Publicação

Lessons learned on the design and the conduct of European Post Authorisation Safety Studies (PASS) : review of 3 years of PRAC oversight

Detalhes bibliográficos
Resumo:	Introduction The new European Union (EU) Pharmacovigilance, implemented in 2012, aimed to establish a more proactive and efficient system for the early detection and prevention of issues related to the safety of medicinal products. This goal is reflected by the legal enforcement of Risk Management activities. As a consequence, it is necessary to submit a Risk Management Plan (RMP) with each application for a new marketing authorisation. This document includes a critical assessment of the known and unknown safety profile of the medicinal product and discusses the need to implement Pharmacovigilance and risk minimisation activities that go beyond the routine ones. A Post-Authorisation Safety Study (PASS) is an additional Pharmacovigilance activity conducted with the goal of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk minimisation measures (RMMs). They bridge Pharmacovigilance, which defines the mission, with Pharmacoepidemiology which provides the study methods. PASS can be imposed as condition or special obligation to the marketing authorisation and may also be requested upon conclusion of a safety related referral. The Pharmacovigilance Risk Assessment Committee (PRAC) is a committee of the European Medicines Agency (EMA) created by the new Pharmacovigilance legislation. It is responsible for the assessment of safety issues at EU level, as well as the monitoring of the Pharmacovigilance activities foreseen in the legislation. In addition, as a consequence of the efforts to increase transparency of the regulatory processes and decisions, the EMA publishes the PRAC monthly minutes on its website. These documents list all the assessed Pharmacovigilance procedures with a brief summary of the plenary decisions. The availability of these and other documents provided an opportunity to identify the PASS protocols submitted to the PRAC. The objective of the current dissertation was to describe the PASS landscape during the first three complete years of the new Pharmacovigilance legislation by characterising the purpose and methodology of the studies. It also aimed to give a critical perspective on the level of public available information on the PASS review process and PRAC feedback. Methods The minutes of the PRAC meeting minutes held from July 2012 to July 2015 were chronologically reviewed to identify and track all PASS protocols and respective rounds of review. The information from the minutes was complemented with a review of the European Public Assessment Reports (EPARs) for the medicinal products covered in the PASS, which provided information about the regulatory background. Moreover, the European Union electronic Register of Post-Authorisation Studies (EU PAS) Register available in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) website was also searched to find information about PASS methodology and protocol documents. Upon protocol availability, it was possible to retrieve more granular information. Metrics regarding the PRAC assessment process were determined among protocols that were considered approved based on the following rules: there was information in the PRAC comments text, the PASS was found in the EU PAS Register, or more than one year had elapsed since the last assessment of that PASS protocol. Descriptive analyses were performed on actual data, with no imputations for missing data. Comparisons using chi-square test (with a significance level of 5%) were conducted. Results In total, 189 different PASS protocols were identified by reviewing the minutes of the PRAC meetings from July 2012 to July 2015, corresponding to 353 PASS protocol submissions to the PRAC. The outcome of PRAC assessment was only available in the minutes for approximately one third (30%) of the 353 assessments. Only half of the 189 PASS were available in the EU PAS Register at the data lock, July 2015. The majority of PASS (58%) concerned new marketing authorisations. About one third (31%) of the 189 PASS were imposed by the regulators. The vast majority of PASS (74%) had at least one objective related with investigation of safety concerns, while approximately one third (34%) included at least one objective of assessing drug utilisation and one fourth (25%) incorporated at least one objective related with assessment of effectiveness of RMMs. Almost one third of the PASS (31%) combined objectives of at least two of those categories. PASS were mainly designed as longitudinal studies (81%). However, the majority of PASS (56%) with at least one objective concerning the assessment of effectiveness of RMM had a cross-sectional design. Overall, slightly more PASS involved a primary data collection approach (58%). Among PASS with at least one objective related with assessment of drug utilisation, 58% leveraged data collection schemes already established for other purposes. More than two thirds of PASS (70%) focused on a single medicinal product as eligibility criteria (either patient exposure or prescribers of the medicinal product of interest), while broader exclusion criteria were less frequent. Among the 57 available protocol documents, only one third (33%) mentioned a comparator, such as another medicinal product, a non-exposed group or external data sources. All 57 PASS included at least one European country. The majority of the 18 available protocols in which at least one objective was to assess effectiveness of RMM did not specify how success of those measures would be