Clinical use of pharmacogenetic tests: an official statement issued by The Japanese Society of Clinical Pharmacology and Therapeutics
Pharmacogenetic tests deal with germline genetic information on drug response (genetic test) and benefit patients as a medical technology that guides individualized medicine in practice. In recent years, the number of pharmacogenetic tests has been increasing; some of them are covered by insurance. Therefore, the Japanese Society of Clinical Pharmacology and Therapeutics makes this statement of proposal to promote pharmacogenetic testing in medical practice further. These recommendations are based on general theories of medical practice and are not intended to be used as materials or grounds for individual medical lawsuits. These recommendations will be revised if the medical environment or scientific basis for pharmacogenetic testing changes with the development of new drugs or genome research in the future.
●Pharmacogenetic testing covered by the proposal
In this proposal, pharmacogenetic testing is defined as “testing handling germline genetic information on drug response (genetic testing)” and applying pharmacogenetic testing for which test results are not related to the definitive diagnosis or risk prediction of genetic diseases requiring medical care is organized. “Drug response” here refers to the pharmacokinetics (absorption, distribution, metabolism, and excretion) and effects (efficacy and adverse effects) of a drug in the body. “Genetic diseases requiring medical care” are defined as diseases that directly affect vital prognosis and quality of life (QOL), and thus require treatment to cure or alleviate symptoms, including diseases for which prophylactic medical care or early detection of disease onset is possible. Generally, genetic testing for these diseases is the subject of genetic counseling. Pharmacogenetics is defined as “the study of DNA sequence variation associated with drug response” in the “The Terminology of pharmacogenomics” (2008) by the Ministry of Health, Labour and Welfare of Japan. Based on this definition, the “Guidelines for Genetic Tests and Diagnoses in Medical Practice” (2011) by the Japanese Association of Medical Sciences defines pharmacogenetic testing as “testing that handles germline genetic information about drug response.”
With the development of new drugs in recent years, some genetic tests used for diagnosis and prediction of disease onset are also used to determine the indication of therapeutic drugs (Note 1). In addition, comprehensive analysis of cancer-related genes may reveal the presence of variants related to drug response in the germline (secondary findings) other than the original purpose of testing. The number of such cases in which pharmacogenetic testing is relevant to diagnosing and predicting disease onset is expected to increase further with the development of genomic medicine. Therefore, future pharmacogenetic testing should clarify whether pharmacogenetic tests are only relevant to drug response or whether they are also relevant to definitive diagnosis and risk prediction of genetic diseases that require medical care.
Pharmacogenetic tests not related to definitive diagnosis or risk prediction for the development of hereditary diseases requiring medical care are listed in Table 1.
On the other hand, the “Guidelines for Genetic Tests and Diagnosis in Medical Practice” (revised in 2022) should be applied to pharmacogenetic testing related to the definitive diagnosis and risk prediction of genetic disorders requiring medical care. In addition, the “Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects” (2021) shall be applied when pharmacogenetic testing is conducted as research, regardless of whether or not it is related to the definitive diagnosis or risk prediction of genetic disorders requiring medical treatment.
(Note 1) Pathological variants of the germline BRCA1/2 gene are used in the diagnosis of hereditary breast and ovarian cancer syndrome (HBOC). On the other hand, the pathological variants cause abnormal DNA homologous recombination repair and are associated with sensitivity to platinum and PARP inhibitors. Recently, it is used as a companion diagnosis in the treatment of breast, ovarian, pancreatic, and prostate cancers, which are HBOC-related tumors, to determine the indication for PARP inhibitors. The diagnosis of high frequency microsatellite instability in tumor cells is used to determine the indication for immune checkpoint inhibitors, and is also used to screen for Lynch syndrome. Lynch syndrome is diagnosed when MLH1/MSH2/MSH6/PMS2 gene variants are identified by genetic testing.
●Characteristics and operation of pharmacogenetic tests not related to definitive diagnosis or risk prediction for the development of genetic diseases requiring medical care
Pharmacogenetic testing provides useful information for patient care by avoiding administering drugs with dangerous adverse reactions or poor efficacy and estimating the appropriate dosage. The germline genetic information revealed by pharmacogenetic testing shares characteristics with another germline genetic information in that it does not change throughout life and is shared among family members. However, suppose the genetic information obtained by pharmacogenetic testing is not directly related to the definitive diagnosis or prediction of the risk of developing a genetic disease requiring medical treatment. In that case, no special ethical considerations are necessary for the test, and the test can be performed in the same way as routine medical care.
On the other hand, although access to genetic information obtained by pharmacogenetic testing does not require meeting special restrictions, it necessitates education and training for medical personnel who do not specialize in pharmacogenetics to further promote the use of pharmacogenetic testing in medical practice.
When pharmacogenetic testing is performed, efforts should be made to ensure quality and accuracy control in accordance with the standards specified in the Medical Care Act and other laws.
Among pharmacogenetic tests that are not related to the definitive diagnosis or risk prediction of hereditary diseases that require medical care, those that are performed as part of insurance-covered care are covered by the broad consent for general medical care (Table 1). Therefore, as with ordinary blood tests and minimally invasive treatments and procedures, these tests and treatments can be performed without written explanation and consent procedures under the broad consent (Note 2).
Pharmacogenetic tests that are not related to the definitive diagnosis or risk prediction of hereditary diseases requiring medical care but are not covered by insurance (Table 1), such as those described only in the package insert or medical care guidelines, can be performed in the same way as blood tests in general medical care if accurate and sufficient information (Note 3) is provided to patients, they understand the information, and they consent without coercion or undue inducement. In principle, a verbal explanation should be given and verbal consent obtained. The details of oral consent, the genetic information obtained, and subsequent actions should be recorded in the medical record (medical charts) to be shared among medical care providers and used for medical treatment. If the test is conducted as research, it should follow the “Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects.”
(Note 2) Broad consent is obtained by thoroughly explaining and securing approval for minimally invasive medical procedures performed in general medical care. There are methods such as obtaining consent by providing a comprehensive explanation in writing to first-time patients at the time of application for medical treatment or by notifying patients of the facility’s policy on a website or hospital bulletin board and using an opt-out method.
(Note 3) Includes test name, purpose and limitations, content and methods, expected information and need, expected benefits and disadvantages, options for patients who choose not to be tested, costs, second opinion, and genetic counseling.
Genetic counseling is not necessarily required for pharmacogenetic tests that are not related to the definitive diagnosis or risk prediction of a genetic disease requiring medical care. However, genetic counseling is provided at the appropriate time as deemed necessary by the physician or if the patient requests it as the test handles germline genetic information.
●Protection of personal information
Regardless of whether it is related to the definitive diagnosis or prediction of the risk of developing a genetic disease requiring medical care, orders and restuls of pharmacogenetic tests (including in-hospital ordering systems) are medical information and, like other medical information, should be shared among medical care providers and recorded in the medical records (medical charts) for use in medical care, and should be managed appropriately as personal information requiring special consideration (Note 4).
(Note 4) Depending on the number of loci and sequences, the sequence of bases that make up the DNA revealed by pharmacogenetic testing is a personal identification code defined by the Act on the Protection of Personal Information (2017) and constitutes personal information requiring special consideration. Guidelines for the Act on the Protection of Personal Information (General Rules) https://www.ppc.go.jp/personalinfo/legal/2009_guidelines_tsusoku/ (last accessed June 20, 2022)
The Japanese Society of Clinical Pharmacology and Therapeutics