Direct-to-Consumer Genetic Testing: A Comprehensive Review.

Emerged in the early 2000s, direct-to-consumer (DTC) genetic testing has helped consumers access and understand their genetic information without the involvement of a healthcare provider. Unlike traditional clinical-based testing, in which a healthcare provider is responsible for ordering, testing, interpreting, and communicating the results, DTC testing provides valuable insights directly to individuals about their genetic information. It empowers consumers and their families to be proactive about their health and lifestyle. The online testing format has become increasingly popular due to its accessibility and affordability. However, it raises concerns about the accuracy and reliability of the results, data security and how to ensure privacy for consumers and regulators. A hybrid model combining elements from both DTC and clinical-based genetic testing has surfaced in the market recently. In the US, current health-related DTC genetic tests are not recognized for diagnostic purposes; instead, these tests are intended to provide genetic information that is associated with certain conditions, which may encourage consumers to take the opportunity to discuss the results and their implications with a healthcare provider. This DTC genetic testing review focuses on the fundamental concepts, applications, benefits, limitations, risks, and consumer concerns, as well as the state of the DTC framework compared with the clinical-based and hybrid models. Additionally, the regulatory oversight, data protection, and healthcare professional perspective on DTC genetic testing in the US will be discussed, including current policies and regulations.

A Mixed Methods Study to Explore Relevant Metrics for a Results Framework Measuring the Public Health Impact of Reliance-Based Pathways.

Reliance-based pathways for the marketing authorization of medical products have been identified as valuable regulatory tools for the timely provision of effective, safe, quality medicines for people worldwide; however, little research has been conducted on the best way to measure the public health impact of using reliance-based pathways. The current mixed methods study was designed to explore which characteristics or "metrics" could be used to measure the impact of reliance-based pathways. A quantitative survey (n = 70) and in-depth interviews (IDIs) (n = 10) were employed to query various stakeholders (e.g., industry, regulatory authorities, NGOs) about the metrics they believed would be important to include in a framework designed to measure the impact of reliance-based regulatory pathways on advancing public health. Based on survey results, (1) ability to meet targeted product assessment timeline, (2) increased access to expertise, which is limited or not available in the agency, (3) shortened median number of days (annually) to market for medical products, (4) lower morbidity and mortality rates due to greater access to medical products, and (5) movement toward technical standards harmonization were the Top Five most important metrics to be included in a framework. IDI results suggest that, while important, the relevance of the Top Five metrics may vary by region or regulatory authority. Interviewed stakeholders intuitively believe reliance-based regulatory pathways are a worthwhile endeavor; however, there must be "harmonization" within the reliance ecosystem that creates a strong understanding of the factors necessary for reliance-based pathways to be utilized in a successful manner.

Regulatory reliance pathways during health emergencies: enabling timely authorizations for COVID-19 vaccines in Latin America.

Objectives: To map the timing and nature of regulatory reliance pathways used to authorize COVID-19 vaccines in Latin America. Methods: An observational study was conducted assessing the characteristics of all COVID-19 vaccine authorizations in Latin America. For every authorization it was determined whether reliance was used in the authorization process. Subgroups of reference national regulatory authorities (NRAs) and non-reference NRAs were compared. Results: 56 authorizations of 10 different COVID-19 vaccines were identified in 18 countries, of which 25 (44.6%) used reliance and 12 (21.4%) did not. For the remaining 19 (33.0%) it was not possible to determine whether reliance was used. Reference agencies used reliance less often (40% of authorizations with a known pathway) compared to non-reference agencies (100%). The median review time was just 15 days and does not meaningfully differ between reliance and non-reliance authorizations. Conclusions: This study demonstrated that for these vaccines, despite reliance pathways being associated with numerous rapid authorizations, independent authorization review times were not considerably longer than reliance reviews; reliance pathways were not a prerequisite for rapid authorization. Nevertheless, reliance pathways provided rapid authorizations in response to the COVID-19 emergency.

