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Objective 1) To compare the Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's (EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products. Methods FDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs. Results We identified 95 drugs on FDA's REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%). Conclusions Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.

The initial results are reported of a case-control study undertaken on the VAMP multi-purpose database and designed to estimate the risk for first-time occurrence of myocardial infarction in users of hormone replacement therapy (HRT). The findings currently available relate to the computerized data and show 2- to 5-fold increases in risk in smokers and those with diabetes mellitus, hypertension or hyperlipidaemia. With any form of HRT, a non-significant protective effect [adjusted odds ratio = 0.83 with 95% CI (confidence intervals) of 0.66-1.03, p = 0.089] has been shown. However, the protective effect of HRT in the data available to date appears to be confined to non-smokers in whom the odds ratio in the absence of other risk factors is 0.70 (95% C1 of 0.49-1.00). The comparable odds ratio in smokers is 1.05 (95% CI of 0.71-1.53). These results should be interpreted with caution as smoking status was unknown for about half of the subjects and was more complete among the cases than controls.

Objective: Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk–benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. Methods: Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. Results: Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk–benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk–benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. Conclusions: Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk–benefit profile.

Bisphosphonates are currently among the most effective therapies for the treatment of osteoporosis and provide one of the mainstays of treatment in the UK. However studies in several countries have all reported sub-optimal compliance and persistence with treatment.To examine the impact of dosing frequency on compliance and persistence with bisphosphonates in the UK.Three UK General Practitioner sourced databases, the General Practice Research Database (GPRD), IMS Disease Analyzer (MEDIPLUS) and the Doctors Independent Network Database (DIN-LINK) were used to identify bisphosphonate naïve postmenopausal women. In each of the three retrospective analyses women were grouped into weekly or daily cohorts and followed for 12 months from an initial prescription. Compliance was measured as a Medication Possession Ratio (MPR), defined as the proportion of days for which patients had prescription coverage. Persistence was measured as the number of continuous days of treatment from the initial prescription to the end of the last prescription issued in the follow-up period.GPRD, MEDIPLUS and DIN-LINK provided access to 7567, 5962 and 1801 women, respectively. All three analyses consistently demonstrated that those on weekly regimens had a higher MPR than those on daily regimens (GPRD 76.2%, CI(95%,) 75.4-77.0 vs. 63.5%, CI(95%) 61.2-65.8, MEDIPLUS 70.3%, CI(95%) 69.3-71.2 vs. 56.3%, CI(95%) 53.8-58.9, DIN-LINK 59.5%, CI(95%) 59.4-59.6 vs. 46.3%, CI(95%) 45.9-46.7) (p0.0001) and persisted longer with treatment (GPRD 249, CI(95%) 246-253 vs. 208, CI(95%) 199-217, MEDIPLUS 228, CI(95%) 224-231 vs. 186, CI(95%,) 176-196, DIN-LINK 235, CI(95%) 234-236 vs. 189, CI(95%) 187-191) days respectively), (p0.0001).Although this study only provided an indirect measure of medication usage, it demonstrated that a less frequent dosing regimen significantly improved levels of both compliance and persistence; however, even on weekly regimens bisphosphonate usage remains sub-optimal thereby reducing the clinical benefits.

Abstract 4549 Introduction Chronic lymphocytic leukemia (CLL) is the most common adult haematological malignancy in the Western world. It remains incurable and follows an extremely variable clinical course with survival ranging from months to decades. In those who become refractory to fludarabine based therapy, median survival is less than 1 year. Methods To identify data related to the clinical and economic sequelae of patients in routine clinical care diagnosed with refractory CLL, a systematic literature search of MEDLINE and EMBASE was conducted for the period January 1999-July 2009. The search terms used included incidence, prevalence, natural history, characteristics, clinical management, clinical outcomes, use of health care resources and was focused on patients with fludarabine refractory CLL also refractory to alemtuzumab (fludarabine and alemtuzumab refractory) or less suitable for alemtuzumab due to bulky lymph nodes (bulky fludarabine refractory). Supplementary checks were made of reference lists, particularly in review articles. Relevant conference proceedings for the period January 2006-July 2009 were also examined. Results The search of MEDLINE and EMBASE identified 102 articles of which 26 reported on the more general populations of patients with haematological malignancies, 61 on CLL and 15 on refractory CLL. Of those articles reporting data in relation to CLL (n=61), 49 described patient characteristics and outcomes, prognostic factors, diagnostic and treatment options, natural history of the disease, epidemiology, patient management and specific treatment outcomes and 12 review articles addressed areas such as prognostic factors and treatment options. Of those reporting on refractory CLL (n=15), one was a review article of novel agents and 14 were studies evaluating outcomes following salvage treatment with various pharmaceutical agents and other therapeutic interventions but mainly in patients refractory to fludarabine. Only one US study had evaluated patients who were refractory to both fludarabine and alemtuzumab or were bulky fludarabine refractory, examining response and survival following a variety of salvage treatments (Tam et al. Leukemia and Lymphoma 2007;48:1931-9). The search of conference proceedings identified 27 abstracts, 19 of which evaluated patients with CLL reporting on a range of topics including natural history and survival, prognostic factors and outcomes achieved with existing and experimental pharmaceutical interventions. Only two abstracts specifically reported on patients who were refractory to both fludarabine and alemtuzumab or were bulky fludarabine refractory, examining response rates following administration of a novel pharmaceutical agent (European Haematology Association Meeting 2009, abstracts 0494 and 0919). Conclusions There is very little data from clinical practice on clinical outcomes and none on economic sequelae for patients with double refractory or bulky nodal refractory disease. The lack of such data is likely to hinder the achievement of better outcomes for patients and the evaluation of cost effectiveness for newer agents. This lack of data to inform clinical practice and decision making has prompted the initiation of an observational study in five European countries with the objectives of characterising the current patterns of care, survival outcomes and resource utilization in double refractory and bulky nodal refractory CLL patients in Europe. The study, based on a retrospective chart review of approximately 250 patients, is currently underway in France, Germany, Italy, Spain and the UK. It is anticipated that the results, planned to be available by the end of 2009, will help to identify unmet clinical needs, quantify the clinical and economic burden in this particular population and contribute to the development of new treatment guidelines. Disclosures: Lévy: GlaxoSmithKline: Consultancy. Payne:GlaxoSmithKline: Consultancy. Wasiak:GlaxoSmithKline: Consultancy. Lis:GlaxoSmithKline: Consultancy.