Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse. METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission. TRIAL REGISTRATION NUMBER: NCT05667766.

The costs and inequities of precision medicine for patients with prostate cancer: A call to action.

Financial toxicity is a growing problem in the delivery of cancer care and contributes to inequities in outcomes across the cancer care continuum. Racial/ethnic inequities in prostate cancer, the most common cancer diagnosed in men, are well described, and threaten to widen in the era of precision oncology given the numerous structural barriers to accessing novel diagnostic studies and treatments, particularly for Black men. Gaps in insurance coverage and cost sharing are 2 such structural barriers that can perpetuate inequities in screening, diagnostic workup, guideline-concordant treatment, symptom management, survivorship, and access to clinical trials. Mitigating these barriers will be key to achieving equity in prostate cancer care, and will require a multi-pronged approach from policymakers, health systems, and individual providers. This narrative review will describe the current state of financial toxicity in prostate cancer care and its role in perpetuating racial inequities in the era of precision oncology.

A scoping review on patient heterogeneity in economic evaluations of precision medicine based on basket trials.

INTRODUCTION: Considerable challenges in the economic evaluation of precision medicines have been mentioned in previous studies. However, they have not addressed how an economic assessment would be conducted based on basket trials (novel studies for evaluation of precision medicine effects) in which the included populations have specific biomarkers and various cancers. Since basket trial populations have remarkable heterogeneity, this study aims to investigate the concept of heterogeneity and specific method(s) for considering it in economic evaluations through guidelines and studies that could be applicable in economic evaluation based on basket trials. AREA COVERED: We searched PubMed, Web of Science, Scopus, Google Scholar, and Google to find studies and pharmacoeconomics guidelines. The inclusion criteria included subjects of patient heterogeneity and suggested explicit method(s). Thirty-nine guidelines and 43 studies were included and evaluated. None of these materials mentioned disease types in a target population as a factor causing heterogeneity. Moreover, in economic evaluations, patient heterogeneity has been considered with four general approaches subgroup analysis, individual-based models, sensitivity analysis, and regression models. EXPERT OPINION: Type of disease is not considered a contributing factor in population heterogeneity, and the probable appropriate method for this issue could be individual-based models.

Development of a computerized intervention to improve health literacy in older Hispanics with type 2 diabetes using a pharmacist supervised comprehensive medication management.

OBJECTIVE: The primary objective was to develop a computerized culturally adapted health literacy intervention for older Hispanics with type 2 diabetes (T2D). Secondary objectives were to assess the usability and acceptability of the intervention by older Hispanics with T2D and clinical pharmacists providing comprehensive medication management (CMM). MATERIALS AND METHODS: The study occurred in three phases. During phase I, an integration approach (i.e., quantitative assessments, qualitative interviews) was used to develop the intervention and ensure cultural suitability. In phase II, the intervention was translated to Spanish and modified based on data obtained in phase I. During phase III, the intervention was tested for usability/acceptability. RESULTS: Thirty participants (25 older Hispanics with T2D, 5 clinical pharmacists) were included in the study. Five major themes emerged from qualitative interviews and were included in the intervention: 1) financial considerations, 2) polypharmacy, 3) social/family support, 4) access to medication/information, and 5) loneliness/sadness. Participants felt the computerized intervention developed was easy to use, culturally appropriate, and relevant to their needs. Pharmacists agreed the computerized intervention streamlined patient counseling, offered a tailored approach when conducting CMM, and could save them time. CONCLUSION: The ability to offer individualized patient counseling based on information gathered from the computerized intervention allows for precision counseling. Future studies are needed to determine the effectiveness of the developed computerized intervention on adherence and health outcomes.

Precision Reimbursement for Precision Medicine: Using Real-World Evidence to Evolve From Trial-and-Project to Track-and-Pay to Learn-and-Predict.

