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Evaluating the evidence base in pharmacovigilance decision making

Student thesis: Doctoral Thesis

Introduction It has been said that through monitoring of drug safety, pharmacovigilance (PV) systems have been instrumental in assisting regulatory decisions on product safety. However, there has been no, systematic, in-depth study of this role. This thesis reports such a study conducted in the UK. On the basis of the results, suggestions are made on how PV data might be produced and used more effectively. Methods In Phase 1, a scoping study was conducted to document all changes made to UK product labelling on safety grounds over a 10 year period (September 1st 1995 to August 31st 2005). In Phase 2, all product withdrawals and major labelling changes made during the 10 year study above, were investigated in depth to determine the therapeutic group, source of ADR data cited as the reason for the change; and product survival probability, using Kaplan-Meier modelling. Phase 3, informed by Phases 1 and 2, used a web-based survey (150 respondents) and structured interviews (13 subjects) with healthcare professionals and scientists with a PV role in the NHS, pharmaceutical companies and the UK regulator, to gain views on the current procedures for handling safety issues in the UK and how these might be improved. Inferences were drawn using interpretative henomenological analysis with NVivo 8 software. Key findings Phases 1 and 2 revealed the fragmentary nature of information in the public domain and the difficulties of obtaining unpublished information. Based on public information, Phase 1 showed that 2,630 safety notices were issued affecting 688 individual products. The two main safety notice categories were drug interactions (841;32%) and side effects (537;20%). The rank order of the four most common therapeutic areas in which safety notices occurred was: CNS (23.5%)> anti-infectives (21.6%) > cardiovascular (15.2%) > cancer chemotherapy (10.8%). The ratio of Type A : Type B side effects (ADRs) was 1:3.3. Phase 2 found that of 518 eligible products launched during the study period, 9 (1.7%) were licensed and withdrawn for safety reasons. The ten-year Kaplan-Meier probability of adverse drug reactions causing the withdrawal of a new product, postmarketingwas 2.2%. All decisions were based on more than one safety data type and all involved UK yellow cards. One decision considered prescription event monitoring (PEM) data. A total of 164 important safety notices affecting 818 individual products were identified. Of 518 products launched during the study period, 56 experienced at least one major labelling change for safety reasons. The ten-year Kaplan-Meier risk of a product experiencing at least one major labelling change on safety grounds was 13.8%. As with product withdrawals, safety decisions were based on a wide range of data sources of variable quality and quantity. Variation in dissemination of the new safety information was observed. Only one fifth of safety notices warranting a ‘Dear Healthcare Professional’ letter or a monograph in ‘Current Problems in Pharmacovigilance’, were accompanied by a boxed warning in the BNF, representing an important inconsistency in notifying prescribers. As with interview participants, respondents to the on-line questionnaire had difficulties placing the yellow card reports in a formal hierarchy of evidence whilst acknowledging that the data were valuable in the decision making process. Suggested ways of improving the quality of such reports included making the reporting more accessible and training all those eligible to report. PEM studies were cited by the majority of respondents as a means of generating credible safety data and raising the general quality of the drug safety database. In terms of dissemination and education about ADRs, Drug Safety Updates (which replaced the ‘Current Problems’ publication from the MHRA in August 2007) were highly thought of; they appeared to be more popular than ‘Dear Healthcare Professional’ letters and because they were web-based, ought to be accessible by a wider audience. Conclusions Safeguarding public health is of utmost importance when making a decision whether or not to withdraw a product or amend its labelling upon the emergence of new safety data. Labelling changes should be made only on the best evidence available at the time and appropriate risk management strategies should be instigated where feasible; not only when a safety signal arises post-marketing, but when a drug is first granted a marketing authorisation. There is no general consensus on what constitutes ‘best evidence’ and rating evidence using traditional hierarchies is problematic, The GRADE hierarchy may be an exception. Improving ADR reporting should lead to improved data bases from which to draw safety conclusions. Methods of improving reporting include early instigation and enforcement of risk management plans by the regulator, education of all those eligible to report, greater transparency of regulatory decisions and better and more rapid dissemination of safety change information.
Original languageEnglish
Awarding Institution
Thesis sponsors
  • Drug Safety Research Unit
Award dateOct 2010
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