Pharm Med 2010; 24 (3): 141-143 1178-2595/10/0003-0141/$49.95/0
CURRENT OPINION
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The Evolution of the Periodic Safety Update Report Still Fit for Purpose? Michael D. Blum Pfizer Inc., Collegeville, Pennsylvania, USA
Abstract
The periodic safety update report (PSUR) has evolved to serve purposes beyond those originally envisioned by the Council for International Organizations of Medical Sciences Working Group II and increasingly requires resources and customization by pharmaceutical companies to meet the expectations of regulatory authorities. By tracing its evolution from a harmonized document to reassure regulatory authorities that companies were periodically reviewing safety data to a more customized document focusing on benefit-risk, one can begin to answer the question ‘‘Is the PSUR still fit for purpose?’’ The European Commission’s vision of a document periodically assessing the benefit-risk of the product, provided it is applied across the entire product lifecycle and adopted globally, would best serve the goals of harmonization across regulatory authorities, transparency between companies and regulatory authorities and, most importantly, optimization of benefit-risk for patients. Until the content and periodicity of such a document can be agreed upon between regulatory authorities and industry, PSURs can continue to meet the goal of transparency, but harmonization of content should be re-emphasized so that resources for production and review are appropriately focused.
Over the past 2 decades, the periodic safety update report (PSUR) evolved to serve purposes beyond those originally envisioned by the Council for International Organizations of Medical Sciences (CIOMS) Working Group II, and its value has begun to be questioned.[1] The Working Group viewed PSURs as ‘‘routine compilations needed so that manufacturers and regulators can be reassured that pertinent safety data available to the manufacturers are systematically reviewed.’’[2] They defined a format and content that was ‘‘practical and achievabley and would preclude the need to produce multiple versions of report formats, contents and period covered.’’[3] However, in order to meet the varying needs of regulatory agencies worldwide, pharmaceutical companies expanded these documents to include more period and cumulative reviews, customized them to region-specific concerns and adapted them to evolving risk management activities. Considerable pharmaceutical company resources are allocated to the production of PSURs that not only meet specifications according to guidelines,[4] but perceived or actual changes in the expectations of regulatory authorities as well. It is time for the pharmacovigilance community to answer the question: ‘‘Is the PSUR still fit for purpose?’’
1. Evolution of the PSUR The recommendations of the CIOMS Working Group II formed the basis of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E2C guideline, which was subsequently amended to include the recommendations of the CIOMS Working Group V for harmonizing and simplifying PSURs. While PSURs are produced for submission to regulatory authorities globally, the European Medicines Agency (EMA) has raised expectations regarding content and focus. Volume 9A of the Rules Governing Medicinal Products in the EU incorporates the content recommendations from ICH E2C(R1), with focus on benefit-risk. According to Volume 9A, the purpose of the PSUR is as follows: ‘‘A Periodic Safety Update Report (PSUR) is intended to provide an update of the worldwide safety experience of a medicinal product to Competent Authorities at defined time points post-authorisation. At these times, Marketing Authorisation Holders are expected to provide succinct summary information together with a critical evaluation of the risk-benefit balance of the product in the light of new or changing
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information. This evaluation should ascertain whether further investigations need to be carried out and whether changes should be made to the marketing authorisation and product information.’’[5] Volume 9A additionally specifies the periodic transmission of the individual case safety reports described in the PSUR line listings, as well as inclusion of progress and final Postauthorization Safety Study (PASS) reports in the PSUR and/or risk management plan. Since risk management plans are required in the EU for most applications for a new (as well as a significant change in) marketing authorization,[5] the expectation is that PSURs will be used routinely as a vehicle for communicating relevant updates to those plans and for addressing specific EMA concerns regarding the plans. For the EMA, PSURs provide routine pharmacovigilance information used to update risk management plans, as well as a means for addressing certain individual safety concerns. According to Volume 9A, specific monitoring of a safety concern for a product with a risk management plan in place could result in a requirement for ‘‘more frequent PSUR submission.’’ The link between risk management plans and the PSUR in Europe has led to the next step in the evolution of PSURs: PSURs as benefit-risk analyses, generated on a schedule proportionate to the risks of the product. The European Commission has proposed that the PSUR ‘‘become an analysis of the risk-benefit balance of a medicinal product rather than a detailed presentation of individual case reports. Besides, the requirements for periodic safety update reports are made proportional to the risks posed by medicinal products, and routine reporting is no longer necessary for products considered low risk or where reporting would be duplicative (with the possibility for ad hoc requests for such products).’’[6] Global adoption of the concepts in the draft amendment to Regulation (EC) No. 726/2004 should theoretically result in better focus on risk in the context of benefit and improved efficiency in pharmacovigilance processes by both regulatory authorities and industry. However, implementation in the EU without adoption globally will move the PSUR even further from the harmonized document envisioned by its creators. As has been the case for the US, where ICH E2C has yet to be implemented (for reasons not publicly disclosed), pharmaceutical companies might need to create a separate document for the EU. That document would expand the analysis of benefitrisk relative to the current PSUR, which would continue to differ from the US FDA periodic report in terms of the analysis of global safety data. In short, without global harmonization, multiple reports for different regions would substantially vary in both content and schedule, creating undue burden for the ª 2010 Adis Data Information BV. All rights reserved.