Regulatory reliance pathways during health emergencies: enabling timely authorizations for COVID-19 vaccines in Latin America

[ABSTRACT]. Objectives. To map the timing and nature of regulatory reliance pathways used to authorize COVID-19 vaccines in Latin America. Methods. An observational study was conducted assessing the characteristics of all COVID-19 vaccine authorizations in Latin America. For every authorization it was determined whether reliance was used in the authorization process. Subgroups of reference national regulatory authorities (NRAs) and non-reference NRAs were compared. Results. 56 authorizations of 10 different COVID-19 vaccines were identified in 18 countries, of which 25 (44.6%) used reliance and 12 (21.4%) did not. For the remaining 19 (33.0%) it was not possible to determine whether reliance was used. Reference agencies used reliance less often (40% of authorizations with a known pathway) compared to non-reference agencies (100%). The median review time was just 15 days and does not meaningfully differ between reliance and non-reliance authorizations. Conclusions. This study demonstrated that for these vaccines, despite reliance pathways being associated with numerous rapid authorizations, independent authorization review times were not considerably longer than reliance reviews; reliance pathways were not a prerequisite for rapid authorization. Nevertheless, reliance pathways provided rapid authorizations in response to the COVID-19 emergency.

[RESUMEN]. Objetivos. Determinar dónde y cuándo se usaron las decisiones de autoridades regulatorias de otras jurisdicciones y la naturaleza de estos mecanismos para autorizar vacunas contra la COVID-19 en América Latina. Métodos. Se realizó un estudio observacional para evaluar las características de todas las autorizaciones de vacunas contra la COVID-19 en América Latina. Para cada autorización se determinó si se emplearon las decisiones de autoridades regulatorias de otras jurisdicciones en el proceso de autorización. Se compararon subgrupos de autoridades regulatorias nacionales (ARN) consideradas de referencia con otras ARN no usadas como referencia. Resultados. Se determinó dónde se otorgaron 56 autorizaciones de 10 vacunas diferentes contra la COVID–19 en 18 países; de estas 56 autorizaciones, 25 (44,6%) hicieron uso de las decisiones de autoridades regulatorias de otras jurisdicciones y 12 (21,4%), no. Para las 19 restantes (33,0%) no fue posible determinar si se hizo uso de las decisiones de autoridades regulatorias de otras jurisdicciones. Los organismos de referencia utilizaron las decisiones de autoridades regulatorias de otras jurisdicciones con menos frecuencia (40% de las autorizaciones con un mecanismo conocido) en comparación con los organismos no usados como referencia (100%). El plazo medio de revisión fue de tan solo 15 días y no difiere significativamente entre las autorizaciones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones y las que no las emplearon. Conclusiones. En este estudio se demostró que, a pesar de que los mecanismos de utilización de las decisiones de autoridades regulatorias de otras jurisdicciones se asocian en muchos casos con autorizaciones rápidas, para estas vacunas los plazos de revisión independiente para la autorización no fueron considerablemente mayores que los de las revisiones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones. También se demostró que para obtener una autorización rápida no se requería la utilización de las decisiones de autoridades regulatorias de otras jurisdicciones. Sin embargo, estos mecanismos proporcionaron autorizaciones rápidas en respuesta a la emergencia por la COVID–19.

[RESUMO]. Objetivos. Mapear a tempestividade e a natureza do uso de decisões regulatórias de outras autoridades (reliance regulatório) para autorização de vacinas contra a COVID-19 na América Latina. Métodos. Em um estudo observacional, foram avaliadas as características de todas as autorizações de vacinas contra COVID-19 na América Latina. Para cada autorização, foi determinado se foram utilizadas decisões de outras autoridades regulatórias para embasar o processo de autorização. Foram comparados subgrupos de autoridades reguladoras nacionais (ARN) de referência (ARNr) e ARN não consideradas de referência. Resultados. Foram identificadas 56 autorizações de 10 vacinas diferentes contra a COVID-19 em 18 países, das quais 25 (44,6%) utilizaram decisões de outras ARN como base para o registro e 12 (21,4%) não. Para as 19 (33,0%) autorizações restantes, não foi possível determinar se decisões de outras ARN foram utilizadas. As ARNr utilizaram decisões de outras autoridades com menos frequência (40% das autorizações com via regulatória conhecida) em comparação com as ARN não consideradas de referência (100%). A mediana do tempo de tramitação foi de apenas 15 dias, sem diferença significativa entre processos nos quais foram utilizadas decisões de outras agências e processos que não as utilizaram. Conclusões. Este estudo demonstrou que, para estas vacinas, apesar de o uso do reliance regulatório estar associado a várias autorizações rápidas, os tempos de tramitação não foram consideravelmente maiores em autorizações independentes do que quando foram utilizadas decisões de outras ARN; o reliance regulatório não foi um pré-requisito para autorização rápida. No entanto, o uso de tais processos viabilizou autorizações rápidas em resposta à emergência de COVID-19.

