Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group.

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.

Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact.

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted.

Same drug, different dosing: differences in dosing for drugs approved in the United States, Europe, and Japan.

With globalization of the pharmaceutical industry, newly approved drugs nearly always become available worldwide, including the 3 major pharmaceutical regions: the United States, Europe, and Japan. One might think that these drugs would have the same recommended dosing throughout the world, but this appears not to be true in many instances. The objective of this study was to identify any patterns of differences in labeled dosing. Approved labeling, for the most widely prescribed proprietary drugs in the United States, was used as a basis for this study. Dosing was compared, for common indications, for the United States, Europe, and Japan. Overall, these data indicate that there are numerous differences in approved dosing for drugs approved in all 3 regions. For about half of the drugs studied, dosing in Japan is considerably lower than the United States or Europe. Some differences in dosing are also apparent between the United States and Europe.

Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999.

PURPOSE: Risks and benefits of marketed drugs can be improved by changing their labels to optimize dosage regimens for indicated populations. Such postmarketing label changes may reflect the quality of pre-marketing development, regulatory review, and postmarketing surveillance. We documented dosage changes of FDA-approved new molecular entities (NMEs), and investigated trends over time and across therapeutic groups, on the premise that improved drug development methods have yielded fewer postmarketing label changes over time. METHODS: We compiled a list of NMEs approved by FDA from 1 January 1980 to 31 December 1999 using FDA's website, Freedom of Information Act request, and PhRMA (Pharmaceutical Research and Manufacturers of America) database. Original labeled dosages and indicated patient populations were tracked in labels in the Physician's Desk Reference. Time and covariate-adjusted risks for dosage changes by 5-year epoch and therapeutic groups were estimated by survival analysis. RESULTS: Of 499 NMEs, 354 (71%) were evaluable. Dosage changes in indicated populations occurred in 73 NMEs (21%). A total of 58 (79%) were safety-motivated, net dosage decreases. Percentage of NMEs with changes by therapeutic group ranged from 27.3% for neuropharmacologic drugs to 13.6% for miscellaneous drugs. Median time to change following approval fell from 6.5 years (1980-1984) to 2.0 years (1995-1999). Contrary to our premise, 1995-1999 NMEs were 3.15 times more likely to change in comparison to 1980-1984 NMEs (p = 0.008, Cox analysis). CONCLUSIONS: Dosages of one in five NMEs changed, four in five changes were safety reductions. Increasing frequency of changes, independent of therapeutic group, may reflect intensified postmarketing surveillance and underscores the need to improve pre-marketing optimization of dosage and indicated population.