ascertained. One third (33%) of these PASS aimed exclusively to assess effectiveness of RMM and were designed as cross-sectional studies using a questionnaire to assess knowledge and auto-reported behaviour. The most common areas of the protocol referred as responsible for the rejection of the protocols by the PRAC were related to inadequate study design (37%) and concerns with study feasibility (30%) requiring evidence that bias and limitations were adequately considered. The comments corroborate the general insight that the there was a limited level of detail in the PASS protocols. PRAC protocol assessment metrics were estimated among 37 imposed PASS considered approved. The results suggested a decrease in the median number of rounds of review from 3 to 2 and an average decrease of 6 months in overall review time between the first and the third year of the review. Discussion This was the first comprehensive characterisation of the PASS protocols submitted to the PRAC during the first three years under the new Pharmacovigilance legislation. Overall, the results showed that despite the unprecedented level of transparency achieved, which made this study possible, there is still room for improvement in the level of information provided by regulators and MAHs. An increased publication of the outcomes of PRAC assessment and more adherence to the EU PAS Register, would increase the pool of knowledge available to further improve PASS. It was also evident that there is and some lack of communication between different stakeholders, which may be worsened by the lack of uniform terminology. The limited level of detail in the protocols is not in line with good pharmacoepidemiology and good pharmacovigilance practices (GPP and GVP), both emphasising the need to include details on the reasoning behind the methodological decisions and feasibility considerations. The recognition of the singularity of PASS, as pharmacoepidemiological studies that have a specific mission within the medicinal products’ RMPs, calls for alignment of different parties and cross-pollination of different skills, including qualitative and quantitative approaches and combined study designs, to tailor the best approach for each safety question. Conclusion Cross-functional collaboration and communication across stakeholders, higher levels of transparency and the use of a harmonised terminology would be key to develop innovative methods, customised for the singular and multifaceted needs of PASS, an example of which being the assessment of effectiveness of RMM. The anticipated result would be the implementation of best practices that will certainly contribute to a safer use of medicinal products.
Autores principais:	Almas, Mariana Ferreira Baltazar de Matos
Assunto:	Post Authorisation Safety Study (PASS) Pharmacovigilance Risk management Pharmacoepidemiology Pharmacovigilance Risk Assessment Committee (PRAC) Teses de mestrado - 2017
Ano:	2017
País:	Portugal
Tipo de documento:	dissertação de mestrado
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade de Lisboa
Idioma:	inglês
Origem:	Repositório da Universidade de Lisboa

Descrição
Resumo:	Introduction The new European Union (EU) Pharmacovigilance, implemented in 2012, aimed to establish a more proactive and efficient system for the early detection and prevention of issues related to the safety of medicinal products. This goal is reflected by the legal enforcement of Risk Management activities. As a consequence, it is necessary to submit a Risk Management Plan (RMP) with each application for a new marketing authorisation. This document includes a critical assessment of the known and unknown safety profile of the medicinal product and discusses the need to implement Pharmacovigilance and risk minimisation activities that go beyond the routine ones. A Post-Authorisation Safety Study (PASS) is an additional Pharmacovigilance activity conducted with the goal of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk minimisation measures (RMMs). They bridge Pharmacovigilance, which defines the mission, with Pharmacoepidemiology which provides the study methods. PASS can be imposed as condition or special obligation to the marketing authorisation and may also be requested upon conclusion of a safety related referral. The Pharmacovigilance Risk Assessment Committee (PRAC) is a committee of the European Medicines Agency (EMA) created by the new Pharmacovigilance legislation. It is responsible for the assessment of safety issues at EU level, as well as the monitoring of the Pharmacovigilance activities foreseen in the legislation. In addition, as a consequence of the efforts to increase transparency of the regulatory processes and decisions, the EMA publishes the PRAC monthly minutes on its website. These documents list all the assessed Pharmacovigilance procedures with a brief summary of the plenary decisions. The availability of these and other documents provided an opportunity to identify the PASS protocols submitted to the PRAC. The objective of the current dissertation was to describe the PASS landscape during the first three complete years of the new Pharmacovigilance legislation by characterising the purpose and methodology of the studies. It also aimed to give a critical perspective on the level of public available information on the PASS review process and PRAC feedback. Methods The minutes of the PRAC meeting minutes held from July 2012 to July 2015 were chronologically reviewed to identify and track all PASS protocols and respective rounds of review. The information from the minutes was complemented with a review of the European Public Assessment