Role of Pharmacogenomics in Comprehensive Medication Management: Considerations for Employers

Abstract

Rising prescription costs, poor medication adherence, and safety issues pose persistent challenges to employer-sponsored health care plans and their beneficiaries. Comprehensive medication management (CMM), a patient-centered approach to medication optimization, enriched by pharmacogenomics (PGx), has been shown to improve the efficacy and safety of pharmaceutical regimens. This has contributed to improved health care outcomes, reduced costs of treatments, better adherence, shorter durations of treatment, and fewer adverse effects from drug therapy. Despite compelling clinical and economic evidence to justify the application of CMM guided by PGx, implementation in clinical settings remains sparse; notable barriers include limited physician adoption and health insurance coverage. Ultimately, these challenges may be overcome through comprehensive programs that include clinical decision support systems and education through employer-sponsored population health management channels to the benefit of the employees, employers, health care providers, and health care systems. This article discusses benefits, considerations, and barriers of scalable PGx-enriched CMM programs in the context of self-insured employers.

Introduction

High and rising medical and pharmacy costs pose an ongoing burden to employees and employers. For example, in 2020, overall pharmaceutical expenditures in the United States grew 4.9% compared with those in 2019, for a total of $535.3 billion,¹ with spending projected to increase by 4%–6% in 2021.¹ Furthermore, nonoptimized medication therapy results in drug-related morbidity and mortality costs of $528.4 billion, equivalent to 16% of total US health care expenditures per year.²

Treatment failure and new medical problems after initial prescription have been reported to cost $2481 to $2610 per patient.² Managing drug utilization is costly to the entire US health care system, including payors, manufacturers, employers, physicians, and patients, costing ∼$93.3 billion each year.³ Employers incur some of the highest cost burden for prescription drugs and medical expenditures.⁴ Because rising prescription costs and avoidable morbidity and mortality present growing burdens to the health system, all stakeholders could benefit from more efficient use of resources, including lower drug prices and lower barriers to patient access.³

Several strategies have been proposed to help manage the growing cost of health care, including medication costs, and improve health outcomes. A patient-centered approach to medication optimization, comprehensive medication management (CMM), enriched by pharmacogenomics (PGx), has been shown to improve health care outcomes. Here the authors describe the delivery of CMM with PGx in the context of self-insured employers with a focus on value, barriers, coverage status, and stakeholder readiness.

CMM as a strategy to improve health care

Medication therapy management

Reimbursement for medication therapy management (MTM) services falls under CPT code 99605 for the initial encounter defined as “service(s) provided by a pharmacist, individual, face-to-face with patient, initial 15 minutes, with assessment, and intervention if provided”; codes 99606 and 99607 are used for subsequent and additional encounters. MTM services enable pharmacists to be involved in improving health care outcomes of patients.⁵ Yet, clinical pharmacy service reimbursement has been limited to distinct services that optimize therapeutic outcomes for individual patients and are independent of the provision of a medication product.⁶

During these encounters, pharmacists generally focus on a specific disease state (eg, diabetes), as MTM services must be associated with a specific diagnosis or disease state for reimbursement. According to the Centers for Medicare & Medicaid Services (CMS) (423.153(d)),⁷ MTM programs must be coordinated with the care management plan established for the individual participating in a chronic care improvement program. This ensures optimum therapeutic outcomes for the beneficiary by improving medication use and reducing risk of adverse events.

