An Evaluation of the Swissmedic Regulatory Framework for New Active Substances.

BACKGROUND: Swissmedic is a major regulatory agency that has been benchmarking its timelines for 20 years. To better understand the Swissmedic review times and to examine whether measures introduced to accelerate the process were effective, a retrospective analysis was undertaken. The objective was to provide a breakdown of where time is spent in the phases of Swissmedic's approval process (validation, scientific assessment, authorisation) and how this compared to other major authorities. METHODS: Data on Swissmedic, EMA and FDA product approvals were collected from websites or through direct communication, using a standardised CIRS method and milestones previously identified, focusing on new active substances approved 2019-2021. RESULTS: In 2019, 2020, and 2021, Swissmedic median approval times were 520, 470, and 392 days, respectively. The decrease over this time was mainly observed in the Authorisation Phase and can be attributed to lower proportions of applications with multiple "labelling loops", in addition to shorter times for final label negotiation. While Swissmedic had the longest overall approval time (447 days) compared to EMA (428) and FDA (244), the timelines were more comparable when considering only the agency's time spent on the scientific assessment, with Swissmedic at 194 days, EMA at 218 days, and FDA at 184 days. CONCLUSIONS: These observations represent an important analysis of Swissmedic regulatory activity timelines, demonstrate the impact of process improvements, and emphasise the importance of measuring timelines. Swissmedic will continue to expedite its processes also by promoting international collaborations with like-minded authorities.

A decade comparison of regulatory decision patterns for oncology products to all other non-oncology products among Swissmedic, European Medicines Agency, and US Food and Drug Administration.

Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato-oncology products (OP) and non-oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not-statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies.

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.

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.

Transparency in European Medicines Agency and US Food and Drug Administration Decision Making: Is It Possible to Identify the Rationale for Divergences in Approved Indication From Public Assessment Reports?

Although it cannot be expected that different medicines' regulatory agencies always reach the same review outcome, it is important that decision making is documented and communicated to ensure transparency. This study examines whether justification for divergences between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding approved indications could be identified from the agencies' public assessment reports (PARs). We focused on 9 products previously identified to have been submitted simultaneously to both agencies with the same indication but had a different indication approved; there were 15 differences in indications. Our analysis confirms that the rationale for observed divergent indication decisions was predominantly found in the benefit-risk section of the PAR (9 of 15 cases for the FDA and 10 of 15 for the EMA). If not found in the benefit-risk section, the rationale for these decisions was found in other PAR sections (eg, labeling or clinical efficacy section) or not at all. Our study found a small number of inconsistencies or gaps in how, where, and whether regulatory decision making on approved indications are documented by the FDA and the EMA. We believe it is important for regulators to standardize their approach and systematically and transparently document their rationale for the approved indication, using a structured benefit-risk assessment format within the PAR. This process is especially important for innovative products for which experience in evaluating similar products worldwide is limited, particularly as agencies are striving to build effective regulatory processes by leveraging assessments by trusted reference agencies through approaches such as reliance. Clear and systematic communication and documentation of the decisions in the PAR are central and should continue to evolve as a best practice; an enabling step toward this would be a harmonized PAR template for use by agencies globally.

Use of the Certificate for Pharmaceutical Products (CPP) in 18 Maturing Pharmaceutical Markets: Comparing Agency Guidelines with Company Practice.

BACKGROUND: The certificate of pharmaceutical product (CPP) was implemented to accelerate the availability of new drugs in developing countries by providing evidence of the quality of products and reducing the time to market through reliance on a prior trusted analysis. However, the CPP format, issuing process and use have not been revised since 1997 and there are significant differences among countries in regard to requirements for CPP timing, terminology, and format. We sought to determine current CPP practices versus national regulatory guidelines and to inform recommendations for the efficient use of the CPP based on the needs of the modern regulatory environment. METHODS: We conducted a comparative analysis of company practice versus agency guidelines across 18 maturing pharmaceutical markets using data from the Cortellis for Regulatory Intelligence® (CRI) and the Centre for Innovation in Regulatory Science (CIRS) Emerging Markets Regulatory Review Times (EMaRReT) databases and regulatory authorities' websites. RESULTS: Of the studied 18 countries, 16 require the CPP for submission of new registrations; many accept alternative documentation but most still require legalization of the CPP and many are not compliant with the complex CPP format. Additional complicating factors include language requirements and varying local guidelines for CPP submission timing and validity dates. CONCLUSIONS: With the implementation of a number of suggested improvements, the CPP can continue to serve an important role in streamlining regulatory efficiency and provide confidence in new medicines, ensuring a more efficient and effective approval process and expediting patient access to safe and effective medicines worldwide.

To what degree are review outcomes aligned for new active substances (NASs) between the European Medicines Agency and the US Food and Drug Administration? A comparison based on publicly available information for NASs initially approved in the time period 2014 to 2016.

OBJECTIVE: To compare review outcome alignment between European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for medicines approved by both agencies in the time period 2014-2016. DESIGN: Using publicly available information from FDA and EMA websites, new active substances (NASs) approved by each agency from 2014 to 2016 were identified and their characteristics assessed. Divergences in regulatory outcomes for simultaneous (within 91 days) submissions to both agencies were identified and then examined for use of facilitated regulatory pathways and orphan designations; submitted versus approved indications; and approval times. RESULTS: In 2014-2016, 115 NASs were approved by EMA or FDA or both; 74/115 were new chemical entities and 41 new biological/biotechnology entities; 82/115 were approved by both agencies, 24 only by FDA and nine only by EMA. Simultaneous submission occurred for 52/115; 13/52 received expedited review by both agencies and 18 only by FDA; 8/52 received conditional approval from both agencies, 2/52 only from FDA and 1/52 only from EMA; 17/52 were designated as orphans by both agencies and 10/52 by FDA only; 31/52 indications were approved as submitted and 21 changed by EMA and 29/46 were approved as submitted (six not assessed) and 17/46 changed by FDA. Median FDA review timelines were 319 days compared with 409 days for EMA. CONCLUSIONS: There was general agreement in EMA / FDA conditional approvals. FDA used expedited pathways and orphan designation more often than EMA, suggesting stricter EMA criteria or definitions for these designations or less flexible processes. Despite consistency in submitted indications, there was lack of concordance in approved indications, which should be further investigated. FDA review times are faster because of a wider range of expedited pathways and the two-step EMA process; this may change with recent revisions to EMA accelerated assessment guidelines and the launch of Priority Medicines.

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.