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Explanation for “Guidelines for Clinical Studies and Tests Using Pharmacogenomics”

Guidelines for Clinical Studies and Tests Using Pharmacogenomics

1. According to the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) and The Ministry of Health, Labor and Welfare the definitions of Pharmacogenomics ( PGx) and Pharmacogenetics (PGt) are as follows; PGx is a study about mutant characters of DNA and RNA related to drug response while PGt is a part of PGx, specifying mutant DNA sequences related to drug response. These definitions have also been described in the guidelines.
2. The current situation of Pharmacogenomics:
Pharmacogenomics has rapidly progressed from an investigational stage to a clinical application. For example some genetic tests are on the NHI (National Health Insurance) price listing as follows; UGT1A1 genetic test to predict adverse events of irinotecan, an antineoplastic agent, Bcr-Abl genetic test to predict the efficacy of imatinib, a drug for leukemia, EGFR genetic test to predict the efficacy of gefitinib, a drug for lung cancer and K-Ras genetic test for cetuximab treatment for colorectal cancer. In addition, the relation between the adverse events of carbamazepine and allopurinol and HLA gene is stated on drug package insert.
Although Pharmacogenomic tests are available in our nation, the applications are limited due to insufficient understanding including matters of ethical issues. Or usually, we might hesitate to use Pharmacogenomic tests because there are no specific guidelines for Pharmacogenomics, excluding some cases. It is assumed that many patients are deprived of an opportunity for better treatment and so is the nation for lower health care costs.
Also, in Japan, many Pharmacogenomic tests are not on the NHI price listing such as the gene expression information analysis to predict the efficacy of breast cancer drugs even though they are applied in foreign countries.
There will probably be many Pharmacogenomic tests appearing in clinical trials because there are a great number of Pharmacogenomic studies in investigational stages.
3. Classification of Pharmacogenomic studies and tests:
Pharmacogenomic studies and tests are classified as (1) germline information studies and tests, (2) somatic mutation studies and tests, and (3) gene expression information studies and tests. Ethical issues particular to human genomes and genes lie only in (1) germline information that are passed down for generations. Therefore other types of studies and testing should be considered as usual clinical tests.
Aforementioned UGT1A1 and HLA gene tests belong to (1), Bcr-Abl gene, EGFR gene and K-Ras gene tests belong to (2) and gene expression information analysis to predict the efficacy of breast cancer drug belong to (3).

4. The difference between Pharmacogenomic studies / tests and genetic studies / tests and basic principle of the present guidelines:
It is often difficult to avoid phenotypes generated as a result of genotypes in frequently conducted genetic studies / tests of germline in genetic diseases. However, in Pharmacogenomic studies / tests, even for germline information, it is possible to avoid phenotypes generated as a result of genotypes. Meaning it is possible to avoid phenotypes that causes ‘no response’ or ‘adverse events’ by choosing the right drug. Therefore the degree of ethical issues is quite low in the latter case. The basic principle of the present guideline suggest that Pharmacogenomic studies / tests should be handled as usual clinical studies excluding some cases of possible monogenic disease accompanied by a health disorder.

5. The range covered by the present guideline is as follows:
(1) Pharmacogenomic tests related to health insurance treatment and advanced medical care.
(2) Pharmacogenomic studies conducted for clinical researches (GCP not applied) that are not clinical trials or post-marketing clinical tests.
(3) Pharmacogenomic studies related to clinical trials or post-marketing clinical test (GCP applied).
This excludes Pharmacogenomic studies / tests for general public such as determination of parentage or constitution tests.

6. Positive influences expected by releasing the present guideline:
(1) Promote public understanding of Pharmacogenomic and Pharmacology.
(2) Promote public understanding of Pharmacogenomic studies / tests and its 3 classes, which also enables us to clarify exactly where ethic issues particular to human genomes lie.
(3) Promote proper use of gene tests that are included in health insurance treatment and advanced medical care. This will encourage doctors who hesitate to try such tests due to insufficient understanding of their classification, contents, issues and guidelines.
(4) Promote proper use of Pharmacogenomic studies to which GCP are not applied. It will encourage researchers who hesitate to try the studies due to insufficient understanding of their classification, contents, issues and guidelines.
(5) Promote proper use of Pharmacogenomic studies related to clinical trials or post-marketing clinical tests to which GCP are applied. It will encourage researchers and companies that hesitate to try such studies due to insufficient understanding of their classification, contents, issues and guidelines, which will help us to catch up on international competition for new drug development.
(6) Because the communities of medicine, pharmacology, and laboratory medicine have joint conferences, the present guidelines are expected to guide many people in those fields.
(7) Help us to understand the reason why specific guidelines for Pharmacogenomics are necessary when we already have ones for genetic tests that are mostly used for genetic diseases or human genome / gene analysis research.