The database search identified 1535 records. After removing 175 duplicates, the title and abstract of the remaining 1360 records were screened. Subsequently, 1238 records were excluded as they did not cover the objective of the study. The remaining 122 records were assessed for eligibility, and inclusion criteria were fulfilled by 27 studies, which were included in the final assessment (Fig. 1).
All studies are characterized by a variety of elements, such as country, perspective, treatment line, active ingredient, treatment strategy, biomarkers, consideration of test costs, consideration of sensitivity, and specificity of the test and funding source. A detailed overview is provided in supplementary material 2.
Quality Assessment (QHES)
The results of the quality assessment using the QHES instrument are presented in Table 4. An average value of 85.81 was calculated. Three studies [46, 47, 56] were assessed to have a fair quality, while all others achieved a high quality score. The objective of all studies was represented in a clear manner (QHES item 1), but seven did not state the perspective of the study (QHES item 2) [22, 33, 37, 40, 45, 53, 56]. In three studies, data were not extracted from the best available source (QHES item 3) [32, 48, 49]. Six studies used data from a subgroup analysis (QHES item 4) [32, 36, 37, 42, 52, 53]. The majority of studies, with the exception of one, handled uncertainties properly (QHES item 5) . All studies, with the exception of five, performed an incremental analysis for costs and outcomes between the alternatives (QHES item 6) [38, 39, 47, 51, 56]. Detailed information for the methodology of data extraction was not reported in four studies (QHES item 7) [37, 46, 47, 56]. The majority of studies fulfilled the criteria of QHES items 8 and 9. Only four studies did not choose the appropriate time horizon or did not discount benefits and costs beyond 1 year (QHES item 8) [43, 46, 51, 55]. Furthermore, four studies failed to measure the costs appropriately or to describe methods for estimations of quantities and unit costs clearly (QHES item 9) [41, 46, 47, 56]. All studies clearly stated the primary outcome (QHES item 10). All studies, except for three, stated valid health outcomes or gave a justification for the measurement used if other more valid and reliable measures were not available (QHES item 11) [12, 47, 48]. In most of the studies, the economic model, methods, and analyses were displayed transparently, except in four (QHES item 12) [22, 39, 46, 52]. All studies gave a justification for the choice of limitations or assumptions (QHES item 13). The authors of seven studies discussed explicitly the direction and the magnitude of the potential bias (QHES item 14) [39–41, 43, 45, 52, 54]. All studies provided proper conclusions or recommendations based on results (QHES item 15). Finally, only six studies did not disclose the source of funding (QHES item 16) [22, 39, 42, 43, 46, 56].
Main Characteristics of the Studies
All main characteristics of the studies are presented in Table 5. The included studies were published between 2002 and 2015. In the years 2000, 2001, and 2003 we did not find publications that satisfied the inclusion criteria. Two-thirds of the selected articles were published in the last 7 years. Furthermore, studies carried out in recent years (between 2009 and 2015) achieved a higher QHES average score than those published previously. AZA is the most frequently considered active ingredient for which PT were evaluated (seven studies out of the 27 included here). Five of these seven evaluations were published between 2002 and 2006, and the latest article was published in 2014. TMPT, which predicts the potential effectiveness of AZA application, is the most commonly evaluated biomarker. Six of the nine studies focusing on TMPT were published between 2002 and 2006. Over two-fifth of the studies included here evaluated the CE of PT-guided therapy in oncological diseases. Table 5 shows the subdivision of the included studies according to the main categories as well as QHES average score and range in the corresponding category.