Basic scientists and drug developers are accelerating innovations toward the goal of precision medicine. Regulators create pathways for timely patient access to precision medicines, including individualized therapies. Healthcare payors acknowledge the need for change but downstream innovation for coverage and reimbursement is only haltingly occurring. Performance uncertainty, high price-tags, payment timing, and actuarial risk issues associated with precision medicines present novel financial challenges for payors. With traditional drug reimbursement frameworks, payment is based on an assumed randomized controlled trial (RCT) projection of real-world effectiveness, a "trial-and-project" strategy; the clinical benefit realized for patients is not usually ascertained ex post by collection of real-world data (RWD). To mitigate financial risks resulting from clinical performance uncertainty, manufacturers and payors devised "track-and-pay" frameworks (i.e., the tracking of a pre-agreed treatment outcome which is linked to financial consequences). Whereas some track-and-pay arrangements have been successful, inherent weaknesses include the potential for misalignment of incentives, the risk of channeling of patients, and a failure to use the RWD generated to enable continuous learning about treatments. "Precision reimbursement" (PR) intends to overcome inherent weaknesses of simple track-and-pay schemes. In combining the collection of RWD with advanced analytics (e.g., artificial intelligence and machine learning) to generate actionable real-world evidence, with prospective alignment of incentives across all stakeholders (including providers and patients), and with pre-agreed use and dissemination of information generated, PR becomes a "learn-and-predict" model of payment for performance. We here describe in detail the concept of PR and lay out the next steps to make it a reality.

How are we evaluating the cost-effectiveness of companion biomarkers for targeted cancer therapies? A systematic review.

BACKGROUND: Despite the increasing economic assessment of biomarker-guided therapies, no clear agreement exists whether existing methods are sufficient or whether different methods might produce different cost-effectiveness results. This study aims to examine current practices of modeling companion biomarkers when assessing the cost-effectiveness of targeted cancer therapies. It investigates the current methods in modeling the characteristics of companion diagnostics based on existing economic evaluations of biomarker-guided therapies in cancer. METHODS: A literature search was performed using Medline, Embase, EconLit, Cochrane library for economic evaluations of biomarker-guided therapies with companion diagnostics in cancer. Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Studies were selected using pre-specified eligibility criteria based on the PICO framework. To make the included studies more comparable, we qualitatively synthesized the data under nine domains of methods where consensus was deemed lacking. RESULTS: Only four of the twenty-two studies included in this review were found to be of good quality with respect to incorporating the characteristics of companion biomarkers in economic evaluations. However, many evaluations focused on a pre-selected patient group rather than including all patients regardless of their biomarker status. Companion biomarker characteristics captured in evaluations were often limited to the cost or the accuracy of the test. Often, only the costs of biomarker testing were modelled. Clinical outcomes and health state utilities were often not included due to the limited data generated by clinical trials. Methods of economic evaluation were not applied consistently in assessments of companion cancer biomarkers for targeted therapies. It was also shown that conflicting cost-effectiveness results were likely depending on what comparator arm was chosen and what comparison structure was designed in the model. CONCLUSION: We found no consistent approach applied in assessing the value of companion biomarker tests and including the characteristics of biomarkers in an economic evaluation of targeted oncology therapies. Currently, many economic evaluations fail to capture the full value of companion biomarkers beyond sensitivity/specificity and cost related to biomarker testing.

Clinical and cost outcomes following genomics-informed treatment for advanced cancers.

BACKGROUND: Single-arm trials are common in precision oncology. Owing to the lack of randomized counterfactual, resultant data are not amenable to comparative outcomes analyses. Difference-in-difference (DID) methods present an opportunity to generate causal estimates of time-varying treatment outcomes. Using DID, our study estimates within-cohort effects of genomics-informed treatment versus standard care on clinical and cost outcomes. METHODS: We focus on adults with advanced cancers enrolled in the single-arm BC Cancer Personalized OncoGenomics program between 2012 and 2017. All individuals had a minimum of 1-year follow up. Logistic regression explored baseline differences across patients who received a genomics-informed treatment versus a standard care treatment after genomic sequencing. DID estimated the incremental effects of genomics-informed treatment on time to treatment discontinuation (TTD), time to next treatment (TTNT), and costs. TTD and TTNT correlate with improved response and survival. RESULTS: Our study cohort included 346 patients, of whom 140 (40%) received genomics-informed treatment after sequencing and 206 (60%) received standard care treatment. No significant differences in baseline characteristics were detected across treatment groups. DID estimated that the incremental effect of genomics-informed versus standard care treatment was 102 days (95% CI: 35, 167) on TTD, 91 days (95% CI: -9, 175) on TTNT, and CAD$91,098 (95% CI: $46,848, $176,598) on costs. Effects were most pronounced in gastrointestinal cancer patients. CONCLUSIONS: Genomics-informed treatment had a statistically significant effect on TTD compared to standard care treatment, but at increased treatment costs. Within-cohort evidence generated through this single-arm study informs the early-stage comparative effectiveness of precision oncology.