Cooperation Agreements, Memorandums of Understanding, and Letters of Intent as Instruments to Facilitate the Implementation of Reliance in Latin America.

For more than a decade, the World Health Organization, Pan American Health Organization, Pan-American Network or Drug Regulatory Harmonization, and the International Conference of Drug Regulatory Authorities, have encouraged regulators to adopt reliance and recognition pathways to reduce duplication, improve efficiency and efficacy, and strengthen regulatory capabilities, in order to facilitate marketing authorization approval, thereby maintaining supply chain integrity. Several factors have limited the more widespread implementation of reliance pathways in Latin America, among which is having the appropriate legal tools in place between and among agencies. Key among these tools are the Memorandum of Understanding (MOU) and cooperation agreements. Herein we have reviewed the content and the characteristics of MOUs and cooperation agreements available on the official websites of the regulatory agencies of the region (we found 11 multilateral MOUs and 8 cooperation agreements published), signed by Latin American agencies and interregional organizations. In this commentary, common characteristics are identified and recommendations for further implementation are made to promote communication, information sharing, and trust, thereby supporting the broader use of reliance pathways in the region.

Regulatory reliance pathways during health emergencies: enabling timely authorizations for COVID-19 vaccines in Latin America / Mecanismos de utilización de las decisiones de autoridades regulatorias de otras jurisdicciones en las emergencias de salud: autorización oportuna de las vacunas contra la COVID-19 en América Latina / Uso de decisões regulatórias de outras autoridades durante emergências sanitárias e a tempestividade da autorização de vacinas contra a COVID-19 na América Latina

ABSTRACT Objectives. To map the timing and nature of regulatory reliance pathways used to authorize COVID-19 vaccines in Latin America. Methods. An observational study was conducted assessing the characteristics of all COVID-19 vaccine authorizations in Latin America. For every authorization it was determined whether reliance was used in the authorization process. Subgroups of reference national regulatory authorities (NRAs) and non-reference NRAs were compared. Results. 56 authorizations of 10 different COVID-19 vaccines were identified in 18 countries, of which 25 (44.6%) used reliance and 12 (21.4%) did not. For the remaining 19 (33.0%) it was not possible to determine whether reliance was used. Reference agencies used reliance less often (40% of authorizations with a known pathway) compared to non-reference agencies (100%). The median review time was just 15 days and does not meaningfully differ between reliance and non-reliance authorizations. Conclusions. This study demonstrated that for these vaccines, despite reliance pathways being associated with numerous rapid authorizations, independent authorization review times were not considerably longer than reliance reviews; reliance pathways were not a prerequisite for rapid authorization. Nevertheless, reliance pathways provided rapid authorizations in response to the COVID-19 emergency.