Comprehensive medication management

CMM is a patient-centered approach for medication optimization where clinical pharmacy is integrated into interdisciplinary care teams to better achieve treatment goals.^8,9 Unlike MTM, CMM utilizes a “whole patient” approach to determine appropriateness, effectiveness, safety, and adherence for all the patient's medications and disease states, not just for a specific disease state.¹⁰ CMM evolved from the American College of Clinical Pharmacy's 1997 position statement⁸ on collaborative drug therapy management as an approach designed to deliver value and optimize medication-related outcomes. Outcomes of prior implementations of CMM by integrating clinical pharmacy services into interdisciplinary care teams in primary care clinics have shown positive provider and patient satisfaction.¹⁰

Most (>90%) participants in a CMM program who responded to a survey agreed that the clinical pharmacist helped them understand why they were taking their medications, made sure that their medications were safe, and helped them feel confident in managing their medications.¹⁰ Providers also reported favorable attitudes toward CMM; 93% agreed that patients benefited from seeing the pharmacist as part of a CMM program.¹⁰ Implementation of CMM in community-based clinics has demonstrated favorable outcomes in resolving medication therapy problems (ie, adverse drug reactions and inappropriate drug dosage), and achieving cost savings, with collaboration from the patient's primary care physician or care team.¹¹

Despite their central role in CMM, pharmacists are seldom reimbursed by payors for providing clinical pharmacy services within a CMM program. Although CMM is reactive, occurring after prescribing, it seeks to identify medication-related problems before they happen. The comprehensive and pre-emptive identification of medication-related problems is a barrier to pharmacist reimbursement by insurers. Consequently, CMM services that are viewed as valuable to the health management of patients are more frequently funded by health systems rather than insurance reimbursement.

PGx as a strategy to improve health care

For several years now, genomics has been integrated into diagnostic medicine to improve clinical care and patient outcomes by informing the selection of the most appropriate targeted therapies. PGx testing can identify inherited (germline) genetic variance that might affect drug effectiveness and safety by examining genes related to pharmacokinetics (absorption, distribution, metabolism, and elimination) or pharmacodynamics (receptor binding, sensitivity, and postreceptor biological effects).¹² PGx has the potential to enhance medication therapy by providing insights into a patient's genetic characteristics that might impact response to medication, information that clinicians seldom have access to.¹² PGx, and specifically the proactive testing of multiple genes, can improve treatment outcomes while reducing adverse drug reactions¹³ and unnecessary costs.¹³

Several organizations have provided guidance for the incorporation of PGx testing into clinical care. The Clinical Pharmacogenetics Implementation Consortium (CPIC) seeks to generate expert recommendations for the use of genetic testing to guide medication prescribing and dosage.¹⁴ CPIC was formed in 2009 to facilitate the translation of research findings into clinical guidance for gene/drug pairs with sufficient evidence.

It has since published 23 clinical practice guidelines, covering 19 genes and 46 drugs across several therapeutic areas, and providing guidance to facilitate the implementation of PGx into routine clinical practice.¹⁴ In addition to CPIC, several organizations support the use of PGx to improve medication selection and dosing, including the U.S. Food and Drug Administration (FDA), American Society of Health-System Pharmacists, and Medicare (through local coverage determinations [LCDs]). Such support highlights the value of PGx in clinical practice despite current barriers to payor coverage.

Patient readiness for PGx

As patients are at the receiving end of PGx-guided medication management, their readiness to adopt PGx testing is an important implementation consideration.¹⁵ Consumer interest in PGx testing to predict serious side effects appears stronger in individuals who are younger (aged 18–34 years), Caucasian, college-educated, or have experienced adverse effects from medications.¹⁶ Public attitude assessments further reveal an interest in PGx testing to predict drug effectiveness and adverse effects, guide dosing, and assist with drug selection, but also a concern with privacy and a need for reports that are easy to understand (ie, reports that avoid complex jargon and are customized to each patient's medications or disease conditions).^16
–18

Therapeutic implications of PGx

Prescription medication use in the United States is common—half of the adult population is taking at least 1 prescription medication.^19,20 Exposure to medications with PGx implications is also prevalent as ∼63% of adults are prescribed medications with actionable PGx biomarkers,²¹ with 64.8% of individuals exposed to at least 1 medication with an established PGx association within a 5-year window.²²

