluation of the impact of reliance on the regulatory performance in the South African Health Products Regulatory Authority: implications for African regulatory authorities.

Introduction: The World Health Organization (WHO) advocates the use of reliance practices to enable national regulatory authorities (NRAs) to improve patients' access to medicines. This study considered whether reliance review translates into swifter medicine authorization. Methods: Abridged review outcomes were examined for New Chemical Entity (NCE) and generic applications to the South African Health Products Regulatory Authority (SAHPRA) in Chemistry, Manufacturing and Controls (CMC) and clinical/bioequivalence (BE), as well as overall NCE authorization times. Results: SAHPRA NCE CMC review time was 91 days (abridged) vs. 179 days (full), applicant response time was 34 vs. 105 days, respectively, and there was a >2-fold time reduction for abridged vs. full CMC review (125 vs. 284 days). There was a 99-day decrease in clinical approval time through an abridged review (230 vs. 329 days) and a decrease in marketing authorization time for NCE abridged assessment (446 vs. 619 days). SAHPRA review time for generic applications was 97 days (abridged) vs. 191 days (full); applicant response time was 26 days (abridged) vs. 81 days (full) and there was a >2-fold time reduction for CMC and BE abridged vs. full review (122 vs. 272 days). Conclusion: These results clearly support World Health Organization recommendations for the use of reliance-based regulatory review to expedite the worldwide availability of safe, effective and needed medications.

Evaluation of the Food and Drugs Authority, Ghana Regulatory Review Process: Challenges and Opportunities.

PURPOSE: This study aimed to assess the current regulatory review process of the food and drugs authority (FDA) Ghana by identifying key milestones, target timelines, good review practices and quality decision-making practices and evaluating the overall regulatory performance from 2019 to 2021, as well as the challenges and opportunities for improvement. METHODS: The FDA Ghana representatives completed the optimising efficiencies in regulatory agencies (OpERA) questionnaire, including data identifying the milestones and overall approval times for all products registered by the FDA Ghana from 2019 to 2021. RESULTS: Of the new active substances approved from 2019 to 2021, 91% were biologicals processed by full or abridged reviews pathways. Timelines for these reviews were within authority targets but were longer compared with generics. Of generics approved from 2019 to 2021, 97% were pharmaceuticals processed by the full review pathway, with timelines within authority targets and shorter compared with new active substances. Regardless of the review model used, approval times for new active substances increased from 84 to 355 calendar days 2019-2021 due to the impact of the pandemic. Guidelines, standard operating procedures and review templates were in place and the majority of indicators for good review practices were implemented. Several quality decision-making practices were implemented, although currently there is not a systematic structured approach. CONCLUSION: The FDA Ghana monitors regulatory performance and currently meets its target timelines. To achieve World Health Organization Maturity Level 4 status, an electronic tracking system, benefit-risk assessment framework and template and the publication of assessment reports are recommended.

Cognitive and physiological responses in humans exposed to a TETRA base station signal in relation to perceived electromagnetic hypersensitivity.

Terrestrial Trunked Radio (TETRA) technology ("Airwave") has led to public concern because of its potential interference with electrical activity in the brain. The present study is the first to examine whether acute exposure to a TETRA base station signal has an impact on cognitive functioning and physiological responses. Participants were exposed to a 420 MHz TETRA signal at a power flux density of 10 mW/m(2) as well as sham (no signal) under double-blind conditions. Fifty-one people who reported a perceived sensitivity to electromagnetic fields as well as 132 controls participated in a double-blind provocation study. Forty-eight sensitive and 132 control participants completed all three sessions. Measures of short-term memory, working memory, and attention were administered while physiological responses (blood volume pulse, heart rate, skin conductance) were monitored. After applying exclusion criteria based on task performance for each aforementioned cognitive measure, data were analyzed for 36, 43, and 48 sensitive participants for these respective tasks and, likewise, 107,125, and 129 controls. We observed no differences in cognitive performance between sham and TETRA exposure in either group; physiological response also did not differ between the exposure conditions. These findings are similar to previous double-blind studies with other mobile phone signals (900-2100 MHz), which could not establish any clear evidence that mobile phone signals affect health or cognitive function.