Cost-effectiveness of Pharmacogenetics Testing in Specific Therapeutic Areas
The cost-effectiveness of pharmacogenetics testing in the treatment of epilepsy was evaluated in three studies. The latest study from Plumpton et al.  focused on the HLA*A*31:01 allele screening test. An ICER of £37,314 (US$53,674) per cutaneous avoided ADR for a prior HLA*A*31:01 allele test and carbamazepine (CBZ) administration following the test result was calculated. Studies from Dong et al.  and Rattanavipapong et al.  also examined the CE of PT prior to CBZ administration; however, these analyses aimed at identifying the presence of the HLA-B*15:02 allele. Rattanavipapong et al.  examined the influence of prescribing CBZ with and without prior HLA-B*15:02 allele test for epilepsy as well neuropathic pain. In the case of epilepsy, they calculated an ICER of THB 220,000 (US$7066) per QALY, while for neuropathic pain, the ICER was THB 130,000 (US$4137) per QALY, gained through PT and CBZ administration following the test results. Dong et al.  investigated the CE of HLA-B*15:02 allele testing prior to initiation of CBZ therapy in Singapore. In comparison with no testing and CBZ prescription to all patients, the test result-based CBZ administration achieved an ICER of US$29,750. The frequency of HLA-B*15:02 allele differs between the three major ethnical populations present in Singapore. Therefore, separate ICERs were calculated for each of these groups. The test strategy led to an ICER of US$37,030 per QALY for Singapore Chinese, an ICER of US$7930 per QALY for Singapore Malays, and an ICER of US$136,630 per QALY for Singapore Indians. Regarding the US$50,000 threshold, PT before CBZ administration is cost-effective for Singapore Malays and Singapore Chinese.
All HIV/AIDS studies included here analyzed the CE of HLA-B*57:01 allele test before abacavir (ABC) administration. Hughes et al.  compared the CE of HLA-B*57:01 allele test prior to ABC prescription (patients with a positive test result received an alternative treatment and patients without HLA-B*57:01 allele were treated with ABC) with that of patients treated with ABC but not tested. A dominant ICER was determined in the first group. However, the incremental CE depends on the costs of the alternative treatment: based on the costs of the highly active antiretroviral therapy (HAART) alternative, a range of dominant ICER (alternative treatment is less expensive and more effective) up to an €22,811 (US$26,714) per avoided HSR was calculated.
Schackman et al.  determined an ICER of US$36,700 per QALY for a previous HLA-B*57:01 allele test and a test result-based treatment in comparison with no testing.
On the other hand, Nieves Calatrava et al.  assessed an ICER of €630.16 (US$807) per avoided HSR, and Kauf et al.  calculated an even lower ICER of only US$328 per avoided HSR for a HLA-B*57:01 allele test-based ABC treatment (as opposed to the prescription of ABC without a predictive test).
The latest published study by Kapoor et al.  provides a detailed analysis for HLA-B*57:01 allele testing before ABC prescription in three ethnicities. Furthermore, differential results regarding the disease stage (early and late stage) and the treatment strategy (tenofovir and ABC can be prescribed as first-line treatment while some patients were contraindicated to tenofovir) were described. For early stage treatment, where tenofovir and ABC can be prescribed as first-line, the CE for a HLA-B*57:01 allele test-based ABC treatment (in contrast to administration of ABC without testing) resulted in an ICER of US$415,845 per QALY for Han-Chinese, an ICER of US$318,029 per QALY for Southeast-Asian Malays, and ICER of US$208,231 per QALY for South-Asian Indians. For this treatment line, where both active ingredients were prescribed, a CE analysis was also performed for patients at a later stage of the disease. In the latter case, ICERs of US$926,938 per QALY for Han-Chinese, of US$624,297 per QALY for Southeast-Asian Malays, and of US$284,598 per QALY for South-Asian Indians were calculated. This study also included a CE analysis for these three patients groups contraindicated for tenofovir. For the early stage treatment group, ICERs of US$252,350 per QALY for Han-Chinese, of US$154,490 per QALY for Southeast-Asian Malays, and of US$44,649 per QALY for South-Asian Indians were analyzed. For patients at a later stage of the disease, ICERs of US$757,270 per QALY for Han-Chinese, of US$454,223 per QALY for Southeast-Asian Malays, and of US$114,068 per QALY for South-Asian Indians were found. This study indicates that a predictive test prior to ABC administration is not effective, independently of the disease stage. Exceptions are tenofovir-contraindicated early-stage patients.