Some of the most frequently used medications with PGx implications are prescribed to address issues in cardiology and psychiatry.^22
–24 Ultimately, the number of people who might benefit from PGx-guided prescribing is substantial.²¹ It has been estimated that >90% of individuals could benefit from genetic testing to guide prescribing decisions currently or in the future,^25,26 as implementations have revealed that 91%–99% of genotyped patients had 1 or more genetic variants that could impact response to medications.^25
–27

Pharmacogenomics impacts economic and clinical outcomes

PGx testing can reduce severe drug-induced adverse reactions²⁸ to improve clinical outcomes and reduce economic burden²⁹ across several disease states including cardiovascular events, bleeding, and myopathies.²⁹ Thus, PGx testing has been shown to be cost-effective,^30
–32 but this varies by treatment area, drug class,³² funding mechanism, payor (both public and private), provider, societal factors, and health care system.³³ Studies have reported cost savings of $1036³¹ to $3962^34,35 per patient per year for psychiatry and depression medications. In cardiovascular care, PGx testing has been shown to be cost-effective when used pre-emptively,³⁶ with cost-effectiveness varying across drugs and conditions.³³

For individuals taking 5 or more medications, annual cost savings of $621 have been reported through the elimination and/or replacement of 1–3 drugs in half of the polypharmacy patients tested.³⁷ In polypharmacy patients, recommended drug changes were primarily based on gene–drug interactions and drug–drug interactions.³⁷ The largest savings were observed for psychotropic drug changes, followed by neurology, cardiovascular, and urology medication changes.³⁷ Further details on economic impact are available in prior research.^{30

–37}

PGx-guided treatment for cardiovascular medications can reduce adverse events and increase effectiveness.³⁸ PGx testing results allow cardiologists to tailor antiplatelet therapy based on CYP2C19 status.³⁹ Approximately 30% of the US population (ranging to >50% in Asian and Oceanian populations) carries a CYP2C19 loss-of-function allele, which poses an increased risk of major adverse cardiovascular events with clopidogrel treatment.⁴⁰

After testing, individuals with poor or intermediate metabolism of the drug are more likely (57.6% and 33.2%, respectively) to switch to alternative antiplatelet therapy within a year, compared with only 8.3% for those with normal metabolism.³⁹ Since the risk for major adverse cardiovascular events is 2.26 times higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years), such changes may reduce major adverse cardiovascular events.⁴¹

PGx-guided treatment for anticoagulant medications can guide dosing and reduce adverse events. Adverse drug effects to the anticoagulant drug, warfarin—one of the most highly prescribed medications with PGx implications—are among the leading causes of emergency department visits and hospitalizations for adverse drug reactions.⁴²

Dunnenberger et al²³ reported that ∼28% (7 million) of the 25 million US prescriptions for warfarin are considered high risk. PGx can inform initial dosing for warfarin treatments, which can differ by 10–20-fold in individuals. In 2010, the FDA revised the warfarin product label to include dose recommendations based on CYP2C9 and VKORC1 genotype. PGx-guided warfarin prescribing has been shown to improve dosing and reduce adverse events.⁴³

PGx-guided treatment can aid in the appropriate selection of antidepressant medications. Treating depression is quite complex with >40 drugs available.⁴⁴ Often, patients with major depressive disorder or anxiety disorders require multiple trials of antidepressant medication to achieve full remission. In fact, some patients may never reach remission, even after multiple trials of antidepressants.^45,46

Dunnenberger et al reported that ∼48% (18 million) of the 38 million US prescriptions for sertraline (antidepressant) are considered high risk and ∼48% (17 million) of the 36 million US prescriptions for citalopram (antidepressant) are considered high risk.²³ Thus, further information may help to guide prescribers in matching the PGx profile of the patient the right drug.⁴⁴ The effect of CYP2C19 genetic polymorphism on the efficacy and safety profiles of citalopram has been demonstrated in individuals with major depressive disorder.⁴⁷ Moreover, individuals with altered enzymatic metabolism (identified by genotyping of CYP2C19/CYP2D6 variants) may benefit from some antidepressants rather than others or need dose adjustments.⁴⁸

