Challenge of Evidence in Individualized Medicine

Kathleen Kraft; Wolfgang Hoffmann


Personalized Medicine. 2012;9(1):65-71. 

In This Article

Individualized Medicine in Guidelines?

Chronic myelogenous leukemia (CML) has been a model disease for the development of targeted therapies for individualized medicine. CML is a neoplastic disease of the bone marrow stem cells and is characterized by the presence of the Philadelphia chromosome (t[9;22][q34;q11]) a translocation that results in the BCRABL fusion gene.[27] In fact, because the disease is caused by this one gene, there is an excellent efficiency of molecular targeted therapy with small molecules designed to block the pathogenetic tyrosine kinase BCR-ABL. The detection of the oncogene allows for a therapy that targets a pathology on the molecular level. In 2002, imatinib was approved for the treatment of newly diagnosed patients with BCR-ABL positive CML and since then is regarded the standard therapy for these patients.

Another successful example is the screening for the HLA-B*5701 allele before prescribing abacavir in patients with HIV.[28] Abacavir is a nucleoside analog reverse transcriptase inhibitor used to treat HIV-infected patients. Therapy with abacavir is well tolerated. The main side effect is an immunologically mediated hypersensitivity reaction, which has been observed in 5–8% of all treated patients.[29] Symptoms of hypersensitivity are fever, skin rash, fatigue, vomiting, diarrhea or dyspnea, which are strongly associated with the HLA-B*5701 allele. Therefore, a genetic testing is recommended in international HIV guidelines[101] before administration of abacavir.[30]

Hence, in a number of diseases, genetic screening is necessary in order to choose the most effective treatment. Altogether, in Germany, for example, there are 16 active agents for which a genetic test is compulsory (abacavir, anastrozol, arsentrioxid, exemestan, letrozol, toremifene, maraviroc, panitumumab, cetuximab, dasatinib, erlotinib, gefitinib, imatinib, nilotinib, lapatinib and trastuzumab) and four other active agents for which a test is recommended (azathioprine, carbamazepine, mercaptopurine and tamoxifen). Therapy with these drugs must only be initiated after a genetic test was performed.[102] Many of these drugs are adopted in guidelines particularly with regard to the treatment of malignant diseases and AIDS. These guidelines state that according to the test results, the treatment has to be adapted or even changed to another drug.

The list of US FDA approved drugs with pharmacogenomic information in their labels has increased rapidly over recent years.[103] Frueh et al. evaluated 121 drugs with genomic biomarker information, which were FDA-approved in 2008 compared with 30 in 1995.[31] Approximately, 50 therapies have actual genetic tests as part of their labeling.[32] Therapeutic areas include oncology (azathioprine, cetuximab, irinotecan and trastuzumab), neurology (carbamazepine) or infectious diseases (voriconazole).[33] One example in cardiology is warfarin, an anticoagulant that is used to prevent heart attacks, strokes and blood clots. Dosing of warfarin is quite complicated owing to its narrow therapeutic range and a wide individual variability and leads to a considerable number of adverse events every year. Thus, genetic testing of the SNPs in CYP2C9 and VKORC1 genes may provide clinical information that is useful to instruct dosing patients receiving oral warfarin.[34] Epstein et al. evaluated that warfarin genotyping reduced hospitalization in outpatients.[35] The FDA revised the warfarin label in August 2007 to indicate that the CYP2C9 and VKORC1 genes are covariates of interindividual variability of warfarin doses. In January 2010, they added specific instructions on how to use genotype information to predict individualized doses.[36] By contrast, in Germany genetic testing of warfarin is currently not recommended.

Individualized medicine provides an approach to a therapeutic concept that directly addresses the earliest causal changes in the pathogenesis of a disease.

In the Future Report entitled 'Individualized medicine and healthcare system' by the German federal government, Hüsing et al. concluded: "Individualized medicine offers promising approaches. Particularly with regard to tumor treatment, individualized medicine has found its way into the guidelines. Nevertheless, their [individualized medicines] acceptance as well as their implementation requires absolute improvement in the future".[37] General recommendations or guidelines on the basis of individualized medicine are presently still a challenge, because there still are only few established applications. Some biomarkers are promising – their relevance for healthcare is presently being evaluated. Hamburg (commissioner of the FDA) and Collins (Director of the NIH) argued "the success of personalized medicine depends on having accurate diagnostic tests that identify patients who can benefit from targeted therapies".[38]

The high costs of testing and treatments are among the most important factors that influence the integration of individualized medicine approaches in general practice. Meckley and Neumann evaluated factors influencing reimbursement of individualized medicine and concluded that cost–effectiveness, which is shown, for example, for HER2 testing in breast cancer,[39] hepatitis C genotyping,[40]CYP2C9 and VKORC1 pharmacogenetic testing in the context of warfarin therapy,[41]UGT1A1 pharmacogenetic testing for irinotecan[42] or BRCA1/2 testing[43] do not appear to be associated with reimbursement. However, irinotecan testing is not reimbursed and warfarin testing is not usually reimbursed, while the other genetic tests are reimbursed even though all tests showed cost savings and are FDA-approved. In the case of warfarin, irinotecan and BRCA1/2 the level of evidence needs to be increased because better reimbursement of individualized medicine awaits better evidence.[44] In that case, integration of EBM and individualized medicine has a lot of potential in the future.