Pharmaceutical Industry Evaluation of the Effectiveness and Efficiency of the ZaZiBoNa Collaborative Medicines Registration Initiative: The Way Forward.

Introduction: The common technical document (CTD) format harmonised the requirements for the registration of medicines, which had traditionally differed from country to country, making it possible for countries to collaborate and conduct joint reviews of applications. One such collaborative medicines registration initiative is the Southern African Development Community ZaZiBoNa, established in 2013. A recent study was carried out with the nine active member regulatory authorities of the ZaZiBoNa to determine their views on its operational effectiveness and efficiency. Having obtained the authorities' views, the aim of this study was to evaluate the effectiveness and efficiency of the current operating model of the ZaZiBoNa initiative including the challenges it faces as well as identifying opportunities for improvement from the applicants' perspective. Methods: Applicants who had submitted registration/marketing authorisation applications for assessment under the ZaZiBoNa initiative during 2017-2021 were recruited into the study. Data was collected in 2021 using the Process, Effectiveness and Efficiency rating questionnaire (PEER-IND) developed by the authors. The questionnaire was completed by a representative responsible for ZaZiBoNa submissions in each company. Results: The pharmaceutical industry was of the view that the ZaZiBoNa initiative has achieved shorter timelines for approval of medicines, resulting in increased availability of quality-assured medicines for patients in the SADC region. Harmonisation of registration requirements and joint reviews have reduced the workload for both the pharmaceutical industry and the regulatory authorities. Some of the challenges identified were the lack of a centralised submission and tracking system, and the lack of information for applicants on the process for submission of ZaZiBoNa dossiers/applications in the individual countries, including contact details of the focal person. The establishment of a regional unit hosted in one of the member countries to centrally receive and track ZaZiBoNa dossiers/applications was identified as the best strategy for moving forward in the interim with the long-term goal being the establishment of a regional medicines authority. Conclusion: There was consensus between the pharmaceutical industry and the regulatory authorities as to the way forward to improve the effectiveness and efficiency of the ZaZiBoNa initiative. Implementation of the recommendations identified in this study will lead to enhanced regulatory performance.

Regulatory Authority Evaluation of the Effectiveness and Efficiency of the ZaZiBoNa Collaborative Medicines Registration Initiative: The Way Forward.

Introduction: ZaZiBoNa, the work-sharing initiative in the Southern African Development Community (SADC) that has been in operation for 8 years has successfully assessed over 300 dossiers/applications, with an overall median time to recommendation of 12 months. All 16 SADC countries participate in the initiative as either active or non-active members. While the successes of ZaZiBoNa are evident, some challenges still exist. The aim of this study was to solicit the views of the participating authorities on the effectiveness and efficiency of the current operating model of the ZaZiBoNa initiative. Methods: Data were collected in 2021 using the Process, Effectiveness and Efficiency Rating (PEER) questionnaire developed by the authors. The questionnaire was completed by the focal person in each country and approved by the head of the authority. Results: ZaZiBoNa serves as a platform for work sharing, information exchange, capacity building and harmonisation of registration requirements. One of the benefits to regulators has been the improvement in the capacity to conduct assessments. Manufacturers have benefited from compiling one package (modules 2-5) for the initial submission as well as a single response package to the consolidated list of questions, which saves time and resources. Respondents were of the view that patients have benefited as the ZaZiBoNa has contributed to an improved availability and accessibility to quality-assured medicines. Some of the challenges identified were the inadequacy of resources and differences in time to the implementation of ZaZiBoNa recommendations by the individual countries. The establishment of a regional unit hosted in one of the member countries to enable centralised submission and coordination was identified as the best strategy to improve the effectiveness and efficiency of the initiative in the interim, with the long-term goal being the establishment of a regional medicines authority. Conclusion: The study identified the strengths of the ZaZiBoNa initiative as well as the opportunities for improvement. The recommendations made would further strengthen this initiative.