Pre-emptive testing

Implementation of PGx to guide clinical care has demonstrated effectiveness at achieving desired treatment outcomes; improving adherence, safety, and efficacy; and reducing adverse effects, hospitalizations, and costs.⁴⁹ Initially, PGx was implemented using single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings when a new prescription medication was ordered, when the medication did not work as intended, or if an adverse drug reaction occurred.⁵⁰

Based on the success of single-gene PGx testing and decreased genotyping cost, interest in pre-emptive (eg, before prescribing) panel-based testing has grown.⁵⁰ In addition, genomic testing can be used in companion diagnostics where cancer drugs can be targeted at specific mutations of a tumor to aid in the selection of therapy, predict serious side effects, and determine how well a treatment is working.⁵¹

Reactive single-gene PGx was initially implemented based on financial reimbursement by health systems that did not cover preventive medicine services or pre-emptive screening services.⁵² Eventually, many payors began to reimburse for single-gene testing. In addition, reactive single-gene PGx testing could be considered more straightforward in terms of translating results into clinical care based on narrow evidence-based drug–gene pairs.⁵⁰

Yet, reactive PGx testing on the per-gene basis has some disadvantages to pre-emptive testing.²³ Disadvantages of reactive per-gene testing include higher cumulative cost; slow turnaround time, which may be too slow to be useful for initial prescribing decisions; and a need for clinicians to be aware of important gene–drug relations to prompt the ordering of a genetic test.²³

Comprehensive pre-emptive PGx, in contrast, has mounting evidence to support its utility and value, is more practical for use in prescribing decisions,^23,26 and can be used to optimize the pharmacotherapy of patients beyond a single gene–drug pair.²³ Comprehensive pre-emptive testing involves panel screening of multiple relevant genes that impact high-risk medications²³ before prescribing, so that results are available and can be used to inform medication selection at the point of care.²⁶

With PGx results available before a new medication is prescribed, clinicians may consider genomic variation as an additional patient characteristic when making prescribing decisions.²³ Pre-emptive PGx testing would also enable PGx test results to be available as part of electronic health records for prospective prescribing. Yet, pre-emptive PGx requires supporting infrastructure to enable both genetic testing results and clinical decision support to be available pre-emptively in electronic health records and drug prescription systems.²³

Although the broad nature of pre-emptive PGx testing can be considered a “once in a lifetime” test, portability of the results between health care providers is a current barrier that needs to be addressed. Multigene panels have been criticized for having irrelevant or low evidence gene–drug associations with questionable clinical utility. By focusing pre-emptive multigene panels on only those gene–drug associations with clinical utility, this concern can be alleviated. Yet, as knowledge expands on the PGx relevance of additional genes and drugs, broad testing would allow for later reinterpretation of the genetic data.

Health plan coverage policy for PGx

Coverage of PGx testing is currently limited and varied by health plans and is most often restricted to coverage of an individual gene–drug pair.^53,54 Health institutions have implemented PGx reactively, ordering a single-gene test when there is a need to prescribe a high-risk drug, to ensure that the optimal treatment is selected.⁴⁹ Historical claims analyses have revealed insights into use of single-gene tests.^53,54

Tests were most commonly ordered in association with long-term (current) use of other medications and diagnosis of depression or anxiety or pain.⁵³ Claims analysis of a US managed care population of 11 million individuals revealed that use of single-gene PGx testing (CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 genotyping) through patient insurance was low (at only 5712 patients), but more than doubled from n = 1995 in 2013 to n = 3946 in 2016.⁵³ Individuals were receiving about 3 single-gene tests per person (ranging up to 12).⁵³

