Stuart Walker

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

To explore the current status and need for a universal benefit–risk framework for medicines in regulatory agencies and pharmaceutical companies.

A Universal Framework for the Benefit-Risk Assessment of Medicines Is This the Way Forward?

A universal framework for the evaluation of the benefit-risk assessment of medicines during development by pharmaceutical companies and in the regulatory review by regulatory authorities is considered of value, as it would result in the systematic structured approach to support transparency in decision making. Several organizations have developed frameworks over the past few years, including those recommended by pharmaceutical companies such as the PhRMA BRAT (Pharmaceutical Research and Manufacturers of America Benefit-Risk Action Team) and the BRAIN (Benefit-Risk Assessment in New and Old Drugs) as well as frameworks advanced by regulatory agencies, including the FDA 5-step framework and the EMA PrOACT-URL. However, a review of the criteria—including logical soundness, comprehensiveness, acceptability of results, practicality, specificity and sensitivity, presentation (visualization), and scope proposed for the development of a universal framework—demonstrated that all these different frameworks described can be incorporated into UMBRA (Universal Methodology for Benefit-Risk Assessment).

Development and Application of Scorecards to Assess the Quality of a Regulatory Submission and Its Review

An efficient review depends not only on timely approval but also on ensuring the quality of the process from construction of the dossier to the ultimate regulatory decision. Two scorecards were developed through a process of conceptualization, item generation, and reduction, as well as psychometric testing, for regulatory authorities to provide feedback to companies on the quality of their submissions while companies report to authorities on the quality of their review. The scorecards included more than 50 items grouped into 7 domains, including application format, content of the dossier, labeling, scientific advice, conduct of the review, communication, and overall assessment. The scorecards were then tested by 3 major regulatory authorities (Health Canada, Swissmedic, and Therapeutic Goods Administration, Australia) and 4 international pharmaceutical companies (AstraZeneca, GlaxoSmithKline, Novo Nordisk, and Pfizer). The study participants responded openly to requests for ratings on the quality of performance by the other parties based on retrospective reviews. The data gave insights into different perceptions of quality in relation to submitted data and their respective review procedures. The findings showed the value and applicability of the proposed scorecards.

Evaluating alignment between Canadian Common Drug Review reimbursement recommendations and provincial drug plan listing decisions: an exploratory study

BACKGROUND The CADTH Common Drug Review was established in 2002 to prepare national health technology assessment reports to guide listing decisions for 18 participating drug plans. The aim of this study was to compare the nonmandatory recommendations from the Common Drug Review in Canada with the listing decisions of provincial payers to determine alignment. METHODS We identified the recommendations issued by the Common Drug Review from Jan. 1, 2009, to Jan. 1, 2015, and compared these with the listing decisions of 3 provincial public payers (Alberta, British Columbia and Ontario) that participate in the Common Drug Review and the recommendations from Quebec. RESULTS We identified 174 medicine-indication pairs in CADTH Common Drug Review reports issued from Jan. 1, 2009, to Jan. 1, 2015; 110 of these met the inclusion criterion. Among the 110 medicine-indication pairs, listing decisions were available for 95 in Alberta, 102 in Quebec, 104 in Ontario and 106 in BC. There was moderate to substantial agreement between provincial listing decisions and Common Drug Review recommendations: 74.5% (κ = 0.47, 95% confidence interval [CI] 0.31-0.64) for Quebec, 78.8% (κ = 0.56, 95% CI 0.41-0.72) for Ontario, 78.9% (κ = 0.58, 95% CI 0.42-0.74) for Alberta and 81.1% (κ = 0.62, 95% CI 0.47-0.77) for BC. INTERPRETATION Our study showed moderate to substantial agreement between Common Drug Review recommendations and provincial listing decisions. Future studies can build on this research by evaluating the concordance between Common Drug Review recommendations and listing decisions of all participating federal, provincial and territorial drug plans.

A Comparison of Reimbursement Recommendations by European HTA Agencies: Is There Opportunity for Further Alignment?

Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to inform health policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization. Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency, and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agencys approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations. Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations. Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe.

Quality of Regulatory Decision-Making Practices Issues Facing Companies and Agencies

Background: The science of decision making is well established, although in reality it is a mixture of science and art. What is currently lacking is research into decision making in medicines research and development. The aims of this study were to determine the current decision-making practices and methodologies for measuring the quality of the decision making and the barriers and solutions for making quality decisions within pharmaceutical companies and regulatory agencies. Methods: Two analogous questionnaires were developed for use in this study. Fourteen agencies and 25 companies were asked to complete the questionnaire, assessing their decision making for submitting or approving a new drug application. Results: The 68% and 71% response rate from companies and agencies, respectively, suggests interest in this topic, but the area is largely unexplored within the pharmaceutical environment. Moreover, all companies and 90% of the agencies believed that decision making at their organizations could be improved. Although both stakeholders have, to some extent, already implemented frameworks and various methodologies, these are often informal and unsystematic. Challenges remain and there is a need to change the organizational culture by increasing the awareness of the quality aspect in decision making. Conclusions: The findings of this study support the need to further characterize and assess the practices and behaviors of individuals and organizations. Furthermore, the barriers, mainly relating to the influence of biases, should be addressed by developing the general principles of a formal quality decision framework and identifying quality decision-making practices in order to ensure that structured decisions are made throughout the life cycle of medicines.