Clinical and economic impact of current ALK rearrangement testing in Spain compared with a hypothetical no-testing scenario.

BACKGROUND: Currently biomarkers play an essential role in diagnosis, treatment, and management of cancer. In non-small cell lung cancer (NSCLC) determination of biomarkers such as ALK, EGFR, ROS1 or PD-L1 is mandatory for an adequate treatment decision. The aim of this study is to determine the clinical and economic impact of current anaplastic lymphoma kinase testing scenario in Spain. METHODS: A joint model, composed by decision-tree and Markov models, was developed to estimate the long-term health outcomes and costs of NSCLC patients, by comparing the current testing scenario for ALK in Spain vs a hypothetical no-testing. The current distribution of testing strategies for ALK determination and their sensitivity and specificity data were obtained from the literature. Treatment allocation based on the molecular testing result were defined by a panel of Spanish experts. To assess long-term effects of each treatment, 3-states Markov models were developed, where progression-free survival and overall survival curves were extrapolated using exponential models. Medical direct costs (expressed in €, 2019) were included. A lifetime horizon was used and a discount rate of 3% was applied for both costs and health effects. Several sensitivity analyses, both deterministic and probabilistic, were performed in order test the robustness of the analysis. RESULTS: We estimated a target population of 7628 NSCLC patients, including those with non-squamous histology and those with squamous carcinomas who were never smokers. Over the lifetime horizon, the current ALK testing scenario produced additional 5060 and 3906 life-years and quality-adjusted life-years (QALY), respectively, compared with the no-testing scenario. Total direct costs were increased up to € 51,319,053 for testing scenario. The incremental cost-effectiveness ratio was 10,142 €/QALY. The sensitivity analyses carried out confirmed the robustness of the base-case results, being the treatment allocation and the test accuracy (sensitivity and specificity data) the key drivers of the model. CONCLUSIONS: ALK testing in advanced NSCLC patients, non-squamous and never-smoker squamous, provides more than 3000 QALYs in Spain over a lifetime horizon. Comparing this gain in health outcomes with the incremental costs, the resulting incremental cost-effectiveness ratio reinforces that testing non-squamous and never-smoker squamous NSCLC is a cost-effective strategy in Spain.

Genetic-guided pharmacotherapy for venous thromboembolism: a systematic and critical review of economic evaluations.

Despite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on cost-effectiveness of genetic-guided pharmacotherapy for VTE, we searched six databases, websites of four HTA agencies and citations, with independent double-reviewers in screening, data extraction, and quality rating. The ten eligible studies, all model-based, examined heterogeneous interventions and comparators. Findings varied widely; testing was cost-saving in two base-cases, cost-effective in four, not cost-effective in three, dominated in one. Of 22 model variables that changed decisions about cost-effectiveness, effectiveness/relative effectiveness of the intervention was the most frequent, albeit of poor quality. Studies consistently lacked details on the provision of interventions and comparators as well as on model development and validation. Besides improving the reporting of interventions, comparators, and methodological details, future economic evaluations should examine strategies recommended in guidelines and testing key model variables for decision uncertainty, to advise clinical implementations.

Variability of treatment modalities and intensity in patients with severe haemophilia A on prophylaxis: Results from the Italian national registry.

