Pharmacogenetics (PGX) is the study of drug response as a function of an 
individual's DNA. PGX is often viewed as an extension of disease association 
genetics, and although this information may be related, it is not the study of 
drug response. Although medicines are used to treat diseases, the value of 
strategies that identify and incorporate DNA biomarkers associated with clinical 
efficacy, or DNA biomarkers for untoward clinical responses, can be applied 
directly to pharmaceutical pipelines. The growth of adverse event PGX studies 
involving marketed medicines generally uses relatively large numbers of affected 
patients, but has been productive. However, the two critical strategies for 
pipeline genetics must make use of fewer patients: (1) the early identification 
of efficacy signals so that they can be applied early in development for 
targeted therapies and (2) identification of safety signals that can 
subsequently be validated prospectively during development using the least 
number of patients with adverse responses. Assumptions are often made that large 
numbers of patients are necessary to recognize PGX hypotheses and to validate 
DNA biomarkers. In some ways, pipeline pharmacogenetics may be viewed as the 
opposite of current genome-wide scanning designs. The goal is to obtain PGX 
signals in as few patients as possible, and then validate PGX hypotheses for 
specificity and sensitivity as development trials go forward--not using hundreds 
of thousand of markers to detect strong linkage disequilibrium signals in 
thousands of patients and their controls. Drug development takes 5-7 years for a 
drug candidate to traverse to registration--and this is similar to the timeframe 
for validating genetic biomarkers using sequential clinical trials. Two 
important examples are discussed, the association of APOE genotypes to the 
demonstration of actionable efficacy signals for the use of rosiglitazone for 
Alzheimer's disease; and the identification of HLA-B(*)5701 as a highly 
sensitive and specific predictive marker for abacavir treated patients who will 
develop hypersensitivity syndrome (HSS). The rosiglitazone study prevented 
pipeline attrition by changing the interpretation of a critical Phase IIB proof 
of concept study (2005) from a failed study, to a positive efficacy response in 
a genetically predictable proportion of patients. Now, three years later, a 
Phase III program of clinical trials using pharmacogenetic designs is months 
away from completion (late08). If successfully registered (early09), millions of 
patients could benefit, and efficacy PGX would have achieved its first 
prospective block-buster. The use of safety candidate gene association genetics 
in patients who received abacavir therapy and developed HSS starting in 1998 
culminated in a double blind clinical trial that determined sensitivity > 97% 
and specificity >99% in 2007. Clinical consensus panels rapidly recommended 
abacavir as the preferred therapy along with HLA-B(*)5701 pre-testing, 
immediately increasing the market share of abacavir with respect to other 
reverse transcriptases that are associated with there own adverse events. 
Targeting of medicines during drug development is now possible, practical, and 
profitable.