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It is anticipated that genotyping at different stages of clinical trials would change
the approach to drug development. Currently there are four phases of clinical trials
followed by postmarketing studies. Suggestions to shorten the clinical drug devel-
opment process by reducing the number of phases are as follows:
- Phase I. Genotyping and ADME studies. Selection of patients for phase II.
- Phase II. Main study.
- Phase III. May be replaced by an extension of the phase II and analysis of data to
identify responders vs non-responders and those who have adverse reactions.
Large-scale genotyping to discover new pharmacogenomic markers. - Post-marketing studies. Detection of rare events and development of diagnostic
tests tied in with the drug therapeutics.
Some drawbacks of pharmacogenomics-based clinical trials are: - Exclusion of certain subjects from trials on the basis of genotype is interpreted s
discrimination similar to exclusion of women and minorities - Stratifi cation into smaller subgroups might confound statistical analysis and
interpretation of results - Statistical differences may not be clinically signifi cant
- Misuse of the good results in a subgroup to portray the drug as a whole
- Need to do separate clinical trials in different countries
Limitations of the Pharmacogenomic-Based Clinical Trials
Large prospective trials to demonstrate the value of genotyping in patient manage-
ment will be required to support the introduction of pharmacogenomics into clinical
practice. Some of the limitations to be considered are:
- Such studies are costly and can be justifi ed only if there is a reproducible
association between genotype and a clinically relevant phenotype. - Non-replication is prevalent among genetic association studies. It may refl ect
real population differences but multiple comparisons, biases and other design
limitations suggest that many initial positive associations represent Type I errors. - Successful detection of a true genetic effect requires not only an informed and
careful selection of candidate genes but also the assiduous application of sound
principles of study design. - Independent and prospective confi rmation of the hypothesized genetic effect in a
population similar to the one originally studied is required.
In selected situations, pharmacogenomic studies in healthy volunteers may sup-
port a decision to perform such prospective association studies. If the results of
these studies are signifi cant and potential health or economic benefi ts of therapy are
considerable, a major clinical trial can be considered to assess the usefulness of a
pharmacogenomics-based therapy.
5 Pharmacogenomics