RESUMEN Objetivos. Determinar dónde y cuándo se usaron las decisiones de autoridades regulatorias de otras jurisdicciones y la naturaleza de estos mecanismos para autorizar vacunas contra la COVID-19 en América Latina. Métodos. Se realizó un estudio observacional para evaluar las características de todas las autorizaciones de vacunas contra la COVID-19 en América Latina. Para cada autorización se determinó si se emplearon las decisiones de autoridades regulatorias de otras jurisdicciones en el proceso de autorización. Se compararon subgrupos de autoridades regulatorias nacionales (ARN) consideradas de referencia con otras ARN no usadas como referencia. Resultados. Se determinó dónde se otorgaron 56 autorizaciones de 10 vacunas diferentes contra la COVID-19 en 18 países; de estas 56 autorizaciones, 25 (44,6%) hicieron uso de las decisiones de autoridades regulatorias de otras jurisdicciones y 12 (21,4%), no. Para las 19 restantes (33,0%) no fue posible determinar si se hizo uso de las decisiones de autoridades regulatorias de otras jurisdicciones. Los organismos de referencia utilizaron las decisiones de autoridades regulatorias de otras jurisdicciones con menos frecuencia (40% de las autorizaciones con un mecanismo conocido) en comparación con los organismos no usados como referencia (100%). El plazo medio de revisión fue de tan solo 15 días y no difiere significativamente entre las autorizaciones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones y las que no las emplearon. Conclusiones. En este estudio se demostró que, a pesar de que los mecanismos de utilización de las decisiones de autoridades regulatorias de otras jurisdicciones se asocian en muchos casos con autorizaciones rápidas, para estas vacunas los plazos de revisión independiente para la autorización no fueron considerablemente mayores que los de las revisiones que emplearon decisiones de autoridades regulatorias de otras jurisdicciones. También se demostró que para obtener una autorización rápida no se requería la utilización de las decisiones de autoridades regulatorias de otras jurisdicciones. Sin embargo, estos mecanismos proporcionaron autorizaciones rápidas en respuesta a la emergencia por la COVID-19.

RESUMO Objetivos. Mapear a tempestividade e a natureza do uso de decisões regulatórias de outras autoridades (reliance regulatório) para autorização de vacinas contra a COVID-19 na América Latina. Métodos. Em um estudo observacional, foram avaliadas as características de todas as autorizações de vacinas contra COVID-19 na América Latina. Para cada autorização, foi determinado se foram utilizadas decisões de outras autoridades regulatórias para embasar o processo de autorização. Foram comparados subgrupos de autoridades reguladoras nacionais (ARN) de referência (ARNr) e ARN não consideradas de referência. Resultados. Foram identificadas 56 autorizações de 10 vacinas diferentes contra a COVID-19 em 18 países, das quais 25 (44,6%) utilizaram decisões de outras ARN como base para o registro e 12 (21,4%) não. Para as 19 (33,0%) autorizações restantes, não foi possível determinar se decisões de outras ARN foram utilizadas. As ARNr utilizaram decisões de outras autoridades com menos frequência (40% das autorizações com via regulatória conhecida) em comparação com as ARN não consideradas de referência (100%). A mediana do tempo de tramitação foi de apenas 15 dias, sem diferença significativa entre processos nos quais foram utilizadas decisões de outras agências e processos que não as utilizaram. Conclusões. Este estudo demonstrou que, para estas vacinas, apesar de o uso do reliance regulatório estar associado a várias autorizações rápidas, os tempos de tramitação não foram consideravelmente maiores em autorizações independentes do que quando foram utilizadas decisões de outras ARN; o reliance regulatório não foi um pré-requisito para autorização rápida. No entanto, o uso de tais processos viabilizou autorizações rápidas em resposta à emergência de COVID-19.

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.

The Qualitative Value of Facilitated Regulatory Pathways in Europe, USA, and Japan: Benefits, Barriers to Utilization, and Suggested Solutions.

