Lawrence Liberti

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).

FDA Facilitated Regulatory Pathways : Visualizing Their Characteristics, Development, and Authorization Timelines

The US Food and Drug Administration (FDA) has four facilitated regulatory pathways (FRPs): Fast Track (FT), Breakthrough Therapy (BTD), Priority Review (PR), and Accelerated Approval (AA). Only PR specifies an expedited review timeline (6 months). We sought to determine to what extent the combination of two or more FRPs influenced development and approval times. We developed a “metro map” to illustrate FRP elements and their influence on review times. We assessed 125 new active substances (approved January 2013 to December 2015) 74 of which used one or more FRPs. For these 74, development times ranged from 1,458 (BTD + PR + AA) to 3,515 days (PR). PR alone had a median approval time of 242 days. The most common combination was FT + PR (median approval 292 days, n = 21). The fastest approval times were for PR + FT + BTD + AA (145 days) and PR + BTD + AA (166 days). Our findings support the combination of FRPs for shortening development and review times beyond that provided by PR alone.

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.

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.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

BACKGROUND Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapys clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. MATERIALS AND METHODS We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). RESULTS Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). CONCLUSION Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. IMPLICATIONS FOR PRACTICE Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies.

An Analysis of Regulatory Timing and Outcomes for New Drug Applications Submitted to Swissmedic Comparison With the US Food and Drug Administration and the European Medicines Agency

Background: This study compared the timing, regulatory marketing authorization decisions, and the final labeling for products submitted to Swissmedic to those submitted to European Medicines Agency (EMA) and the US Food & Drug Administration (FDA). Methods: The Centre for Innovation in Regulatory Science (CIRS) conducted an analysis of a representative cohort of 63 new molecular entities (NMEs) that were submitted to Swissmedic from 2006 through 2010 and that were also submitted to, and approved by, the EMA centralized procedure and FDA. Parameters considered included the outcome and timing of regulatory marketing authorization decisions and the comparison of each product’s Summary of Product Characteristics (SPC) from the 3 agencies. The results were presented at the Swissmedic 10th Anniversary Symposium, “The Challenges of Regulation and Changing Regulations Paradigms,” and they form the basis of this article. Results: The median approval times for these NMEs were longer for Swissmedic (480 days) compared with FDA (303 days) and EMA (416 days). However, if an expedited application review procedure (a “priority review” [FDA], “accelerated assessment” [EMA], or “accelerated review” [Swissmedic]) was applied, Swissmedic was faster (207 days) than EMA (300 days) and essentially as fast as FDA (229 days). The main differences were in the nature of the wording of parts of the initial SPC, particularly the “Contraindications” and “Special warnings and precautions” for FDA and “Special warnings and precautions” for EMA. Conclusions: Results suggest there is no clear evidence that Swissmedic was substantially different in its initial regulatory decisions or SPC recommendations compared with the EMA or FDA.

Characterizing Good Review Practices A Survey Report Among Agencies of APEC Member Economies

As a first step in the implementation of the Asia-Pacific Economic Cooperation (APEC) Best Regulatory Practice Project, the Centre for Innovation in Regulatory Science conducted a gap analysis survey among regulatory agencies of 14 APEC member economies to assess the current use of good review practices (GRevP) to support transparent, consistent, predictable, and good-quality regulatory decision making. Although the majority of responding agencies have established some form of GRevP, most practices are currently evolving and are applied on an informal basis. Most agencies have developed standard operating procedures and guidelines and use a variety of training methods. The use of a common approach to regulatory review across jurisdictions would help build trust and confidence in each agency’s processes, setting the stage for the possibility of work sharing across resource-constrained agencies and bringing consistency and transparency to the review process.

Accelerated approval of medicines: fit for purpose?

The uptake of a new medicine represents a balance between benefit–risk assessment and value considerations. In the case of products approved via accelerated pathways, the increased uncertainty adds to the challenge. Here, we suggest solutions so that regulators, companies, payers and patients can align around management of the uncertainties and expectations.

The Benefit-Risk Assessment of Medicines: Experience of a Consortium of Medium-Sized Regulatory Authorities

Background: In 2008, a consortium of 4 regulatory authorities, the Australian Therapeutic Goods Administration (TGA), Health Canada, Swissmedic, and Singapore Health Sciences Authority (HSA) approached the Centre for Innovation in Regulatory Science (CIRS) to support the development of a benefit-risk framework and template that could be used by all 4 authorities and that would enable joint and shared reviews to maximize resources. CIRS facilitated this collaboration, the Consortium on Benefit-Risk Assessment (COBRA), between 2008 and 2013. Methods: COBRA developed a benefit-risk assessment template based on the EMA reflection paper of 2008, which was constructed and then evaluated in 3 phases: a feasibility study, a retrospective pilot study, and a prospective study. The final template corresponded to the Universal Methodology for Benefit-Risk Assessment (UMBRA) developed by CIRS. Results: By 2014, elements of the template, which had been developed during the program of work, aided the authorities in documenting the benefit-risk assessment of medicines in a systematic and structured way. However, its role in the individual authority’s assessment toolkit was influenced by the number of key elements within the template that were already included in their current clinical assessment templates. Notably, the agencies indicated that they will modify their clinical assessment templates to align with the UMBRA 8-step framework approach. Conclusions: Overall, the authorities believed that the project had given them a better understanding of the value of using a structured approach to the benefit-risk assessment of medicines as well as enabling shared learnings between the authorities.