Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan

Abstract

Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non-responders and high-/lowrisks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of

Pharmacogenomics in the clinic

“…Given the high bar required for clinical actionability, the number of actionable inherited genes (those that have at least one actionable “high risk” diplotype) and the list of medications for which clinical actions can be recommended (pharmacogenetically “high risk” drugs) is relatively short (Table 1). We acknowledge that there are additional medications for which regulatory agencies include pharmacogenomic information in their labels; 35–37 however, not all such mentions are actionable. Information on genetic variation is sometimes included even when the effects are modest (and therefore don’t translate into changes in the prescribing sections of the drug label), and have been included for some drugs when the evidence is weak or conflicting.…”

“…37 Although about 15% of EU-EMA and US-FDA approved medications contain pharmacogenomic information in their label 35 http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm), only a subset of these are deemed actionable. As summarized in Figure 2, the use of only about7% of medications have actionable germline pharmacogenetics (https://www.pharmgkb.org/cpic/pairs, corresponding to CPIC level A and level B genes/drugs---corresponding to actionable prescribing recommendations).…”

Personalized Medicine: The Future of Health Care

“…Such translation requires that effective, alternative therapy is available for those with 'high-risk' genotypes, as well as improvements to health care systems, structured approaches to guide prescribing (for example, algorithms), and implementation of point-of-care electronic clinical decision support, to make it feasible to utilize genetics appropriately to guide drug prescribing. (75) More than 1,200 individual molecular entities have been approved as drugs by the US Food and Drug Administration (FDA) (76), the European Medicines Agency (EMA) (77) or by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) (78). Although about 15% of the medications approved by the FDA and EMA contain pharmacogenomic information on their label, Pharmacogenomics only a subset of the corresponding pharmacogenes is deemed actionable.…”

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

“…Genomewide association studies focusing on the response to drugs, which include analyses of candidate genes encoding DMEs, reveal the endogenous effects of genetic variations that affect drug metabolism and drug responses (Low et al, 2014;Sim et al, 2013). However, the application of pharmacogenomics in the treatment of individual patients is rarely undertaken (Ishiguro et al, 2013). Furthermore, systematizing relevant information about genetic variants is important for optimizing pharmacotherapy administered to Japanese populations, particularly because of different in allelic and genotypic frequencies and drug dose requirements among ethnic groups (Ota et al, 2015).…”