Comparisons of Food and Drug Administration and European Medicines Agency risk management implementation for recent pharmaceutical approvals: report of the International Society for Pharmacoeconomics and outcomes research risk benefit management working group.

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.

A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group.

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.

The impact of dosing frequency on compliance and persistence with bisphosphonates among postmenopausal women in the UK: evidence from three databases.

BACKGROUND: 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. OBJECTIVE: To examine the impact of dosing frequency on compliance and persistence with bisphosphonates in the UK. METHODS: 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. RESULTS: 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) (p < 0.0001) 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), (p < 0.0001). CONCLUSIONS: 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.

Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines.

The initial identification of the ALK gene, expressed as C-terminal part of the transforming fusion protein NPM-ALK in the t(2;5)(p23;q35) lymphoma-associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK). In order to expand the knowledge on ALK expression in the human system, we examined a panel of human cell lines for ALK expression and found that transcription is completely repressed in cell lines of entodermal origin (0/21). Furthermore, full length receptor expression is absent in cell lines of the hematopoietic system with the exception of t(2;5)-associated anaplastic large cell lymphomas lines (ALCL), which are known to express chimeric NPM-ALK mRNA. Cell lines established from solid tumors of ectodermal origin, including melanoma and breast carcinoma, exhibited widespread mRNA expression of the ALK receptor at a broad range (53/64), an association which was found to be strongest in cell lines derived from neuroblastoma (6/6), glioblastoma (8/8) as well as in cell lines established from Ewing sarcoma (4/4) and retinoblastomas (2/2). Because of the reported involvement of neutrophin tyrosine kinase receptors in autocrine differentiation in neuroblastomas, we analyzed cell lines positive for full length or chimeric ALK protein for the presence of phoshotyrosine residues within the intracellular region of ALK. While the constitutive activation of chimeric NPM-ALK molecules could be shown, no evidence was found for induced or constitutively activated ALK receptors in neuroblastoma, melanoma or breast carcinoma cell lines. Although the receptor could be shown to be consistently expressed with exclusive specificity in tissues developed from the ectoderm, our results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation so far, indicating that ALK expression is a physiologic rather than a pathologic phenomenon.