Inflammatory Bowel Diseases
Winter et al.  conducted a CE analysis for a PT, which analyzed TMPT activity. The dosage of AZA is based on TMPT activity. Hence, a standard AZA dose without prior testing was compared to an activity-based AZA dosage administration. Costs of £487 (US$776) per LSY for a 30-year-old patient and of £951 (US$1515) for a 60-year-old patient were determined.
On the other hand, Dubinsky et al.  and Priest et al.  identified CE for a genotype test-based TMPT activity initiation of AZA, compared to administering a standard dosage of AZA without a prior predictive test. Furthermore, Priest et al.  compared the phenotypic and genotypic testing and showed that the phenotypic TMPT test strategy was the most cost-effective approach.
Rheumatologic Conditions (Rheumatoid Arthritis and Systematic Lupus Erythematosus)
Marra et al.  and Oh et al.  evaluated the CE of PT in the therapeutic area of rheumatologic conditions. In both studies, administering a TMPT test result-based dose of AZA is more effective and less costly than administering a standard dose of AZA without prior testing.
Idiopathic Pulmonary Fibrosis
Hagaman et al.  evaluated the CE of TMPT testing in idiopathic pulmonary fibrosis. The performance of a TMPT test and the test result-based AZA dosage (in contrast to the administration of a standard dose AZA without prior TMPT test) resulted in an ICER of US$29,663 per QALY.
Thompson et al.  investigated the CE of TMPT testing prior to AZA administration in autoimmune diseases. An incremental cost of £421.06 (US$625) and an incremental net benefit of £256.89 (US$381) for TMPT activity test prior to AZA administration (in contrast to the administration of a standard dose of AZA without TMPT test) were determined.
Breast Cancer (Early Stage)
Lyman et al.  investigated the CE of PT in early stage breast cancer relative to the recurrence of the disease. A comparison between testing the risk of relapse and administration of the standard therapy, consisting of tamoxifen and chemotherapy, was conducted. Patients at low risk of relapse only received tamoxifen, the others tamoxifen and chemotherapy. Lyman et al.  determined an ICER of US$3385 per LYS (no indication of age), whereas Hall et al.  indicate an ICER of US$8852 per QALY (patients above 60 years of age). In this study, Hall et al.  concluded that a general statement on the cost-effectiveness could not be made because of substantial uncertainties.
Blank et al.  investigated the CE of PT in early stage breast cancer prior to administration of trastuzumab. In this study a comparison of a test result-based administration of trastuzumab and the administration of the drug without a prior test was conducted. In the test strategy, patients with proven HER2 overexpression received trastuzumab, whereas patients without HER2 overexpression received an alternative therapy. Two testing procedures were considered: immunohistochemistry (IHC test) and fluorescence in situ hybridization (FISH test). The therapy with both tests alone or in combination (compared with no previous test) had significantly lower costs, but the FISH test alone was considered the most cost-effective approach. However, administering trastuzumab with no previous test achieved a higher benefit, as a result of the imperfect sensitivity and specificity of the tests. A CE ratio was not calculated.
Metastatic Breast Cancer
Elkin et al.  evaluated the CE of PT prior to trastuzumab administration in metastatic breast cancer. HER2 overexpression test prior to trastuzumab prescription was compared with the prescription of trastuzumab and chemotherapy without a predictive test. Patients with HER2 overexpression received a combination treatment, consisting of trastuzumab and chemotherapy. Patients without HER2 overexpression only received chemotherapy. In this study, IHC and FISH tests were used to determine HER2 overexpression. The use of a FISH test resulted in a dominant ICER. Furthermore, performing the IHC test before the FISH test was the most cost-effective approach. However, the benefit provided by this strategy compared to trastuzumab administration without prior test was less.