The most commonly covered single-gene pharmacogenetic tests among commercial insurers included CYP2C19 for clopidogrel, CYP2D6 for tetrabenazine, HLA-B*15:02 for carbamazepine (only for persons of Asian ancestry), HLA-B*57:01 for abacavir, EGFR for erlotinib, and TPMT for mercaptopurine and azathiopurine.^53,55 Payors have also been critical of the multigene testing panels commonly offered by laboratories⁵⁶ and are reluctant to support multiplexed PGx testing. Still, several health systems, such as University of Pittsburgh Medical Center, St. Jude Children's Research Hospital, and Vanderbilt University Medical Center, have invested in large, population-scale, multigene pre-emptive testing programs.⁵⁷

In addition to wide-ranging coverage policies, commercial reimbursement amounts for PGx testing have varied greatly.⁵³ For single-gene testing, CYP2D6 had the highest coverage amount ($288.60 on average, ranging from $0 to $6780).⁵³ The lowest coverage amount was observed for VKORC1 ($57.79 on average, ranging from $0 to $830).⁵³ Coverage amounts were generally higher under commercial plans ($317.43 on average for CYP2D6) compared with managed Medicare/Medicaid ($270.73).⁵³ The average cost for a single-gene pharmacogenetic test in a Medicare population of ∼1.5 million beneficiaries was ∼$193 per test,⁵⁴ based on 611,199 tests (CYP2D6, CYP2C19, CYP2C9, VKORC1), which represented 33% of genetic tests and amounted to $117,845,531 in spending.⁵⁴

Although the value of PGx testing must be demonstrated for policymakers to adopt and reimburse PGx testing,⁵⁸ the diversity of coverage and lack of alignment for both single-gene and multigene tests has contributed to the stalling of the broad delivery of PGx to patients who could benefit. However, we are reminded that PGx-guided treatment has been demonstrated to be a cost-effective and even a cost-saving strategy in some settings.³²

Since one of the greatest obstacles to large-scale clinical implementation of PGx is the limited reimbursement from commercial payors,⁵⁹ a deeper understanding of this barrier is necessary to overcome this challenge. Interviews of medical or pharmacy directors from 14 payor organizations covering 122 million US lives have provided some insights into barriers and potential facilitators for developing cohesive reimbursement policies for PGx.⁶⁰

Interviews revealed clinical utility concerns and limited exposure to pre-emptive germline testing, continued preference for outcomes from randomized controlled trials, interest in further guideline development, importance of demonstrating an impact on clinical decision making, concerns of downstream cost and benefit predictability, and the impact of public stakeholders such as the FDA and CMS.⁶⁰ Moreover, an employer panel on genomics in health and wellness revealed that “the number of available tests and their complexity can make it difficult for insurance companies to decide what to cover.”⁶¹

Developing cohesive reimbursement policies for PGx, especially pre-emptive testing, will require additional evidence on clinical utility,⁵⁹ including precisely defined target populations and predictive economic models.^56,60 Coverage decisions will require clear evidence of clinical effectiveness and utility and an understanding of how adoption will impact health care costs and utilization within a payor's network.⁵⁶ By pairing clinical outcomes with claims and cost data and collaboratively conducting well-designed pragmatic clinical or observational studies, all stakeholders can learn from more meaningful and relevant outcomes.⁵⁶

As evidence for clinical utility mounts, payors have slowly begun reimbursing for PGx. Several national agencies such as CPIC and the Personalized Medicine Coalition are working on strategies to reach out to payors for PGx reimbursement while recognizing existing barriers.⁶⁰

An important milestone in payor coverage occurred in 2019 when the United Health Group (the largest private payor in the United States) instituted new coverage for testing that guides antidepressant and antipsychotic prescribing in some settings.⁵⁷ According to the current policy,⁶² multigene PGx panels are proven and medically necessary to guide therapy decisions for antidepressants and antipsychotics when an individual has a diagnosis of major depressive disorder or generalized anxiety disorder, has failed at least 1 prior medication to treat their condition, and the panel contains no more than 15 relevant genes.