BACKGROUND: A shift from a standard to a personalized prophylaxis has been increasingly adopted in patients with severe haemophilia A (SHA). This approach has raised the likelihood of a significant variability in the prophylactic approaches and the relative Factor VIII (FVIII) consumptions. The aim of our study was to assess the treatment variability of SHA patients without inhibitors and on prophylaxis regimen in Italy. MATERIAL AND METHODS: Data reported in the National Registry of Congenital Coagulopathies (NRCC) were analysed to assess treatment distribution within SHA patients without inhibitors, focussing on FVIII consumption in 2017, associated with prophylaxis regimen. The analysis was stratified based on age groups and Italian regions to describe the variability of FVIII consumption in Italy. RESULTS: In 2017, the Registry reported the therapeutic plans of 1068 SHA patients without inhibitors on prophylaxis. The mean (95% CI) individual consumption ranges from 123 127 IU (99 736-146 518) in the age group 0-6 years to 345 000 IU (336 000-354 000) in the age group >20 years. A significant FVIII consumption variability was identified within the adult population. Regions with less than 50 patients reported the higher variability in mean FVIII consumption per patient-year within the different age groups. Similar difference in FVIII consumption variability was reported also in the age groups comparing "low," "middle" and "high" patient volume regions. DISCUSSION: A reliable estimation of FVIII consumption for patients' treatment is necessary to manage and plan the appropriate budget and keep treatment's costs affordable. However, without the implementation of a methodology aiming to assess the overall value produced by these FVIII consumptions, the scenario will keep driven by FVIII consumptions, its costs and the budget available. An effort by haemophilic community, haemophilia treatment centres and institutions is required to develop and share this cultural shift in improving haemophilia management and assessment.

Precision medicine testing in ovarian cancer: The growing inequity between patients with commercial vs medicaid insurance.

INTRODUCTION: Precision medicine technologies have significant impact in the care of patients with ovarian cancer. Compared to affluent patients, socioeconomically vulnerable patients are less likely to have access to this testing. There is little data that demonstrate this inequity over time. METHODS: We used the IBM Truven Health MarketScan Research Database to identify patients in the United States who underwent surgery for ovarian cancer between 2011 and 2017. The presence of claims for precision medicine testing within six months of surgery was assessed for each patient. Precision medicine testing included both molecular genetic testing (BRCA limited or full sequencing, somatic and germline testing) as well as ancillary pathology tests (immunohistochemistry, microsatellite instability). Demographic data was extracted. RESULTS: We identified 27,181 patients who met eligibility. Of these, 88.6% had commercial insurance, and 11.4% had Medicaid. While the proportion of patients who underwent precision medicine testing increased over time for both cohorts (47.0% to 66.6% for commercially insured, 41.4% to 57.6% for Medicaid insured, p < 0.0001), the inequity in testing rates widened (5.6% disparity to 9.0%, p < 0.0001). This was driven by growing inequity in germline and somatic genetic testing (7.6% disparity to 21.3%, p < 0.0001). CONCLUSIONS: There is widening inequity in precision medicine testing rates between commercially insured and Medicaid insured poate patients with ovarian cancer.

Inaugural Pharmacogenomics Access and Reimbursement Symposium.

The Pharmacogenomics Access & Reimbursement Symposium, a landmark event presented by the Golden Helix Foundation and the Pharmacogenomics Access & Reimbursement Coalition, was a 1-day interactive meeting comprised of plenary keynotes from thought leaders across healthcare that focused on value-based strategies to improve patient access to personalized medicine. Stakeholders including patients, healthcare providers, industry, government agencies, payer organizations, health systems and health policy organizations convened to define opportunities to improve patient access to personalized medicine through best practices, successful reimbursement models, high quality economic evaluations and strategic alignment. Session topics included health technology assessment, health economics, health policy and value-based payment models and innovation.

Can Cost-effectiveness Analysis Inform Genotype-Guided Aspirin Use for Primary Colorectal Cancer Prevention?

