Evaluation of the review models and approval timelines of authorities participating in the East African Medicine Regulatory Harmonisation initiative: alignment and strategies for moving forward.

Introduction: Medicines regulatory harmonisation has been embraced by many national regulatory authorities (NRAs) to improve public health through faster availability of safe, high-quality, and effective medical products to patients and enhanced standardisation of technical guidelines and work sharing, leading to reduced cost to pharmaceutical companies. After ten years of implementing regulatory harmonisation by the East African Community Medicines Registration Harmonization (EAC-MRH) initiative, it is now imperative for participating NRAs to rely on each other to minimise duplication of use of limited resources. Major challenges in implementing reliance are the lack of clear registration processes and delays in the approval. The aim of this study was to compare review models, target timelines and data requirements used in assessing applications by EAC-MRH NRAs so as to align and propose strategies for improvement. Methods: A validated questionnaire that standardises and captures review processes was completed by the head of the medicine's registration division in each of the seven EAC-MRH NRAs. A country report based on the completed questionnaire was developed for each NRA and validated by the heads of the respective authorities. Results: Most applications received by all countries were for generics except Kenya, which received a significant number of new active substance applications (55 and 53 in 2020 and 2021). Mean approval times for generics using full review varied, with Tanzania's time declining for the three years. Target timelines for full review for the five countries ranged between 180 calendar days (Tanzania) to the highest 330 days (Zanzibar). The three countries (Kenya, Rwanda and Uganda) utilising the verification review model had a target timeline of 90 days. All six authorities conducted abridged reviews and fast-track assessments through a priority review track. The common technical document format was mandatory for applications in all authorities. The target timeline for key milestones in the review process varied for each country with a few similarities. Discussion: The study has provided a baseline for review models, target timelines and data requirements utilised in assessing applications for registration by EAC-MRH NRAs. Implementing the recommendations from this study will enable the NRAs to align and improve their registration processes.

Evaluation of good review practices in member authorities of the East African Medicines Regulatory Harmonisation initiative: strategies for alignment with African medicines agency.

Introduction: The East African Community Medicines Regulatory Harmonisation (EAC-MRH) programme was established to address challenges faced by national regulatory authorities (NRAs) of the region. Work sharing through joint assessments and inspections was adopted to manage limited resources and capacity; however, NRA good review practices (GrevP) are also a key determinant to success. This study evaluated GReVP among the EAC-MRH NRAs and mapped required strategies for countries to align themselves with the African Medicines Agency (AMA). Methods: A validated questionnaire (Optimising Efficiency in Regulatory Agency-OpERA) that standardises and captures review processes was completed by the head of the medicines registration division in each NRA. A country report based on the completed questionnaire was developed for each NRA and validated by the heads of the respective authorities. Results: The population and size of the NRAs vary and four of the countries have semi-autonomous authorities and three NRAs are autonomous. The Burundi and South Sudan authorities were fully government funded, Kenya and Uganda entirely from fees, while Rwanda, Tanzania and Zanzibar were partially funded from different sources. All authorities except South Sudan, which does not receive or review applications had backlogs. Authority fees varied based on the different application categories. Key milestones for standardised regulatory processes are implemented in all authorities. Queue times range from a few weeks to about one year. Three NRAs use internal technical agency staff for scientific assessments and three use both internal and external experts. Clock stop time varies and target timelines for review committee range from one day to three months. All the NRAs implement some best practices on quality measures, transparency and communication. Some have activities for transparency improvement but with minimal attention to training and education. Most employ some quality decision-making practices. Discussion: GrevP in EAC-MRH NRAs still needs to be improved and it is imperative that these authorities streamline and harmonise their practices. Increasing human resources and an investment in training and education of staff will enable the implementation of all measures for GRevP. This is vital, as the effectiveness and efficiency of the AMA will depend on the strength of these NRAs.

Comparison of PD-L1 assays in head and neck carcinoma.

Programmed cell death-ligand 1 (PD-L1) expression is a predictive biomarker for response to immune checkpoint inhibitor in head and neck squamous cell carcinoma. Given the range of antibodies and platforms for PD-L1 testing, it is essential to understand the performance of different staining and scoring methods. PD-L1 expression in 156 head and neck mucosal squamous cell carcinoma (HNmSCC) cases at Asan Medical Center was assessed using 106 tissue microarray (TMA) cores and 50 whole slides. Three standardised PD-L1 assays (22C3 pharmDx, SP263, and 28-8 pharmDx) and one laboratory-developed test (22C3 LDT) were evaluated: the combined positive score (CPS) with ≥1, ≥20, and ≥50 cut-offs, and the tumour positive score (TPS) with ≥1%, ≥20%, ≥50% cut-offs. Concordance on a continuous scale among the assays was good to excellent for CPS [intraclass correlation coefficient (ICC) range 0.73-0.94] and TPS (ICC range 0.70-0.94) and in both TMA and whole slides cohorts. Stratification by variable cut-offs demonstrated moderate to good agreement among most assays, as analysed by Gwet's AC1. PD-L1 expression was significantly correlated with tumour location using the 22C3 pharmDx assay (CPS, p=0.014; TPS, p=0.033). Notable concordance was found among PD-L1 assays, suggesting their potential interchangeability in HNmSCC.

Measuring bile acids: Are we all talking the same language?

In this paper, we discuss the Bile Acid Comparison and Harmonisation project, a sub-study of the Trial of URsodeoxycholic acid vs RIFampicin in early-onset severe Intrahepatic Cholestasis of pregnancy, giving an overview of the current state of affairs for total bile acid measurements.

