Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Pharmacoepidemiology: A time for a new multidisciplinary approach to precision medicine.

The advent of the genomic age has created a rapid increase in complexity for the development and selection of drug treatments. A key component of precision medicine is the use of genetic information to improve therapeutic effectiveness of drugs and prevent potential adverse drug reactions. Pharmacoepidemiology, as a field, uses observational methods to evaluate the safety and effectiveness of drug treatments in populations. Pharmacoepidemiology by virtue of its focus, tradition, and research orientation can provide appropriate study designs and analysis methods for precision medicine. The objective of this manuscript is to demonstrate how pharmacoepidemiology can impact and shape precision medicine and serve as a reference for pharmacoepidemiologists interested in contributing to the science of precision medicine. This paper depicts the state of the science with respect to the need for pharmacoepidemiology and pharmacoepidemiological methods, tools and approaches for precision medicine; the need for and how pharmacoepidemiologists use their skills to engage with the precision medicine community; and recommendations for moving the science of precision medicine pharmacoepidemiology forward. We propose a new integrated multidisciplinary approach dedicated to the emerging science of precision medicine pharmacoepidemiology.

Correction to: Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations.

In the original version of this Article, the affiliation details for Personalized Medicine & Targeted Therapeutics, USA were incorrectly given as Personalized Medicine & Targeted Therapeutics, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania, USA. This has now been corrected in both the PDF and HTML versions of the Article.

Cancer patients acceptance, understanding, and willingness-to-pay for pharmacogenomic testing.

BACKGROUND: Pharmacogenomics is gaining increasing importance in the therapeutics of cancer; yet, there is little knowledge of cancer patients' attitudes toward the use of pharmacogenomic testing in clinical practice. We carried out this study to explore cancer patients' acceptance, understanding, and willingness-to-pay for pharmacogenomic testing. MATERIALS AND METHODS: A broad cross-section of gastrointestinal, lung, breast, and other cancer patients were interviewed in terms of their acceptance of pharmacogenomic testing using hypothetical time, efficacy, and toxicity trade-off and willingness-to-pay scenarios. RESULTS: Among the 96% of 123 adjuvant patients accepting chemotherapy under optimal conditions, 99% wanted pharmacogenomic testing that could identify a subset of patients benefiting from chemotherapy, accepting median incurred costs of $2000 (range $0-25,000) and turnaround time for test results of 16 days (range 0-90 days). Among the 97% of 121 metastatic patients accepting chemotherapy, 97.4% wanted pharmacogenomic testing that could detect the risk of severe toxicity, accepting median incurred costs of $1000 (range $0-10,000) and turnaround time for results of 14 days (range 1-90 days). The majority of patients wanted to be involved in decision-making on pharmacogenomic testing; however, one in five patients lacked a basic understanding of pharmacogenomic testing. CONCLUSION: Among cancer patients willing to undergo chemotherapy, almost all wanted pharmacogenomic testing and were willing-to-pay for it, waiting several weeks for results. Although patients had a strong desire to be involved in decision-making on pharmacogenomic testing, a considerable proportion lacked the necessary knowledge to make informed choices.

Exploring trust development in families of children towards surgical and emergency care providers: A scoping review of the literature.

BACKGROUND: Trust is central to the therapeutic relationship between patients and their providers, yet little is known about how it is developed in the unique context of children facing surgical emergencies. We sought to identify factors fostering trust development, gaps, and areas for improvement. METHODS: We searched eight databases from inception to June 2021 to identify studies focusing on trust in pediatric surgical and urgent care settings. PRISMA-ScR protocols were followed, and screening carried out by two independent reviewers. Data collection included study characteristics, outcomes, and results. RESULTS: Out of 5578 articles screened, 12 fulfilled the inclusion criteria. Four major trust constructs were identified: competence, communication, dependability, and caring. Despite various instruments used, all studies reported a high level of parental trust. Nearly all studies (11/12) noted trust depending on parents' sociodemographic background, with ethnicity (3/12) and level of education and language barriers (2/12) limiting parents' confidence in physicians. High trust levels significantly correlated with effective communication and perceived quality of care. Most effective interventions enhancing trust included communication and caring trust constructs (10/12) rather than competence and dependability (5/12). Parents' individual experiences, development of compassionate interactions, and practice of family-centered care appeared important in developing trust. CONCLUSIONS: Improving communication and providing compassionate care, as well as encouraging a patient-centered approach, appear to be most effective in promoting trust in pediatric surgical and urgent settings. Our findings can guide future educational interventions towards strengthening parental trust and promoting child- and family-centered care in pediatric surgical settings.