BACKGROUND: Despite the growing application of facilitated regulatory pathways (FRPs), little attention has focused on assessing the perception of pharmaceutical companies regarding their usefulness beyond increasing timeliness. OBJECTIVES: The aim of this study was to characterize the perceived value of four key FRPs, based on industry experiences in using these pathways. In addition, we sought to characterize the perceived impact based on benefits and barriers as well as suggested solutions for their use and recommendations as identified by companies, to outline how these FRPs may be further evolved as tools for expediting the development and regulatory review of important medicines. METHODS: A study was undertaken to characterize the perceived value and impact of US FDA (i.e., Breakthrough Therapy Designation, Fast Track), European Medicines Agency (i.e., PRIME), and Japanese Pharmaceutical and Medical Devices Agency (i.e., Sakigake) FRPs through a comprehensive analysis of strengths, weaknesses, opportunities, and threats (SWOT) as well as suggested solutions based on industry experiences with their use. The finalized survey comprised six questions and was sent to senior management in regulatory affairs departments at 22 multinational pharmaceutical companies in March 2019, with a deadline for completion by April 2019. The responses were analyzed using descriptive statistics. SWOT and free-text responses were reviewed and manually grouped into key themes according to high concordance. RESULTS: Survey results were returned by 11 pharmaceutical companies. Based on their perceived value and positive impact, the evaluated FRPs seem to be generally recognized as helpful tools for ensuring timely development and review of important medicines while ensuring multistakeholder involvement. Respondents overwhelmingly felt that the Breakthrough Therapy Designation carried a positive influence, both within and outside their organizations. Following closely with a positive although varied perception was Sakigake, but respondents exhibited more ambivalence about Fast Track and PRIME. Companies felt the impact of the FRPs was generally positive for most stakeholders except for health technology assessors/payers, highlighting the need to better align FRPs with flexible access and reimbursement pathways to expedite the equitable availability of high-quality, safe, effective medicines. CONCLUSIONS: This study highlighted common recommendations across all four FRPs (relating to resource optimization, education, alignment, and communication to improve effective use), as well as agency-specific recommendations, some of which are already being addressed by the regulators.

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.

An evaluation of the Caribbean regulatory system centralized assessment process for medicines submitted 2017-2018 using the OpERA methodology.

BACKGROUND: The Caribbean Regulatory System is a centralized medicine assessment procedure established to serve the needs of the Member States of the CARICOM region. In order to better understand the effectiveness and efficiency of the processes implemented by the Caribbean Regulatory System for the regulatory assessment of medicines for the region, the system has been participating in the Optimizing Efficiencies in Regulatory Agencies (OpERA) program, a multinational endeavor to characterize the assessment procedures and the corollary metrics associated with medicine review activities in regulatory agencies and regional regulatory initiatives. METHODS: The OpERA tool was used to collect process and specific milestone data for products approved by the Caribbean Regulatory System during 2017 (n = 10) and 2018 (n = 11). RESULTS: The median total approval time was 57.5 days (25th/75th percentiles: 54, 60) in 2017 and 148 days (120, 163) in 2018. The median time to conduct the scientific assessment of the dossier was 37 days (24, 42) in 2017 and 66 (40, 132) days in 2018, within the target of 90 days for this activity. The time increases observed in 2018 were due to staff manpower limitations that reduced the ability of the system to conduct the timely assessment of applications. Based on these observations, recommendations to optimize the effectiveness and efficiency of the Caribbean Regulatory System include a commitment from Member States and partner organizations to the use of the procedure to accelerate product availability, encouraging the use of the Caribbean Regulatory System for non-generic products approved by a reference agency, ensuring the establishment of policy and legal frameworks to facilitate the rapid uptake of Caribbean Regulatory System registrations as marketing authorizations in the Member States, and maintaining the sustainability of the process through a fee-based approach. CONCLUSIONS: The observations obtained using the OpERA methodology indicate the Caribbean Regulatory System is an effective and efficient mechanism to provide recommendations to Member States for important medicines.

Benchmarking health technology assessment agencies-methodological challenges and recommendations.

OBJECTIVES: The objectives of the study were to establish a benchmarking tool to collect metrics to enable increased clarity regarding the differences and similarities across health technology assessment (HTA) agencies, to assess performance within and across HTA agencies, identify areas in the HTA processes in which time is spent and to enable ongoing performance improvement. METHODS: Common steps and milestones in the HTA process were identified for meaningful benchmarking among agencies. A benchmarking tool consisting of eighty-six questions providing information on HTA agency organizational aspects and information on individual new medicine review timelines and outcomes was developed with the input of HTA agencies and validated in a pilot study. Data on 109 HTA reviews from five HTA agencies were analyzed to demonstrate the utility of this tool. RESULTS: This study developed an HTA benchmarking methodology, comparative metrics showed considerable differences among the median timelines from assessment and appraisal to final HTA recommendation for the five agencies included in this analysis; these results were interpreted in conjunction with agency characteristics. CONCLUSIONS: It is feasible to find consensus among HTA agencies regarding the common milestones of the review process to map jurisdiction-specific processes against agreed metrics. Data on characteristics of agencies such as their scope and remit enabled results to be interpreted in the appropriate local context. This benchmarking tool has promising potential utility to improve the transparency of the review process and to facilitate both quality assurance and performance improvement in HTA agencies.

