Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies

Abstract

Background: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).

Objectives: We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.

Data sources: Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.

Study appraisal and synthesis methods: Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.

Results: From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of >or=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.

Conclusions and implications of key findings: The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered.

Figure 1. Flow chart of methodology for identifying pharmacogenetic studies in the systematic review.

From PRISMA 2009 guidelines .

Figure 2. Growth in publications in the field of pharmacogenetics from 1967–2007 (inclusive).

Our detailed search strategy incorporating both Medical Subject Headings (MeSH) and free-text terms (filtered for Humans and excluding Reviews/Editorials) identified 6,548 original articles (purple bars) of which 1,668 fulfilled the inclusion criteria (green bars). By contrast the total number of articles obtained based on a search using the MeSH term “pharmacogenetics” (including reviews and editorials) was 4,674, of which only 183 were original articles (red bars), indicating a ratio of approximately 1∶25 of original research to commentary/review.

Figure 3. The 50 most frequently studied genes and the aggregate number of participants per gene.

(a) pharmacodynamic genes (n = 305); (b) pharmacokinetic genes (n = 70); and (c) somatic genes (n = 176). * refers to >1 gene and/or non-HUGO nomenclature.

Figure 4. Categories of drugs evaluated in pharmacogenetic studies of the 10 most frequently studied genes.

(a) pharmacodynamic; and (b) pharmacokinetic. Numbers represent total studies per gene and drug category, with cell color shading to emphasize value (heat matrix). CNS = central nervous system; ENT = ears, nose and throat. Drugs are classified as in British National Formulary (http://www.bnf.org).

Figure 5. Sample size of pharmacogenetic studies from 1987 to 2007 (inclusive).

Horizontal bars designate the median, boxes indicate 25^th and 75^th centiles of the distribution and vertical bars represent the non-outlier range.

Figure 6. Distribution of p values in 161 full-text primary research articles in pharmacogenetics.

Figure 7. The theoretical number of total comparisons in 161 full-text articles.

Calculated by multiplying the number of gene alleles studied by the number of drugs investigated by the number of outcomes recorded.

Figure 8. Medline annotation of studies provided by U.S. Food and Drug Administration (FDA; n = 136) as references for “approved biomarkers.”