This milestone sets the stage for increased adoption of PGx. In August 2020, new Molecular Diagnostic Services (MolDx) LCDs expanded coverage for Medicare patients.⁶³ In addition, 7 different third-party payors and Medicare reimbursed for CYP2C19 genotyping during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month.⁶⁴

CMM enriched by PGx

Including PGx information in CMM enables clinicians and pharmacists to better assess appropriateness, effectiveness, and safety of medications for the individual. The multidisciplinary approach of CMM, where a pharmacist is included as part of the care team, enables the physician and pharmacist to consult and share expertise. PGx+CMM can improve drug safety,⁶⁵ disease management,⁶⁶ and medication adherence^31,67 and effectiveness,⁶⁸ and reduce adverse drug reactions.^13,22 PGx+CMM has shown positive impact for guiding medication changes³⁹ and avoiding cardiovascular episodes.⁴¹

Implementation of PGx+CMM has been shown to be feasible in primary care,⁶⁹ a psychology clinic,⁷⁰ and community settings.⁷¹ Implementations have demonstrated effectiveness in identifying medication-related problems including drug–gene interactions that may have gone unnoticed without PGx testing.^69,70

Most individuals (90%–97%) pre-emptively tested in primary care settings had actionable variants, and 24%–31% were on a medication associated with an actionable variant (gene–drug interaction).⁷¹ In the psychology setting, genetic variants that could potentially affect the safety and effectiveness of at least 1 psychiatric medication were identified in 96% of patients.⁷⁰ Implementations where PGx was included in medication management have also reinforced the essential role pharmacists play in facilitating the clinical applications of genetic information for optimizing drug therapy decisions.⁷⁰

As case in point, a recent longitudinal retrospective study demonstrated the feasibility and successes of a PGx+CMM program that was offered as a benefit in a teachers' retirement system health care plan.⁷² In brief, the authors evaluated an operationalization of PGx and noted positive impacts of PGx+CMM across the quadruple aim for health care improvement. In addition to a substantial reduction in direct medical charges—$37MM in the first 32 months of the program—the authors noted significantly decreased health care utilization, including in emergency room visits and hospitalizations. These findings have profound implications for the future of clinical medicine.⁷²

Barriers to broader implementation of PGx+CMM

Despite the observed improvements in health outcomes and cost reduction, several barriers challenge the broad implementation of PGx+CMM. Among the barriers are the limitations in traditional payment models and modes of care delivery.⁹ In addition, widespread adoption of PGx+CMM has been limited by clinicians' resistance to use genetic data. This resistance often stems from insufficient training and guidance for how to use the information in the clinic, inadequate infrastructure to process, report, and recall the data, limited payor support, and concerns about incidental or secondary findings from genetic testing.^12,73 Moreover, there remain gaps in provider acceptance of pharmacists' recommendations and pharmacist–provider relationships.¹⁰

Health care practitioner considerations

The success of PGx+CMM is attributed largely to the communication of clinical recommendations from the pharmacist—the health care provider/expert who has combined the genetic test results with clinical expertise to provide instructions to the prescribing physician. Most practitioners have a favorable view of PGx testing⁷⁴ and agree that genetic variations influence drug response.^73,75

Yet only a minority of primary care practitioners (13%) indicated they felt comfortable ordering tests and almost a quarter reported not having any education about PGx.⁷⁶ Moreover, enthusiasm was reserved among primary care providers (PCP) due to concerns about clinical utility, insurance coverage, delay of treatment, and ability to communicate and interpret ancillary disease risk information.⁷⁴ Although physicians perceive several benefits to and have favorable attitudes toward PGx-enriched medication management, they often feel unprepared to use the genetic test information,⁷⁷ especially to care for genetically “high-risk” patients.⁷⁸

