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Chapter: Pharmacovigilance: Periodic Safety Update Reports

The PSUR process relies heavily on the availability of adequate resources, particularly since CIOMS V intro-duced the concept of PSURs covering periods longer than 6 months .


In a recent paper, Michael J. Klepper of North Carolina-based Integrated Safety Systems, Inc., a safety surveillance and consulting firm for phar-maceutical, biological and medical device compa-nies, outlined some of the ways that companies could maximise the efficiency of their procedures for producing PSURs, avoid potential pitfalls and ensure full compliance (Klepper, 2004):


The PSUR process relies heavily on the availability of adequate resources, particularly since CIOMS V intro-duced the concept of PSURs covering periods longer than 6 months (including the five yearly reports for local product renewals in Europe) which still have to be submitted within 60 days of the DLP. The resources needed depend on factors including: the size of the company, the number of marketed products, when these products were approved, the number of coun-tries where these medical products are marketed, the volume of ADRs and the complexity of the medi-cal condition for which the medical product is indi-cated. For example, the process of producing a PSUR for a newly approved AIDS drug that is marketed in many countries will require considerably more resources than the same process for a 15-year-old topical formulation, which is only approved in a few countries worldwide for the treatment of athlete’s foot. Those resources are not solely restricted to the product safety department. As in the Lundbeck SOP, contributions are also required from regulatory departments, which provide information regarding the status of worldwide approval and any regulatory action taken anywhere in the world; clinical research departments, which provide data on any important safety issues emerging from ongoing clinical trials and marketing/financial services departments, which hold the sales/prescriptions data needed to estimate patient exposure. Summary bridging reports and addendum reports require additional resources. When allocating resources to the PSUR process, companies should also be aware that the same departments will be called upon to produce the clinical trial annual reports required under the EU Clinical Trials Directive (see Clinical Trial Annual Report). Over a given period, say a year, the MAH should know the number of PSURs due in that year, including the DLPs and submission dates of these reports. It should also factor in an estimate of volume and complexity of cases. The MAH can then allocate its resources accordingly and put in place a contingency plan in case new work arises, for example an unexpected regulatory query. If there are too few resources available, the MAH may consider outsourcing the work, hiring more people, providing more training or re-prioritising projects. It is also essential that communication between depart-ments is good, so that all the personnel involved in producing the PSUR are aware of expectations, deliv-erables and dates of completion.


Reported ADR data are, in general, incomplete and of poor quality (Venulet, 1986). Although most suspected ADRs are reported by physicians trained in what is called Western medicine, there are consid-erable cultural differences in the use and interpre-tation of certain medical terms. Reporting Adverse Drug Reactions: Definitions of Terms and Crite-ria for Their Use (CIOMS, 1999) is one attempt to cross those cultural differences by establishing standard definitions for selected terms for ADRs and minimum requirements for the use of those terms in international reporting. In an introductory chapter to that book, Ronald Mann, former direc-tor of the University of Southampton’s Drug Safety Research Unit, emphasises the importance of keeping the patient’s own words when reporting complaints, so as not to corrupt the data at source. At the next stage of the communication process – when the physician-reporter passes the information on to a company representative – Klepper suggests that scripts should be developed that are designed to extract the criti-cal information from the reporter. Those responsible for the intake of ADR information should be thor-oughly trained in the use of these scripts. A script dealing with liver necrosis, for example, would guide the representative to ask specific questions, such as the basis of the diagnosis (e.g. viral serologies and needle biopsy). Examples of some medically impor-tant ADRs (FDA, 2003; Mann, 2005) are summarised in Table 6.2. The World Health Organization Critical Term list provides an even more extensive list of such ADRs (WHO, 1998).


The personnel involved in the PSUR process require training in four broad areas:

·     Product training: To fully understand a product’s pharmacology or biological activity, mechanism of action and the known risks associated with its use;

·        Clinical training: To fully understand the charac-teristics of the targeted patient population likely to take the product, with respect to underlying comor-bidities and concomitant medications;

·    Pharmacovigilance training: To fully understand the critical concepts, disciplines, and components associated with pharmacovigilance, the methods used with key considerations affecting risk versus benefits analysis and the medical significance of the most important ADRs and

·    MedDRA training: To fully understand the dictionary, its hierarchy and the implications of its granularity (see ‘STANDARDISED AND HARMONISED MEDDRA CODING’).


One of the characteristics of MedDRA that distin-guishes it from traditional dictionaries is its extreme specificity or granularity. Slightly different verba-tim terms are prone to be coded to different preferred terms and even entirely different SOCs, with important implications for subsequent statisti-cal analyses. The quality of the term used by the reporter (verbatim term) drives the coding process. A high quality verbatim term is likely to autoencode, whereas a poor quality term is more likely to require manual assignment of a MedDRA term, which in turn increases the potential for inconsistencies. To ensure coding consistency for global companies where it is likely that cases will be entered remotely into the MAH’s central database, a global coding convention should be created, maintained and revised as neces-sary. This document could include, for example, the Points to consider developed by the Maintenance and Support Services Organization for MedDRA (MSSO, 2006), as well as other conventions. An example of a coding convention would be the establishment of a ‘rule’ that states that for any surgical procedure, the ADR that led to the surgery will be coded rather than the procedure itself, e.g. ‘gallstones’ rather than ‘cholecystectomy’.


Prespecified search criteria for data retrieval should be developed, used and documented. This will ensure consistent and reproducible data retrieval.


Because the presentation of individual case histories and the overall safety evaluation are the most time-consuming parts of the PSUR process, companies should commit themselves to an ongoing review process, regardless of when a PSUR falls due. It is also advisable to set up an in-house safety review commit-tee, as Lundbeck has done. The medical reviewer responsible for a given medical product may become too close to the data to judge it objectively and may end up overlooking signals. The safety review committee should be composed of senior, experienced individuals who are not directly involved in the safety evaluation of the medical product. This committee should meet regularly, say quarterly, to take a fresh look at the data and to bring to the review process a broader medical expertise than was available in the initial evaluation.


Measures should be put in place to monitor existing processes, to ensure that they remain effective and efficient and that corrective actions are having the intended effect. An example of such a metric would be looking at the number of avoidable ADRs that were due to a newly identified drug–drug interaction. Risk management initiatives could be put in place to address such a finding, such as a label change or patient education. The results of these initiatives should be reflected in subsequent PSURs. Other examples of PSUR metrics are summarised in Table 6.3.

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