BACKGROUND: Inherited genetic variants can modify the cancer-chemopreventive effect of aspirin. We evaluated the clinical and economic value of genotype-guided aspirin use for colorectal cancer chemoprevention in average-risk individuals. METHODS: A decision analytical model compared genotype-guided aspirin use versus no genetic testing, no aspirin. The model simulated 100,000 adults ≥50 years of age with average colorectal cancer and cardiovascular disease risk. Low-dose aspirin daily starting at age 50 years was recommended only for those with a genetic test result indicating a greater reduction in colorectal cancer risk with aspirin use. The primary outcomes were quality-adjusted life-years (QALY), costs, and incremental cost-effectiveness ratio (ICER). RESULTS: The mean cost of using genotype-guided aspirin was $187,109 with 19.922 mean QALYs compared with $186,464 with 19.912 QALYs for no genetic testing, no aspirin. Genotype-guided aspirin yielded an ICER of $66,243 per QALY gained, and was cost-effective in 58% of simulations at the $100,000 willingness-to-pay threshold. Genotype-guided aspirin was associated with 1,461 fewer polyps developed, 510 fewer colorectal cancer cases, and 181 fewer colorectal cancer-related deaths. This strategy prevented 1,078 myocardial infarctions with 1,430 gastrointestinal bleeding events, and 323 intracranial hemorrhage cases compared with no genetic testing, no aspirin. CONCLUSIONS: Genotype-guided aspirin use for colorectal cancer chemoprevention may offer a cost-effective approach for the future management of average-risk individuals. IMPACT: A genotype-guided aspirin strategy may prevent colorectal cancer, colorectal cancer-related deaths, and myocardial infarctions, while minimizing bleeding adverse events. This model establishes a framework for genetically-guided aspirin use for targeted chemoprevention of colorectal cancer with application toward commercial testing in this population.

Assessment and clinical utility of pharmacogenomics by healthcare practitioners in North Carolina.

Aim: Perceived knowledge, use and perceptions of pharmacogenomics (PGx) testing were assessed among healthcare practitioners in North Carolina. Materials & methods: A validated survey was distributed to various healthcare professionals and analyzed for differences among the groups. Results: The majority of the 744 survey respondents acknowledged the perceived benefits of PGx testing, but indicated either never or rarely using it. A substantial percentage of practitioners reported educational experiences but the majority had received no training. Among groups reporting using PGx testing, barriers to implementation were cost and insufficient training. Conclusion: The perceived cost of PGx testing and insufficiency or lack of training are major contributing factors to the infrequent use of PGx testing by healthcare providers in North Carolina.

Basics of practice management: managing many for the care of one.

In today's changing health care landscape, it has become necessary that providers have a fundamental understanding of practice management as pertinent to the care they provide. The reproductive endocrinology and infertility (REI) practice is a uniquely complex setting with many component parts, necessitating frequent assessment and collaboration to provide safe, quality, and cost-effective care. In this review, we aim to describe the basics of medical practice management, divided into six sections: practice models; operations; patient safety; patient experience; employee recruitment; development, and satisfaction; and technology. These topics will be presented with a focus on the application of these principles to the REI practice.

Establishment and implementation of Cancer Genomic Medicine in Japan.

Approximately 1 in 2 Japanese people are estimated to be diagnosed with cancer during their lifetime. Cancer still remains the leading cause of death in Japan, therefore the government of Japan has decided to develop a better cancer control policy and launched the Cancer Genomic Medicine (CGM) program. The Ministry of Health, Labour, and Welfare (MHLW) held a consortium at their headquarters with leading academic authorities and the representatives of related organizations to discuss ways to advance CGM in Japan. Based on the report of the consortium, the CGM system under the national health insurance system has gradually been realized. Eleven hospitals were designated in February 2018 as core hospitals for CGM; subsequently, the MHLW built the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) as an institution to aggregate and manage genomic and clinical information on cancer patients, and support appropriate secondary use of the aggregated information to develop research aimed at medical innovation. As the first step in Japan's CGM in routine practice, in June 2019 the MHLW started reimbursement of 2 types of tumor profiling tests for advanced solid cancer patients using the national insurance system. Japan's CGM has swiftly been spreading nationwide with the collaboration of 167 hospitals and patients. The health and research authorities are expected to embody personalized cancer medicine and promote CGM utilizing state-of-the-art technologies.