Metastatic Colorectal Cancer
Shiroiwa et al.  analyzed the CE of a PT prior administration of cetuximab in metastatic colorectal cancer. A comparison of KRAS mutation test and a result-based administration of cetuximab (patients with wild-type KRAS received cetuximab and patients with KRAS mutations received best supportive care, BSC) and cetuximab treatment without a predictive test were conducted. A dominant ICER for the testing strategy was determined.
Vijayaraghavan et al.  determined the cost-effectiveness of a KRAS mutation test prior to administration of cetuximab monotherapy, treatment with cetuximab in combination with chemotherapeutics, and panitumumab monotherapy. Patients with a KRAS mutation received exclusively chemotherapeutics in combination therapy and BSC for monotherapy. The use of a KRAS mutation test before prescription of cetuximab monotherapy, panitumumab monotherapy, and cetuximab combination therapy achieved a dominant ICER compared to the treatment without the predictive test.
Blank et al.  evaluated the CE for a KRAS mutation test and a subsequent BRAF gene test before administration of cetuximab in combination with BSC for metastatic colorectal cancer. Patients with a KRAS or BRAF mutation received exclusively BSC. The subsequent verification of BRAF status after KRAS test was the most cost-effective approach compared to treating all patients without testing or solely after the KRAS test. However, perhaps as a result of the imperfect sensitivity and specificity, there was a higher benefit in prescribing cetuximab without a prior test compared with the test strategies. An ICER for a predictive test prior cetuximab administration as compared to without prior testing and treating all patients with cetuximab was not reported.
Behl et al.  also evaluated the CE of a subsequent BRAF gene test in addition to a KRAS mutation analysis prior to cetuximab administration in combination with BSC. The subsequent verification of BRAS status after the KRAS test was also the most cost-effective approach. However, even in this case, perhaps as a result of the imperfect sensitivity and specificity of the testing procedures, cetuximab without a prior test led to a higher benefit. An ICER was not stated.
Acute Lymphoblastic Leukemia
Van den Akker-van Marle et al.  conducted a CE study for a PT prior to mercaptopurine administration in acute lymphoblastic leukemia in children. There, an ICER of €4800 (US$5702) per LYG for a genotypic TMPT activity test and TMPT activity-based mercaptopurine dosage, compared to no testing and administration of a standard initial dose of mercaptopurine, was determined.
On the other hand, in the study by Donnan et al.  neither a phenotypic nor a genotypic test for determining TMPT activity prior to mercaptopurine administration proved to be cost-effective (higher costs for the same benefit).
Advanced Non-Small Cell Lung Cancer
Carlson et al.  conducted a CE study for a PT prior to erlotinib administration in advanced non-small cell lung cancer patients. A comparison was made between the use of an EGFR test and the result-based erlotinib administration in patients with EGFR mutations or an alternative therapy for patients without EGFR mutation, and the treatment of all patients with erlotinib without a prior test. An ICER of US$162,018 per QALY for the use of a gene copy number test was determined. The ICER clearly surpassed that of the study set threshold of US$100,000 to US$150,000 per QALY.
De Lima Lopes et al.  evaluated the cost-effectiveness of the EGFR test prior to gefitinib prescription. A dominant ICER for the comparison of the use of an EGFR test prior to gefitinib administration and no testing while prescribing chemotherapy with subsequent gefitinib administration was determined. In the test strategy, patients with an EGFR mutation received gefitinib followed by chemotherapy as second-line therapy. Patients without EGFR mutation received chemotherapy with subsequent BSC.
Main Results of This Systematic Review
In this systematic review, six main results were obtained:
In the majority of studies, a PT-guided administration of an active ingredient was found to be cost-effective or leads to cost savings.
A general statement on CE for a test-guided application of an active ingredient (independently of the indication for which it has been prescribed) was not observed.
The majority of studies analyzed the CE of targeted therapies in oncological diseases.
The CE depends on various factors (e.g., prevalence of biomarkers, test costs, threshold value, prevalence of ADRs, response rate of therapy).
The CE of a PT-guided therapy can differ between indications as well as within the same indication.
The results depend on the perspective of the study (society, healthcare system, and payer).