Cost effectiveness of gene expression profiling for early stage breast cancer: a decision-analytic model.

BACKGROUND: Gene expression profiling (GEP) is being used increasingly for risk stratification to identify women with lymph node-negative, estrogen receptor-positive, early stage breast cancer who are most likely to benefit from adjuvant chemotherapy. The authors of this report evaluated the cost effectiveness of recurrence score-guided treatment using 2 commercially available GEP tests, Oncotype DX (Genomic Health, Redwood City, Calif) and MammaPrint (Agendia Inc., Irvine, Calif), from a third-party payer's perspective. METHODS: A 10-year Markov model was developed to compare the costs and quality-adjusted life-years (QALYs) of treatment decisions guided by either Oncotype DX or MammaPrint in a hypothetical cohort of women with early stage, lymph node-negative, estrogen receptor-positive breast cancer who may experience recurrence. Outcomes included no recurrence, recurrence, and death. The costs considered included gene test costs, the costs of adjuvant chemotherapy and other chemotherapy (including premedication, oncology visits, and monitoring for adverse events), the cost of treating recurrence, costs associated with the treatment of adverse events, and end-of-life care costs. RESULTS: The model demonstrated that the patients who received the Oncotype DX test to guide treatment spent $27,882 (in US dollars) and gained 7.364 QALYs, whereas patients who received the MammaPrint test to guide treatment spent $21,598 and gained 7.461 QALYs. Sensitivity analyses demonstrated that the results were robust to changes in all parameters. CONCLUSIONS: The model suggested that MammaPrint is a more cost-effective GEP test compared with Oncotype DX at a threshold willingness-to-pay of $50,000 per QALY. Because Oncotype DX is the most frequently used GEP in clinical practice in the United States, the authors concluded that the current findings have implications for health policy, particularly health insurance reimbursement decisions.

Evaluating the quality of the economic evidence in colorectal cancer genomics studies.

The increase in the use of genome-based screening and diagnostic tests adds to the overall costs of oncologic care for colorectal cancer. This, in turn, has resulted in an increase in published economic analyses. Aim: To perform a systematic literature review of the available economic evidence evaluating the value of genomic testing for colorectal cancer and appraise the quality of the economic studies conducted to date. Methods: A systematic review of the literature for economic studies of colorectal cancer genomics from January 2006 through October 2020, and evaluation of study quality using the Quality of Health Economic Studies (QHES) instrument was conducted. The validated QHES was then applied to a final set of articles that met eligibility criteria. Results: Our search of the literature initially yielded 12,859 records. A final set of 49 articles met our inclusion criteria. The QHES score ranged from 24 to 100, with an average score of 82. Most of the studies (n = 40, 82%) scored above 75 and were considered of good quality. Conclusion: Our analysis revealed that most of the economic analyses of colorectal cancer genomic molecular diagnostics in the literature may be of good quality. There is, however, some variation in methodological rigor between the articles.

Cost-effectiveness of precision molecular diagnostic tests for stage II colorectal cancer.

