Textbook of Personalized Medicine - Second Edition [2015]

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Impact of Genetic Profi ling on Clinical Studies

Genotyping is important in design and interpretation of clinical studies. Advantages
of molecular genetic profi ling in clinical studies are:

• It is a contribution to molecular defi nition of the disease


• Correlation of drug response to the genetic background of the patient


• Prediction of dose-response and adverse effects


• SNP mapping data can be used to pinpoint a common set of variant nucleotides
  shared by people who do not respond to a drug


• Samples collected during clinical trials can be used for drug discovery

Clinical trials should be structured in such a way that all the test groups will
contain adequate numbers of different phenotypes within polymorphisms. In case of
a genotype-specifi c drug, test groups should contain only the targeted phenotypes.
Molecular genetic methods may be applied both for genetic profi ling (polymorphisms,
mutations, etc.) of cohorts and for monitoring and guidance of therapies.
Genetic profi ling can be used for stratifying subjects in clinical trials. Genotype/
phenotype correlations based on identifi cation of mutations and polymorphisms are
used for population segmentation. For example, pharmaceutical companies could
use the correlation data from phase I and phase II clinical trials to determine the size
of the patient population that would benefi t from the drug under development. They
would also know the size of the clinical group needed for a phase III clinical trial to
obtain statistically signifi cant data to support the clinical development program.
This number should be much lower than that required currently for phase III clinical
trials because by this stage, the patients are known to have a genotype that suggests
a favorable response to the drug.
Pharmacogenomic tests used by the pharmaceutical companies themselves can
be used to help identify suitable subjects for clinical trials, aid in interpretation of
clinical trial results, fi nd new markets for current products and speed up the devel-
opment of new treatments and therapies.

Table 5.4 Examples of pharmacogenomics-based clinical studies

Disease Drug Polymorphism Results
Asthma Zileutin ALOX5 genotype Reduced response among
heterozygotes
Alzheimer’s
disease

Tacrine ApoE4 genotype Those with ApoE4 gene
show poor response
Coronary heart
disease

Pravastatin Polymorphism of cholesteryl

ester transfer protein at

site B1B1

Better response to pravastatin
than those with
polymorphism at B2B2
Schizophrenia Clozapine 5HT2A receptor C102 allele Improved response to
clozapine
© Jain PharmaBiotech

Pharmacogenomics and Clinical Trials