Improving access to quality medicines in East Africa: An independent perspective on the East African Community Medicines Regulatory Harmonization initiative.

Alexander Giaquinto and co-authors discuss the East African Community's Medicines Regulatory Harmonization initiative.

A Baseline Analysis of Regulatory Review Timelines for ANVISA: 2013-2016.

BACKGROUND: The Brazilian health regulatory agency (Agência Nacional de Vigilância Sanitária, ANVISA) has embarked on transformational initiatives to fulfill its mandate to provide timely access to safe, effective, and quality therapeutics. A new Brazilian law was enacted to provide the agency with greater flexibility. Optimizing Efficiencies in Regulatory Agencies (OpERA) is a regulatory-strengthening program that seeks to provide benchmarking data that can be used to define performance targets and focus performance improvement. The objective of this study was to use OpERA methodology to undertake a retrospective analysis of the timelines associated with important components of the ANVISA regulatory review process to establish a baseline against which the influence of the new law could be measured. METHODS: The OpERA tool was used to collect specific milestone data that identify time periods, review stages, and data points for products approved by ANVISA 2013-2016. RESULTS: For the 138 products approved in this cohort, the overall median approval time was 795 days. ANVISA and submitting companies will need to reduce their review and response times by approximately half in order to meet the total time goal of 365 days. CONCLUSIONS: The observations from this baseline study have identified opportunities for ANVISA and sponsor companies to collaborate to reduce regulatory assessment times while assuring the timely approval of safe and effective, quality medicines. These analyses will be repeated to determine how the provisions of the new Law will impact the activities of ANVISA and the extent of sponsors' contributions to this effort.

A Proposed Framework for a Globally Applicable Pragmatic Approach to Using Facilitated Regulatory Pathways.

BACKGROUND: As regulatory agencies come under increased pressure to review medicines of critical importance through efficient regulatory systems to provide equitable access, the benefits of using expedited review pathways are being explored. These facilitated regulatory pathways (FRPs) provide a variety of review strategies that can also expedite assessments. Stringent regulatory authorities (SRAs) use primary FRPs to accelerate development or to shorten review time. Some emerging national regulatory authorities can implement primary FRPs but are more likely to use secondary FRPs that rely on or recognize an SRA or reference agency decision, the World Health Organization Collaborative Prequalification of Medicines Programme, "altruistic" reviews, or collaborative work sharing. Despite their availability, there are no formal guidelines or consensus for the definition, basic elements, or best practices for FRPs. METHODS: Herein, we present a 4-step pragmatic approach to a framework designed to help agencies determine how best to use FRPs. Each step is based on characteristics identified through research, surveys, literature assessments, regulatory capacity categorization analyses, and practical experience. RESULTS: Step 1 assesses 4 domains of the environment preparedness, step 2 offers process criteria that should be in place to effectively use an FRP, step 3 tiers agencies through a self-assessment of readiness and capacity, and step 4 provides a pathway for agencies to determine the most relevant FRP for their use. Target timelines are proposed for FRPs. CONCLUSIONS: This framework represents the first endeavor to holistically address the multifaceted aspects that should be considered for the effective use of an FRP.

Companies' Health Technology Assessment Strategies and Practices in Australia, Canada, England, France, Germany, Italy and Spain: An Industry Metrics Study.