Background: In colorectal cancer, inappropriate use of adjuvant chemotherapies may lead to significant increases in healthcare costs and harms to patients. Genome-based interventions are being increasingly used in the stratification of patients according to their risk profiles. However, earlier cost-effectiveness analyses of precision molecular diagnostics have indicated a paucity of data on comparative health economic outcomes. Our aim was to compare the cost-effectiveness of marketed genomic tests used in the prognosis of stage II colorectal cancer patients. Methods: A Markov model was developed to compare the cost-effectiveness of treatment guided by any one of the following genomic tests: 12-gene assay or the 18-gene expression assay or the 482-gene signature or the Immunoscore assay in a hypothetical cohort of patients (n=1,000) with stage II colorectal cancer. Our study investigated outcomes in three health states: no recurrence, recurrence and death. This study was conducted from a societal perspective, and a 3% discount was applied to the costs and health outcomes. Sensitivity analyses were performed to assess the uncertainty of model parameters on the results. Results: The cost of the Immunoscore assay strategy in stage II colorectal cancer patients was estimated to be US $23,564 with a gain of 3.903 quality-adjusted life years (QALYs) as compared with the 12-gene assay strategy at US $24,545 and 3.903 QALYs; the 18-gene assay strategy at US $28,374 and 3.623 QALYs; and the 482-gene signature treatment strategy at US $33,315 with 3.704 QALYs. Sensitivity analyses indicated that incremental cost-effectiveness ratio (ICER) values were sensitive to costs of genomic tests and adjuvant chemotherapies; and utilities related to patients in the no-recurrence health state. Conclusions: Overall, the Immunoscore assay seems to be a dominant strategy at a threshold willingness-to-pay of $50,000 per QALY, but in the US other tests have been used for longer. Thus, the 12-gene assay may generate cost savings compared to the 18-gene expression assay. The findings of our study may provide useful information to policymakers regarding selection of the most appropriate genomic test, and resource allocation decisions.

Deliberations about clinical pharmacogenetic testing in pediatric oncology.

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

Diagnostics and biomarker development: priming the pipeline.

The decrease in the rate at which novel medical products are reaching the market, despite major scientific achievements and investment that might have predicted otherwise, is causing much concern. Although this 'pipeline problem' has often been discussed in the context of drug development, it is also crucial to examine the unique characteristics of the pipeline for biomarkers and diagnostics. Here, we characterize the pipeline problem for biomarkers and diagnostics, and consider what steps could be taken to solve it.

Ethical perspectives on pharmacogenomic profiling in the drug development process.

Pharmacogenomics, which is a field that encompasses the study of genetic polymorphisms that underlie individual differences in drug response, is rapidly advancing. The potential for the widespread use of pharmacogenomics in the drug development process merits an examination of its fundamental impact on clinical-trial design and practice. This article provides a critical analysis of some of the issues that pertain to pharmacogenomics in the drug development process. In particular, four areas will be discussed: clinical-trial design; subject stratification; some new social risks; and economic concerns. Recommendations are offered for addressing the issues that are discussed and anticipating the regulatory needs for pharmacogenomics-based trials.

The role of hospital pharmacists in the adoption and use of pharmacogenomics and precision medicine.

AIM: Our aim was to assess the knowledge and attitudes of US hospital pharmacists about the implementation of clinical pharmacogenomics, and examine liability risks of adopting pharmacogenomics by pharmacists. METHODS: We surveyed hospital pharmacists. Linear regression models of predictor variables for pharmacist adoption and use of pharmacogenomics were analyzed. RESULTS: The survey was administered to 660 hospital pharmacists (23% response rate; n = 149). The majority of respondents (72%) favor implementing pharmacogenomics into pharmacy practice. However, only 25% are confident in their abilities to interpret pharmacogenomic test results. CONCLUSION: Pharmacists lack confidence in their abilities to interpret and use pharmacogenomic information in clinical care. These results raise potential liability risks that are pertinent to pharmacists.

Implementation of a Standardized Medication Therapy Management Plus Approach within Primary Care.

