In July 2012, new legislation substantially amended the European Union’s pharmacovigilance (PV) requirements by strengthening and consolidating the PV system. However, according to a recent Quintiles poll spanning multiple organizations and a wide range of disciplines, only 12 percent of biopharmaceutical professionals feel that their company is fully ready (in terms of staff resources, processes and technology) to address the new legislative changes required to conduct non-interventional Post Authorisation Safety Studies (PASS). Quintiles PV experts Michelle Bulliard and Deirdre McCarthy offer tips and considerations for designing and conducting PASS that comply with the new requirements, and also explain the key changes to the format and content of Periodic Safety Update Reports (PSURs).*
Considerations for Designing and Conducting PASS that Comply with the New Requirements
As Adverse Drug Reactions (ADRs) are the fifth most common cause of hospital death – not to mention the EU societal cost of £79 billion per year they are accountable for – the new EU PV legislation is a clear priority. With the recent changes, the EU intends to promote and protect public health by reducing burden of ADRs and optimizing the use of medicines. But what are the technical aspects of this legislation that you need to know to be compliant in your PASS? We can break down the large-scale changes in three key documents:
- Regulation (EU) No 1235/2010 was enforced on July 2, 2012 for centrally authorized products (CAP). This is primarily an amendment to Chapter 3 of the regulation (EC) No 726/2004
- Directive 2010/84/EU was enforced on July 21, 2012 for nationally authorized products (NAP). This is primarily an amendment to Title IX of the directive 2001/83/EC
- Guideline on Good Pharmacovigilance Practices (GVP) will replace the former Volume 9A of the Rules for Governing Medicinal Products in the EU
The GVP guidelines will be key to the successful migration to this new legislation, as it comprises 16 modules that give clear guidelines on how to implement the adapted regulation and directive. The first set of these modules was published in June 2012, and the full set will be available by the end of 2013. In the meantime, Volume 9A remains the reference document as applicable until the specific GVP module addressing your question is published. Additionally during the transition period and until full implementation of the new EU PV legislation, the EMA have made a Question and Answer (Q&A) document available to provide practical considerations concerning the initial phases of operation of the new pharmacovigilance legislation [1]. It provides a series of questions and answers to clarify procedural elements related to the implementation of the new legislation, including PASS and PSUR. This Q&A document is updated on an ongoing basis by the EMA.
The GVP guidelines are comprehensive, but in this article we will focus only on the planning phases of your PASS and the evaluation phase of PSURs. These activities correspond to Modules XI, XII and XIII in the GVP.
GVP Module VIII - Non Interventional PASS: How Is It Different From Volume 9A?
If you have already conducted NI studies, you are familiar with EudraLex Volume 9A. GVP Module VIII will replace 9A, and there are several key changes you should be aware of:
- Draft protocols must now be reviewed and approved within 60 days by the EMA via the Pharmacovigilance Risk Assessment Committee (PRAC), a new group that has been developed under the legislation.
- Once you receive PRAC approval, GVP Module VIII dictates that you must now send the approval letter and a copy of the protocol to the competent authority in each country where you plan to conduct the study prior to the study start date. You must also take local considerations into account, as PASS requirements may vary significantly by country.
- Whereas Volume 9A simply recommended posting the study on the public register, we are now obligated to post them on the EU PAS Register. While this is under development (likely until 2015), the interim obligation is to post the study on the ENCePP Register.
- Significant study amendments must be sent to PRAC within 30 days, and the final study report must be sent to PRAC within 12 months.
NI PASS Protocol Changes
As of January 10, 2013, Market Authorization Holders (MAH) are now obligated to comply with the format and content of PASS study protocol [1]. The EMA has provided specific guidance on the development of PASS protocols to ensure consistency. Here are some key requirements [1]:
- All headings and sub-headings of the format presented in the guidance should be included without exception.
- Where a heading or sub-heading does not apply to the study, “not applicable” should be stated with a short justification.
- All dates should be indicated in the format “DD Month YYYY.”
- Annex 1 should be used to list stand-alone documents not included in the protocol (e.g., contact details of responsible parties and all investigators).
- Annexes can be added to provide documents referred to in the protocol.
- MAH should keep a copy of the protocol available for any future request or inspection.
The new legislation also calls for some key changes to the NI PASS title page and table of contents. For instance, the title page must now include the EU PAS register number if available, and the table of contents is now required to feature sections offering more detail on study design and rationale. GVP Module VIII provides a comprehensive list of requirements.
Safety Reporting During a PASS
We are also seeing some changes to safety reporting for a PASS in the new legislation. The definition of “adverse drug reactions” has been amended to include any reaction from medication error and uses outside the terms of the marketing authorization (including misuse and abuse). In addition, any non-serious adverse reaction now needs to be reported within 90 days by the MAH into the EudraVigilance Database. Since this database will not be active until 2015, GVP Module VI offers an interim arrangement for expedited timeframes that varies by region. For retrospective studies with secondary data, expedited reporting of adverse reactions is not required, but must be included in progress reports and final summary.
