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Marketing authorisations of advanced medicinal products in Europe and USA: a comparative analysis of post- authorisation measures
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Ao longo do tempo, tanto a Agência Europeia de Medicamentos (EMA) como a Food and Drug Administration (FDA) dos EUA estabeleceram quadros regulamentares que exigem a recolha de dados adicionais na fase pós-autorização, relativamente à segurança e, em certos casos, à eficácia, qualidade ou optimização terapêutica de medicamentos autorizados. Designadas por medidas pós-autorização (PAMs) pela EMA e por requisitos pós-comercialização (PMRs) e compromissos pós-comercialização (PMCs) pela FDA, estas medidas têm uma relevância acentuada no contexto de medicamentos de terapia avançada (ATMPs) ou de produtos de terapia celular e genética (CGTPs), tal como designados nos EUA, onde, frequentemente enfrenta-se o desafio duplo de equilibrar a aprovação ágil e conduzir avaliações exaustivas do risco-benefício. Esta dissertação descreve e contrasta as medidas pós-autorização impostas, exigidas e acordadas para uma coorte de 15 ATMPs aprovados tanto pela Comissão Europeia, na sequência de um parecer positivo da EMA, como pela FDA, no período de 2009 a 2023. Estende-se à identificação e discussão dos mecanismos regulamentares expeditos atribuídos aos mesmos ATMPs e a reflexão sobre o papel dos dados do mundo real no apoio aos objetivos destas medidas. Documentos regulamentares disponíveis nos websites da EMA e da FDA serviram de fonte para a extração sistemática de todas as medidas pós-autorização. As PAMs extraídas da EMA incluem condições do Anexo II, obrigações específicas, estudos pós-autorização de segurança de Categoria 3 no plano de gestão de risco, recomendações e pedidos de medidas juridicamente vinculativas. As PAMs da FDA incluem PMRs ao abrigo de quatro autoridades - secção 505(o)(3) do Food and Drug Administration Amendments Act, Aprovação Acelerada, Lei da Equidade da Investigação Pediátrica e Regra da Eficácia Animal, bem como PMCs acordados. Foram realizadas análises descritivas, contemplando variáveis como a categoria da medida, os seus objetivos, os desenhos de estudo, taxas de registo em repositórios eletrónicos e o estado relativo à data fixada para a conclusão da medida, tal como estabelecido pela EMA e pela FDA. Foram identificadas 53 PAMs impostas pela EMA e 44 estudos de Categoria 3. Em contrapartida, a FDA impôs 27 PAMs, tendo sido identificados 43 compromissos pós-comercialização acordados. Os resultados obtidos ressaltam diferenças na quantidade e na natureza das PAMs, entre a EMA e a FDA, tendo em conta a amostra do estudo. Variações observadas refletem principalmente diferenças nas estruturas organizacionais e nas abordagens para a recolha de dados pós-autorização, em vez de disparidades nas avaliações iniciais de benefício/risco.
Over time, both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have established regulatory frameworks requiring the collection of additional data during the post-authorization phase, concerning the safety and, in certain cases, the efficacy, quality or optimal use of authorised medicinal products. Referred to as Post-Authorization Measures (PAMs) by the EMA and as Post-Marketing Requirements (PMRs) and Post-Marketing Commitments (PMCs) by the FDA, these measures have a pronounced relevance in the context of Advanced Therapy Medicinal Products (ATMPs) or Cell and Gene Therapy Products (CGTPs), as designated in the US, where the dual challenge of balancing the timely approval with thorough benefit-risk evaluations is often faced. This dissertation described and contrasted post-authorization measures imposed, required, and agreed upon for a cohort of 15 ATMPs approved both by the European Commission following a positive opinion from the EMA and by the FDA, from 2009 to 2023. It extends to the identification and discussion of expedited regulatory mechanisms allocated to the ATMPs, and a reflection on the role of real-world data in supporting measures objectives. Regulatory documents publicly available on the EMA and FDA websites served as sources for the systematic extraction of all post-authorization measures. The EMA extracted PAMs include Annex II conditions, Specific obligations, category 3 post-authorization safety studies in the risk management plan, Recommendations, and requests for Legally Binding Measures. FDA PAMs included PMRs under four authorities - Food and Drug Administration Amendments Act (FDAAA) section 505(o)(3), Accelerated Approval, Pediatric Research Equity Act, and the Animal Efficacy Rule, as well as agreed-upon PMCs. Descriptive analysis considered variables such as measure category, objectives, study designs, registration rates and status concerning the set date for completion, as set by regulatory agencies. Results evidenced that each selected ATMP received an expedited development program, with most benefiting from multiple FDA and EMA programs. 53 EMA-imposed PAMs and 44 category 3 studies were identified. In contrast, the FDA imposed 27 PAMs, while 43 agreed-upon post-marketing commitments were identified. The study highlights differences in the quantity and nature of PAMs between the EMA and FDA for ATMPs. These variations primarily reflect differences in organizational structures and post-authorization data collection approaches, rather than disparities in initial benefit/risk assessments.
Over time, both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have established regulatory frameworks requiring the collection of additional data during the post-authorization phase, concerning the safety and, in certain cases, the efficacy, quality or optimal use of authorised medicinal products. Referred to as Post-Authorization Measures (PAMs) by the EMA and as Post-Marketing Requirements (PMRs) and Post-Marketing Commitments (PMCs) by the FDA, these measures have a pronounced relevance in the context of Advanced Therapy Medicinal Products (ATMPs) or Cell and Gene Therapy Products (CGTPs), as designated in the US, where the dual challenge of balancing the timely approval with thorough benefit-risk evaluations is often faced. This dissertation described and contrasted post-authorization measures imposed, required, and agreed upon for a cohort of 15 ATMPs approved both by the European Commission following a positive opinion from the EMA and by the FDA, from 2009 to 2023. It extends to the identification and discussion of expedited regulatory mechanisms allocated to the ATMPs, and a reflection on the role of real-world data in supporting measures objectives. Regulatory documents publicly available on the EMA and FDA websites served as sources for the systematic extraction of all post-authorization measures. The EMA extracted PAMs include Annex II conditions, Specific obligations, category 3 post-authorization safety studies in the risk management plan, Recommendations, and requests for Legally Binding Measures. FDA PAMs included PMRs under four authorities - Food and Drug Administration Amendments Act (FDAAA) section 505(o)(3), Accelerated Approval, Pediatric Research Equity Act, and the Animal Efficacy Rule, as well as agreed-upon PMCs. Descriptive analysis considered variables such as measure category, objectives, study designs, registration rates and status concerning the set date for completion, as set by regulatory agencies. Results evidenced that each selected ATMP received an expedited development program, with most benefiting from multiple FDA and EMA programs. 53 EMA-imposed PAMs and 44 category 3 studies were identified. In contrast, the FDA imposed 27 PAMs, while 43 agreed-upon post-marketing commitments were identified. The study highlights differences in the quantity and nature of PAMs between the EMA and FDA for ATMPs. These variations primarily reflect differences in organizational structures and post-authorization data collection approaches, rather than disparities in initial benefit/risk assessments.
Descrição
Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Advanced Therapy Medicinal Products (ATMPs) European Medicines Agency (EMA) Food and Drug Administration (FDA) Postmarketing requirement (PMR) Teses de mestrado - 2024