PURPOSE: The purpose of this study was to implement a clinical pharmacist-led medication therapy management (MTM) service within a primary-care setting that is enhanced by 1) a clinical decision support system (CDSS) that includes a unique combination of medication risk mitigation factors, which aids the pharmacist in interpreting the medication profile, and 2) pharmacogenomics (PGx) testing. METHODS: This was a service implementation study, whereby Medicare beneficiaries were eligible if they were patients of Elmwood Family Physicians, a private family, primary care practice with 2 locations in New Jersey, and were on at least 7 medications. Patients had a medication reconciliation completed by a pharmacist and performed a PGx buccal swab. Patient information was run through a CDSS to aid the pharmacist with screening for multidrug interactions and assessing patient's medication-related risks. The output of the CDSS was used to create recommendations and provide a consult to the physicians. Recommendations were followed up by return of the consult. RESULTS: Enrolled patients used a mean (± standard deviation) of 12.1 (± 4.6) medications. The turnaround time for the MTM Plus consults was 11.7 (± 6.2) days. During the consults, the pharmacist identified 138 medication-related problems (MRPs). The most common MRPs were drug-drug interactions (29.0%) and drug-gene interactions (DGIs; 24.6%). CONCLUSION: Implementing a clinical pharmacist-led MTM Plus service in the primary care setting is feasible. This study highlights that DGIs are common in older adults in family practice and indicates that PGx testing identifies additional MRPs that may otherwise go unnoticed in these patients. The experiences we shared can aid other clinicians in establishing successful MTM Plus services. Future studies should also measure the impact of such personalized medicine services on economic, clinical, and humanistic outcomes. This study has been registered with ClinicalTrials.gov (study No. NCT02748148).

Effects of omega-3 fatty acids on cancer risk: a systematic review.

CONTEXT: Omega-3 fatty acids are purported to reduce the risk of cancer. Studies have reported mixed results. OBJECTIVE: To synthesize published and unpublished evidence to determine estimates of the effect of omega-3 fatty acids on cancer risk in prospective cohort studies. DATA SOURCES: Articles published from 1966 to October 2005 identified through MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CAB Health; unpublished literature sought through letters to experts in the neutraceutical industry. STUDY SELECTION: A total of 38 articles with a description of effects of consumption of omega-3 fatty acids on tumor incidence, prospective cohort study design, human study population; and description of effect of omega-3 among groups with different levels of exposure in the cohort were included. Two reviewers independently reviewed articles using structured abstraction forms; disagreements were resolved by consensus. DATA EXTRACTION: Two reviewers independently abstracted detailed data about the incidence of cancer, the type of cancer, the number and characteristics of the patients, details on the exposure to omega-3 fatty acids, and the elapsed time between the intervention and outcome measurements. Data about the methodological quality of the study were also abstracted. DATA SYNTHESIS: Across 20 cohorts from 7 countries for 11 different types of cancer and using up to 6 different ways to categorize omega-3 fatty acid consumption, 65 estimates of the association between omega-3 fatty acid consumption were reported. Among these, only 8 were statistically significant. The high degree of heterogeneity across these studies precluded pooling of data. For breast cancer 1 significant estimate was for increased risk (incidence risk ratio [IRR], 1.47; 95% confidence interval [CI], 1.10-1.98) and 3 were for decreased risk (RR, 0.68-0.72); 7 other estimates did not show a significant association. For colorectal cancer, there was 1 estimate of decreased risk (RR, 0.49; 95% CI, 0.27-0.89) and 17 estimates without association. For lung cancer one of the significant associations was for increased cancer risk (IRR, 3.0; 95% CI, 1.2-7.3), the other was for decreased risk (RR, 0.32; 95% CI, 0.13-0.76), and 4 other estimates were not significant. For prostate cancer, there was 1 estimate of decreased risk (RR, 0.43; 95% CI, 0.22-0.83) and 1 of increased risk (RR, 1.98; 95% CI, 1.34-2.93) for advanced prostate cancer; 15 other estimates did not show a significant association. The study that assessed skin cancer found an increased risk (RR, 1.13; 95% CI, 1.01-1.27). No significant associations between omega-3 fatty acid consumption and cancer incidence were found for aerodigestive cancer, bladder cancer, lymphoma, ovarian cancer, pancreatic cancer, or stomach cancer. CONCLUSIONS: A large body of literature spanning numerous cohorts from many countries and with different demographic characteristics does not provide evidence to suggest a significant association between omega-3 fatty acids and cancer incidence. Dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer.