Changes to the Format, Content and Submission of PSURs
In addition to the PASS changes, we would like to briefly discuss changes to PSURs as a result of the new legislation. These changes are far reaching, meaning this article cannot cover all of them. However, we will provide an overview of the main areas of focus to help you develop a good quality, value-add report.
The objective of the new EU PSUR is to present a comprehensive and critical analysis of new or emerging information on the risks and, where pertinent, new evidence of benefit to enable an appraisal of the overall benefit-risk profile of the product. The PSUR also contains an evaluation of new relevant information that became available during the reporting interval, in the context of cumulative information. As with the changes to PASS studies, the key to understanding the new requirements is the GVP – in this case, GVP Module VII.
Three sections of the PSUR are entirely new as a result of the recent legislation, and therefore require more focus:
Section 16: Signal and Risk Evaluation
The section itself spans five subsections, but it is important to note that it should not repeat information already noted previously in the PSUR. Instead, it should provide an interpretation of that information with a view toward characterizing the risks.
- Subsection 16.1 is a summary of safety concerns for your product at the start of the period of the PSUR (both identified and potential risks). If a Risk Management Plan is already in place, this will aid in the compilation of this section. If not, you will need to perform a risk analysis to build the risk profile for your product.
- Subsection 16.2 is a summary of results of signal evaluation. Your routine signal detection process should feed into this section of the PSUR.
- Subsection 16.3 is an evaluation of new information existing risks. This evaluation should include any new information collected after the start of the period of the PSUR that may change your evaluation of the safety concerns outlined in Subsection 16.1.
- Subsection 16.4 should contain a characterization of the above risks. It is important to focus on the significance of the new information in the cumulative context.
- Subsection 16.5 should be used to discuss the effectiveness of your risk minimization activities. If you have risk minimization in place, how are you determining effectiveness?
Section 17: Benefit Evaluation
It is important to look only at the approved indications when writing this section, unless information is identified from an unapproved perspective that you believe could impact the benefit-risk profile.
- Subsection 17.1 covers baseline efficacy and effectiveness information. Typically, this is the data that the product was approved with; this subsection can be quite brief.
- Subsection 17.2 is newly identified information on efficacy. For example, this would include any post-marketing reports on lack of efficacy that you may have encountered.
- Subsection 17.3 is a characterization of benefits. This is a cumulative review integrating old and new data.
Section 18: Integrated Benefit-Risk Analysis for Approved Indications
This benefit-risk analysis is at the heart of the new legislation. The section is divided into two subsections.
- Subsection 18.1 focuses on the benefit-risk context, as well as the medical need for the indication (including any alternative treatments available).
- Subsection 18.2 is the benefit-risk evaluation itself. This should be specific to the indication and population.
Concluding Thoughts
There is a lot to consider when conducting your PASS studies and preparing the PSUR under the new guidelines. PASS will require new approaches to effectively measure safety and efficacy. You can facilitate the migration to the new legislation by revising your templates and SOPs now to account for the changes, getting staff training under way, and ensuring your Regulatory department is aware of the changes. You must also ensure that your signals are properly tracked and evaluated for inclusion in the PSUR and that the various contributors to the document are aware of their new roles and responsibilities in plenty of time.
The desired long-term outcome of the new legislation will be a stronger PV system in the EU that is more consolidated and easier to manage. The changes described in this article, which place more emphasis on the cumulative benefit-risk profile, will improve and strengthen the writing of safety documents, contributing to the ultimate goal of promoting and protecting public health. Full implementation is estimated to save between 500 and 5,000 lives per year.
* Although this material contains information of a legal nature, it is for informational purposes only and does not constitute legal advice as to the current operative laws, regulations, or guidelines of any jurisdiction. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers should always check with regulatory authorities/legal counsel to ensure compliance with legislation.
References
1. "Questions and Answers to Support the Implementation of the Pharmacovigilance Legislation - UPDATE, NOVEMBER 2012." European Medicines Agency 2012, 30 Nov. 2012. <http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127658.pdf>.
This document provides a series of questions and answers to clarify procedural elements in relation to the implementation of the new legislation. This Question and Answer (Q&A) document provides practical considerations concerning the initial phases of operation of the new pharmacovigilance legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU). The Q&A applies to all medicinal products for human use regardless of the route of authorization. The Q&A document should be read in conjunction with Commission Questions and Answers on transitional arrangements. The questions and answers in this document represent the view of the EMA and Member States and have been subject to consultation with the European Commission. In case of doubt reference is given to Regulation (EU) No 1235/2010 and Directive 2010/84/EU as well as to the Commission Implementing Regulation (EU) No 520/2012.