Background: Health technology assessment (HTA) has increased in importance in supporting payer decision making by assessing the relative effectiveness and cost effectiveness of new medicines. Thus, pharmaceutical companies need to address the HTA requirements early during development to improve reimbursement outcomes. Currently, there is a lack of research to assess the impact of HTA on development and jurisdictional outcome from companies' perspectives. This study aimed to assess companies' HTA strategy and characterise HTA practice in seven jurisdictions. Methods: A multi-year, annual study collected information for individual products, focusing on development activities regarding inclusion of HTA requirements and selection of global comparators. The generation of local contextual information, submission strategies and predictability of HTA outcomes was examined jurisdictionally in Australia, Canada, England, France, Germany, Italy and Spain. The study questionnaire was built into a secure online data collection platform and data were provided annually by participating companies. Results: Data for 169 compounds were provided by nine international companies between 2014 and 2018. HTA requirements were implemented in evidence generation plan for 63% of products during development. Global comparators were accepted by HTA bodies for more than half of studied products; Spain showed the highest acceptance rate (85%). Companies took advantages of parallel process in Australia and Canada to shorten product rollout time. Australia demonstrated general consistency in HTA review time, and England had the longest variation (interquartile range, 216 days). Requirements for additional information after submission occurred at all HTA bodies. Germany and Italy showed the highest percentage of products being reimbursed as per regulatory label (80 and 68%, respectively). Canada was the most predictable jurisdiction, with the highest proportion of review outcome (90%) that met companies' expectations. Conclusion: Companies are addressing HTA requirements during development for many products; however, they are challenged by varying requirements and practices and product success ultimately depends on how HTA organisations and payers assess added value in the context of the national healthcare systems. This ongoing study created a baseline to help capture fact-based changes for company HTA strategies and HTA body practices.

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.

The Confluence of Accelerated Regulatory and Health Technology Assessment Access Pathways.

There is a growing interest in aligning accelerated regulatory pathways with flexible access and reimbursement pathways to expedite the equitable availability of high-quality, safe, and effective medicines that provide a value-based approach to meeting society's most important healthcare needs. The Centre for Innovation in Regulatory Science (CIRS) identified key issues regarding the confluence of regulatory and health technology assessment processes from discussions and presentations given by international regulators, health technology assessment bodies, payers, patient representatives, and multinational pharmaceutical company representatives on this topic at CIRS workshops held in 2014 and 2017 that focused on the commonalties and differences across these pathways. Recent publications have also been highlighted. The barriers to and opportunities for aligning stakeholder expectations and needs were investigated and recommendations provided. Early dialogue among the stakeholders is the process that will likely provide the greatest return on investment of time and effort to identify, develop, review, and recommend important new medicines, especially those that address an unmet medical need.

Building Synergy between Regulatory and HTA Agencies beyond Processes and Procedures-Can We Effectively Align the Evidentiary Requirements? A Survey of Stakeholder Perceptions.

OBJECTIVES: To evaluate the current practice of companies and agencies to assess the changes made in aligning regulatory and health technology assessment (HTA) stakeholders; to identify areas of commonality of evidentiary requirements that could occur; and to identify strategic issues and trends of regulatory and HTA synergy. METHODS: Two separate questionnaires were developed to assess stakeholders' perceptions on regulatory and HTA alignment, one for pharmaceutical companies and the other for regulatory and HTA agencies. The responses were analyzed using descriptive statistics. RESULTS: Seven regulatory and 8 HTA agencies from Australia, Canada, and Europe and 19 international companies developing innovative medicine responded to the survey. This study provided a snapshot of the current regulatory and HTA landscape. Changes made over the past 5 years were reflected in three main areas: there is an increasing interaction between regulatory and HTA agencies; current conditional regulatory approvals are not always linked with flexible HTA approaches; and companies are more supportive of joint scientific advice. Four types of evidentiary requirements were identified as building blocks for better alignment: acceptable primary end points, inclusion of an active comparator, use of patient-reported outcomes, and choice and use of surrogate end point. CONCLUSIONS: The study showed that the gap between regulatory and HTA requirements has narrowed over the past 5 years. All respondents supported synergy between regulatory and HTA stakeholders, and the study provided several recommendations on how to further improve evidentiary alignment including the provision of joint scientific advice, which was rated as a key strategy by both agencies and companies.

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.

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 agency's 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.