Factors affecting the adoption and use of gene expression profiling by oncologists in clinical practice.

AIM: In this study, we evaluated the association between oncologists' perceptions of and attitudes toward one frequently used gene expression profiling assays, the Oncotype DX® and oncologists' intention to use this assay in making treatment recommendations for breast cancer patients. METHODS: A nationally representative sample of breast cancer oncologists was surveyed using an adapted technology acceptance model. RESULTS: The survey response rate was 44.1%. The test characteristics `validity of the test' (p = 0.006) and 'use of Oncotype DX by fellow oncologists' (p = 0.0068) were significantly associated with use of the assay by oncologists. Oncologists' intention to use Oncotype DX increased consistently with their perceptions about its usefulness (ß = 0.222). Insurance status of the patients was also significantly associated with physicians' use of Oncotype DX (p = 0.008). CONCLUSION: We report a novel application of an adapted technology acceptance model to understand the adoption of gene expression profiling by oncologists who treat breast cancer patients in making treatment recommendations.

The value of multigene predictors of clinical outcome in breast cancer: an analysis of the evidence.

OBJECTIVE: Multigene predictors are being used increasingly in early-stage breast cancer patients for prediction and prognosis. However, one consequence of the increased use of multigene predictors, and the heightened efforts toward their incorporation into routine clinical practice, is the potential for future malpractice litigation. It is, therefore, important to ascertain the strength of the evidence for using the different commercially available multigene predictor assays clinically. We evaluated the literature for evidence of clinical validity of four currently available gene signatures and to assess the influence of the 21-gene-expression assay on changes in treatment recommendations. METHODS: A systematic search of the peer-reviewed literature from January 2002 to March 2014 for multigene predictor assays was carried out, and a meta-analysis was conducted. RESULTS: The adjusted Cox hazard ratio average for studies that met the eligibility criteria was 3.538 (95% CI: 1.513-8.469). The 21-gene signature showed the highest stability in the estimation of likelihood of distant risk of recurrence. Using the recurrence scores resulted in changes in treatment recommendations in 31.8% of all patients in the studies. CONCLUSION: This study may provide insight about the use of multigene predictors in clinical practice for prediction and prognosis of breast cancer.

The regulation of pharmacogenomics-based drugs and policy making.

In addition to potential future clinical benefits such as reducing adverse drug reactions and optimizing therapeutic efficacy, pharmacogenomic applications promise numerous benefits for the pharmaceutical and biotechnology industries, including decreasing the size and expense of clinical trials and streamlining the drug development process. The application of pharmacogenomics and related technological advances to drug development has prompted various regulatory agencies such as the United States Food and Drug Administration to issue guidance documents and other advisory statements. This article delineates the impact of pharmacogenomic-guided drug development on the regulatory process in the United States including relevant highlights of industry guidance documents and policy statements. Hypothetical vignettes are used to illustrate a number of issues that are challenging to policy makers and the potential impact of pharmacogenomic based drug research and development on the regulatory environment.

Pharmacogenomic profiling in postmarketing surveillance: prospects and challenges.

Adverse drug reactions (ADRs) represent a major public health and economic global problem. Growing evidence suggests that pharmacogenomics may potentially play a role in reducing drug-induced adverse events. Research efforts are increasingly directed towards this goal. However, knowledge about whether or not pharmacogenomics may be useful as a novel approach in postmarketing surveillance programs is at present rather limited. A critical analysis of some of the methodological design and ethical issues generated by the potential incorporation of pharmacogenomic profiling into pharmacosurveillance programs is presented.

Taking off the white coat: can family members who are physicians be good surrogate decision-makers?

The challenges inherent in physicians treating members of their own families are well known. However, the issues related to physicians acting as surrogate decision-makers on behalf of relatives have not been addressed. The growing number of older persons will increase the need not only for healthcare resources, but also for physicians to act on behalf of incapacitated family members as surrogate decision-makers. In this paper, some of the clinical and ethical tensions evoked by physicians serving as surrogate decision-makers for family members are explored. Some recommendations for managing these tensions are suggested.