Improving the Regulatory Review Process: Assessing Performance and Setting Targets

Foreword. 1. Assessing Performance and Setting Targets T. Eaves. 2. Current Regulatory Reforms and Improvements in the Review Process F. Sauer. 3. Establishing Performance Targets for the Review Process: The View of the FDA M. Lumpkin. 4. Current Regulatory Reforms: CBER K. Zoon. 5. Improving the Review Process: The View of the Japanese MHW Y. Hirayama. 6. Comparing the Performance of the Canadian Therapeutic Products Directorate with Other Regulatory Authorities B. Pieterson. 7. Measuring Performance: The View of the TGA J. McEwen. 8. Why Have Targets for the Review Process? The View of the EMEA R. Bass. 9. Why Have Targets for the Review Process? The European View of a Pharmaceutical Industry Individual E. Donnelly. 10. Key Milestones in the Regulatory Review Process? The View of the European Pharmaceutical Industry K. Thomas. 11. How do You Measure the Quality of the Scientific Assessment and the Process? The View of the MCA D. Jefferys. 12. Ensuring the Quality of the Scientific Assessment and the Review Process: The FDAs Good Review Practice Initiative M. Lumpkin. 13. Recommendations for the Syndicate Sessions: Define Mutually Agreeable Measures and Targets for the Review Process for Authorising NMEs and Abridged Applications V. Silano, et al. 14. Recommendations for Syndicate Sessions: What Are the Appropriate Measures of the Quality of the Review M. Lumpkin, et al.

The Saudi Arabia Food and Drug Authority: An Evaluation of the Registration Process and Good Review Practices in Saudi Arabia in Comparison with Australia, Canada and Singapore

ObjectiveThis study compares the current regulatory review process and good review practices at the Saudi Food and Drug Authority (SFDA) with those of regulatory agencies in Australia, Canada, and Singapore and identifies opportunities for developing the SFDA as a Regional Centre of Excellence.MethodsA questionnaire completed by the SFDA included data regarding the organisation, key milestones, review timelines, and good review practices of the agency. Similar information was obtained within the same timeframe (2014/2015) through the same standard questionnaire regarding the processes and practices for Health Canada, Singapore’s Health Sciences Authority, and Australia’s Therapeutic Goods Administration.ResultsAll four regulatory agencies have established target times for scientific assessment and regulatory review, examine dossier sections in parallel, and separate company response time from overall timing. Additionally, all four agencies have instituted good review practices including standard operating procedures, templates, dossier monitoring, and continuous improvement processes, and assign a high priority to transparency in their relationships with the public, healthcare professionals and industry. Of the four agencies, however, only the SFDA requires a Certificate of Pharmaceutical Product (CPP) at the time of the submission and pricing negotiations before final product approval.ConclusionsTo assist the SFDA in its efforts to become a Regional Centre of Excellence, it is suggested that the agency explore a risk stratification approach to select dossiers for verification, abridged, or full reviews; use forms of certification other than the CPP; make pricing negotiations independent to the review process; and introduce a feedback process for the quality of the dossier.

Evaluation of the Gulf Cooperation Council centralized procedure: the way forward

The aim of the study was to evaluate the Gulf Cooperation Council (GCC) centralized regulatory review process. Regulatory review times—including submission and application dates for new active substances (NASs) and existing active substances (EASs) using a standardized template for the period of 2006 to 2010—were collected directly from the GCC office located in Riyadh, Saudi Arabia. A total of 413 products (96 NASs and 317 EASs) were approved during the period, with an overall significant increase in the EASs (P < .001). The median approval times increased from 107 calendar days in 2006 to 265 in 2010 (P < .001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) (P < .001). These data were also analyzed according to therapeutic classes and dosage forms. The results also showed that the lowest number (n = 16) approved during the period was in 2010, and this was due to a major regulatory change implementing the International Conference on Harmonisation product stability guideline for the region. The findings indicate that the delay and the wide range in approval times could be reduced by utilizing a standard assessment template for product review and the implementation of a clock stop system for company responses to questions from the GCC central registration committee. Furthermore, using information technology tools would speed up the registration process rather than the manual exchange of product registration files between the executive office and the member states.

Strategy for communicating benefit-risk decisions: a comparison of regulatory agencies' publicly available documents.

The assessment report formats of four major regulatory reference agencies, US Food and Drug Administration, European Medicines Agency, Health Canada, and Australias Therapeutic Goods Administration were compared to a benefit-risk (BR) documentation template developed by the Centre for Innovation in Regulatory Science and a four-member Consortium on Benefit-Risk Assessment. A case study was also conducted using a US FDA Medical Review, the European Public Assessment Report and Australias Public Assessment Report for the same product. Compared with the BR Template, existing regulatory report formats are inadequate regarding the listing of benefits and risks, the assigning of relative importance and values, visualization and the utilization of a detailed, systematic, standardized structure. The BR Template is based on the principles of BR assessment common to major regulatory agencies. Given that there are minimal differences among the existing regulatory report formats, it is timely to consider the feasibility of a universal template.