Reports (EPARs) for the medicinal products covered in the PASS, which provided information about the regulatory background. Moreover, the European Union electronic Register of Post-Authorisation Studies (EU PAS) Register available in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) website was also searched to find information about PASS methodology and protocol documents. Upon protocol availability, it was possible to retrieve more granular information. Metrics regarding the PRAC assessment process were determined among protocols that were considered approved based on the following rules: there was information in the PRAC comments text, the PASS was found in the EU PAS Register, or more than one year had elapsed since the last assessment of that PASS protocol. Descriptive analyses were performed on actual data, with no imputations for missing data. Comparisons using chi-square test (with a significance level of 5%) were conducted. Results In total, 189 different PASS protocols were identified by reviewing the minutes of the PRAC meetings from July 2012 to July 2015, corresponding to 353 PASS protocol submissions to the PRAC. The outcome of PRAC assessment was only available in the minutes for approximately one third (30%) of the 353 assessments. Only half of the 189 PASS were available in the EU PAS Register at the data lock, July 2015. The majority of PASS (58%) concerned new marketing authorisations. About one third (31%) of the 189 PASS were imposed by the regulators. The vast majority of PASS (74%) had at least one objective related with investigation of safety concerns, while approximately one third (34%) included at least one objective of assessing drug utilisation and one fourth (25%) incorporated at least one objective related with assessment of effectiveness of RMMs. Almost one third of the PASS (31%) combined objectives of at least two of those categories. PASS were mainly designed as longitudinal studies (81%). However, the majority of PASS (56%) with at least one objective concerning the assessment of effectiveness of RMM had a cross-sectional design. Overall, slightly more PASS involved a primary data collection approach (58%). Among PASS with at least one objective related with assessment of drug utilisation, 58% leveraged data collection schemes already established for other purposes. More than two thirds of PASS (70%) focused on a single medicinal product as eligibility criteria (either patient exposure or prescribers of the medicinal product of interest), while broader exclusion criteria were less frequent. Among the 57 available protocol documents, only one third (33%) mentioned a comparator, such as another medicinal product, a non-exposed group or external data sources. All 57 PASS included at least one European country. The majority of the 18 available protocols in which at least one objective was to assess effectiveness of RMM did not specify how success of those measures would be ascertained. One third (33%) of these PASS aimed exclusively to assess effectiveness of RMM and were designed as cross-sectional studies using a questionnaire to assess knowledge and auto-reported behaviour. The most common areas of the protocol referred as responsible for the rejection of the protocols by the PRAC were related to inadequate study design (37%) and concerns with study feasibility (30%) requiring evidence that bias and limitations were adequately considered. The comments corroborate the general insight that the there was a limited level of detail in the PASS protocols. PRAC protocol assessment metrics were estimated among 37 imposed PASS considered approved. The results suggested a decrease in the median number of rounds of review from 3 to 2 and an average decrease of 6 months in overall review time between the first and the third year of the review. Discussion This was the first comprehensive characterisation of the PASS protocols submitted to the PRAC during the first three years under the new Pharmacovigilance legislation. Overall, the results showed that despite the unprecedented level of transparency achieved, which made this study possible, there is still room for improvement in the level of information provided by regulators and MAHs. An increased publication of the outcomes of PRAC assessment and more adherence to the EU PAS Register, would increase the pool of knowledge available to further improve PASS. It was also evident that there is and some lack of communication between different stakeholders, which may be worsened by the lack of uniform terminology. The limited level of detail in the protocols is not in line with good pharmacoepidemiology and good pharmacovigilance practices (GPP and GVP), both emphasising the need to include details on the reasoning behind the methodological decisions and feasibility considerations. The recognition of the singularity of PASS, as pharmacoepidemiological studies that have a specific mission within the medicinal products’ RMPs, calls for alignment of different parties and cross-pollination of different skills, including qualitative and quantitative approaches and combined study designs, to tailor the best approach for each safety question. Conclusion Cross-functional collaboration and communication across stakeholders, higher levels of transparency and the use of a harmonised terminology would be key to develop innovative methods, customised for the singular and multifaceted needs of PASS, an example of which being the assessment of effectiveness of RMM. The anticipated result would be the implementation of best practices that will certainly contribute to a safer use of medicinal products.