Blum
industry and the potential for discrepant communication to regulatory authorities. The concept of a risk-based PSUR schedule bears further discussion. Identified and potential risks evolve during the product lifecycle. A risk-based PSUR schedule felt to be appropriate at the time of approval may change in the postapproval period as new risks are identified. This complicates the planning required by pharmacovigilance departments for efficient PSUR production. Moreover, the recommended schedule may vary by regulatory authority, depending upon its assessment of the impact of the risks on the overall benefit-risk of the product. The draft amendment to Regulation (EC) No. 726/2004 lists the responsibilities of the marketing authorization holder (MAH) as follows:[6] Continuously monitor the safety of its products. Notify regulatory authorities of ‘‘any changes that might have an impact on the marketing authorisation.’’ Keep the product information up to date. Provide all available information on off-label use. Take into account all relevant information collected on safety when renewing the marketing authorization. The CIOMS Working Group II envisioned a document that would ‘‘reassure regulators that current safety data had been reviewed.’’[3] Since that time, continuous monitoring of the safety of their products has become the cornerstone of the work of pharmacovigilance departments in industry and of key importance in their inspection by regulatory authorities. With adherence to the principle of continuous safety monitoring as communicated in ICH E2E,[7] it should become increasingly uncommon to detect significant new safety issues during the preparation of a PSUR. As the MAH responsibilities delineated in the draft amendment to Regulation (EC) No. 726/2004 indicate, regulatory authorities expect the MAH to notify them of emerging safety issues in timely fashion and not solely through the vehicle of the PSUR. While reassurance is now a less compelling reason to produce PSURs, the expectation of transparency in the communication of safety issues between industry and regulatory authorities remains. The CIOMS Working Group II also envisioned a document that was ‘‘practical and achievabley and would preclude the need to produce multiple versions of report formats, contents and period covered.’’[3] The CIOMS Working Group V addressed the format and content of long-term or high-volume PSURs, as well as the need for ‘bridging’ reports, ‘addendum’ reports and simplified PSURs when little or no safety information is available.[3] Their recommendations were designed to standardize the content and harmonize the submission of Pharm Med 2010; 24 (3)
Evolution of the Periodic Safety Update Report
aggregate safety summary documents to regulatory authorities. Harmonization remains an important goal, which is potentially threatened by region-specific concerns. While an integrated development safety update report (DSUR)-PSUR document was outside the scope of its work, the CIOMS Working Group VII recommended a format and content for the DSUR that was similar to that of the PSUR. According to the working group, ‘‘the DSUR is not meant to serve as any of the following: a formal benefit-risk assessment for the product; a comprehensive integrated safety summary of the type used in marketing application submissions; a repository or detailed discussion of all individual case safety reports; a signal detection tool; an ‘expert report’.’’[8] The same can be said for the current PSUR. Re-purposing the PSUR will necessitate re-purposing the DSUR if these documents are to be integrated for continuity across the product lifecycle. Moreover, clear guidance distinguishing ‘formal benefit-risk assessment’ (excluded from the scope of DSURs) from ‘analysis of risk-benefit balance’ (proposed in the draft amendment to Regulation (EC) No. 726/2004) is necessary.
2. Conclusions The European Commission’s vision of a document periodically assessing the benefit-risk of the product, provided it is applied across the entire product lifecycle and adopted globally, would best serve the goals of harmonization across regulatory authorities, transparency between companies and regulatory authorities, and, most importantly, optimization of benefit-risk for patients. Signal detection and risk assessment would be ongoing activities within the companies, and subject to appropriate regulatory reporting and inspection. However, rather than capture these activities in a periodic document for regulatory authorities, they would contribute to periodic benefitrisk assessment, which would be the focus of a new document. Delineating the appropriate content and periodicity of such a document will require time and coordinated effort between regulatory authorities and industry. In the meantime, PSURs can continue to meet the goal of transparency, but harmonization of content should be re-emphasized so that resources for production and review are efficiently allocated. Once there is
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agreement within the pharmacovigilance community that PSURs are no longer fit for purpose, resources can be focused on an appropriate replacement, with the ultimate goal of optimizing outcomes for patients.
Acknowledgements The author was a full-time employee of Pfizer Inc. during the writing of this review and did not receive additional funding for its preparation. The views expressed in this review reflect those of the author and not necessarily those of Pfizer Inc.
References 1. Edwards R, Harrison-Woolrych M, Lindquist M. Are PSURs worthwhile? Uppsala Reports 2007; 36: 12-3 2. Council for International Organizations of Medical Sciences (CIOMS). International reporting of periodic drug-safety update summaries: final report of CIOMS Working Group II. Geneva: CIOMS, 1992 3. Council for International Organizations of Medical Sciences (CIOMS). Current challenges in pharmacovigilance: pragmatic approaches. Report of CIOMS Working Group V. Geneva: CIOMS, 2001 4. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline, clinical safety data management: periodic safety update reports for marketed drugs E2C(R1). Parent Guideline, 1996 Nov 6; Addendum, 2003 Feb 6 [online]. Available from URL: http://www.ich.org/LOB/media/MED IA477.pdf [Accessed 2010 May 24] 5. Volume 9A of the Rules Governing Medicinal Products in the European Union. Guidelines on pharmacovigilance for medicinal products for human use. 2008 Sep [online]. Available from URL: http://ec.europa.eu/enterprise/sectors/ pharmaceuticals/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf [Accessed 2010 May 24] 6. Commission of the European Communities. Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. 2008 Dec 10 [online]. Available from URL: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=COM:2008:0664:FIN: en:PDF [Accessed 2010 May 24] 7. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: pharmacovigilance planning: E2E. Step 4 version. Geneva: International Conference on Harmonisation Secretariat, 2004 Nov 18 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA1195.pdf [Accessed 2010 May 24] 8. Council for International Organizations of Medical Sciences (CIOMS). The Development Safety Update Report (DSUR): harmonizing the format and content for periodic safety reporting during clinical trials. Geneva: CIOMS, 2006
Correspondence: Dr Michael D. Blum, Pfizer Inc., 500 Arcola Road, Dock E, Collegeville, PA 19426, USA.
Pharm Med 2010; 24 (3)