Blood Harmonisation of Endoscopic Transsphenoidal Surgical Video Frames on Phantom Models.

Physical phantom models have been integral to surgical training, yet they lack realism and are unable to replicate the presence of blood resulting from surgical actions. Existing domain transfer methods aim to enhance realism, but none facilitate blood simulation. This study investigates the overlay of blood on images acquired during endoscopic transsphenoidal pituitary surgery on phantom models. The process involves employing manual techniques using the GIMP image manipulation application and automated methods using pythons Blend Modes module. We then approach this as an image harmonisation task to assess its practicality and feasibility. Our evaluation uses Structural Similarity Index Measure and Laplacian metrics. The results we obtained emphasize the significance of image harmonisation, offering substantial insights within the surgical field. Our work is a step towards investigating data-driven models that can simulate blood for increased realism during surgical training on phantom models.

Floating microplastics in Svalbard fjords: High spatial variability requires methodological consistency in estuarine systems.

Microplastic pollution was studied in surface waters of Isfjorden, Svalbard in July 2021 as a part of an international regional harmonisation exercise. Surface microplastics (0.5-5 mm) were sampled with a neuston net in triplicate per study site in several branches of Isfjorden, covering populated and unpopulated fjords. High spatial variability of microplastic abundance (0-32,700 items/km2) was observed within a single fjord resulting from the hydrodynamic pattern formed through the interaction of surface currents, freshwater runoff, and wind conditions. Maximum microplastic abundance was not correlated with the distance from the local source and was instead defined by local small-scale hydrodynamics. Future recommendations for correct assessment of surface microplastics concentration in estuarine environments are presented.

Data and Process Harmonisation of Multi-National, Multi-Site Research Data.

To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.

Facing further challenges in cancer data quality and harmonisation.

This article highlights the recent and ongoing activities of European population-based cancer registries (PBCRs) in data quality and harmonisation in the framework of the collaboration between the European Network of Cancer Registries (ENCR) and the Directorate-General Joint Research Centre (JRC), the science and knowledge centre of the European Commission. The article concludes the Frontiers in Oncology's Research Topic "Joining Efforts to Improve Data Quality and Harmonization Among European Population-Based Cancer Registries", which has been an opportunity for several European researchers to share their experience on cancer data quality and harmonisation. Such experience will be helpful for PBCRs in view of future challenges and opportunities in cancer epidemiology, with a few examples discussed in the present article.

Comparison of Three Regional Medicines Regulatory Harmonisation Initiatives in Africa: Opportunities for Improvement and Alignment.

BACKGROUND: The African Medicines Regulatory Harmonisation (AMRH) Initiative was formed in 2009 and subsequently, three regional initiatives (East African Community Medicines Regulatory Harmonisation [MRH], Southern African Development Community [SADC]/ZaZiBoNa MRH, and the Economic Community of West Africa States MRH) were established. As these initiatives serve as a foundation for the African Medicines Agency (AMA), the aim of this study was to compare their operating models, successes and challenges to identify opportunities for improvement and alignment. METHODS: A mixed method approach was used for the data collection using a questionnaire, the Process, Effectiveness and Efficiency Rating (PEER), developed by the authors specifically for this study and semi-structured interview techniques. There were 23 study participants (one from each agency of the member countries of the three regions). It was hoped that data generated from this study would lead to a series of recommendations, which would then be ratified by the regulatory authorities. RESULTS: Most respondents stated that AMRH contributed to the strengthening of regulatory systems and harmonising regulatory requirements across economic regions of Africa, potentially resulting in improved access to quality-assured medicines. Although established at different times and at the discretion of each region, the marketing authorisation application review processes are largely similar, with a few differences noted in the eligibility and submission requirements, type of procedures employed, the timelines and fees payable. The challenges identified in the three regions are also similar, with the most noteworthy being the lack of a binding legal framework for regional approvals. CONCLUSION: In this study, we compared the process, successes and challenges of these three regional harmonisation initiatives in Africa addressing the areas of legal frameworks, information management systems, the accessibility and affordability of medicines and reliance that will bring greater alignment and efficiency in their operating models, thereby strengthening the foundation of the soon-to-be-operationalised AMA.

C-Reactive Protein and Brain Natriuretic Peptides Harmonization.

The harmonization of laboratory biomarkers is pivotal in ensuring consistent and reliable diagnostic outcomes across different clinical settings. This systematic review examines the harmonization of C-Reactive Protein (CRP) and N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) measurements, both of which are jointly utilized in the diagnosis and management of cardiovascular diseases. To identify relevant studies, we searched the PubMed electronic database using specific medical subject headings and keywords such as C-Reactive Protein, CRP, high sensitivity C-Reactive Protein (hs-CRP), N-terminal pro B-type natriuretic peptide, and NT-proBNP, focusing on publications from June 1 to September 26, 2021. The query filtered studies to include only those in English involving human subjects. From our search, 97 articles met the inclusion criteria and were included for in-depth analysis. Despite their widespread use, significant variability remains in the measurements of CRP and NT-proBNP due to a lack of standardized pre-analytical, analytical, and post-analytical practices. This review highlights the consequences of this variability on clinical decision-making and patient outcomes and emphasizes the need for international standards and guidelines to achieve better harmonization. Our findings advocate for the establishment of universal protocols to enhance the reliability of these biomarker measurements across different clinical environments, ensuring improved healthcare delivery.