Only 10.3% felt adequately informed about PGx testing and 29.0% received any education in the field.⁷³ This lack of preparation often stems from limited PGx training in medical schools⁷⁹ or health profession programs.⁸⁰ Early and future adopters of testing were more likely to have received training in PGx.⁷³ Thus, the need remains for more effective physician education on the clinical value, availability, and interpretation of PGx tests.^73,79

In addition to adequate training, many clinicians are unsure of how to implement PGx in their practices. Challenges for clinicians arise in ordering tests (knowing which tests to order), interpreting tests, and applying PGx to complex clinical practice.⁸¹ Only 12.9% of physicians had ordered a PGx test in the previous 6 months, and 26.4% anticipated ordering a PGx test in the next 6 months.⁷³ Clinician resistance varies by practice, where family physicians are less likely to adopt PGx, likely due to fewer perceived benefits, less training, and fewer sources of information than physicians in other specialties.⁷⁷

Nearly 20% of surveyed specialty physicians indicated that they had ordered a PGx test during the past year in 2014, with significantly more cardiologists than psychiatrists having ordered a test (32.2% vs. 11.7%).⁸¹ Many physicians (39%) report obtaining PGx test information from drug labeling.⁸² As such, overcoming knowledge barriers may enhance physicians' readiness to adopt PGx-empowered medication management.⁷⁷

PCPs envision a major role for themselves in the delivery of PGx testing but recognize their lack of adequate knowledge and experience about these tests.⁷⁶ Most commonly requested education from physicians includes how to interpret PGx test results (88.4%), recommendations for prescribing (88.1%), effect of genetic variation on mechanism of drug action (79.9%), and demographics of populations likely to carry variations (76.9%).⁸¹ As health care providers are generally unfamiliar with how to use PGx information to make clinical decisions, engaging the provider community in CMM may facilitate success of implementation.^83,84

Leveraging multidisciplinary teams enables prescribers to rely on medication experts (pharmacists) to help analyze and review medication-related problems (PGx or otherwise). Also, clinical decision support tools utilizing PGx can be helpful in the clinic and as a supplement to the pharmacists' knowledge when delivering CMM. In addition, integrating the use of simplified genetics-guided recommendations to improve attitudes and preparedness to implement disease genetics in care is important.⁷⁸ Practitioners favored immediate notification when a clinically actionable variant was detected in a patient on a target drug.⁷⁵ PCPs also felt an obligation to disclose information about ancillary disease risk.⁷⁴

Infrastructure challenges

Successful implementation of PGx, with or without CMM, into clinical practice requires supporting infrastructure to facilitate education, PGx testing, DNA sequencing and genotyping, clinical interpretation, data storage, medication review, and communication of information to prescribing physicians to inform clinical decision making. Components of this infrastructure include education and engagement of patients, laboratories for genotyping, clinical decision support tools, and involvement of all stakeholders.

Currently, a barrier to implementation of PGx is the absence of infrastructure to handle the genetic data and make it accessible to the prescriber at all times of prescribing throughout the lifetime of the patient. Ideal clinical implementation of PGx will integrate PGx data into clinical decision support and workflows,⁵⁹ electronic health records, and pharmacy ordering systems.⁵² This would include an interface that could integrate clinical decision support tools and PGx guidelines in the electronic health record to reliably translate PGx insights for broad and timely use in clinical practice and prescribing.^59,85

Effective integration into clinical workflows will require institutional-level support and investment of resources.⁸⁵ In addition, supporting infrastructure is necessary to facilitate and promote the implementation of genomics in clinical care with research and education.⁸⁶ Supporting infrastructure may include educational materials and clinical decision support for physicians and others working to implement the use of genomic findings in clinical care⁸⁶ and curricula for health care students, trainees, and advanced practitioners.⁸⁶ There also remains the challenge of balancing decision-making ability for clinicians and patient safety within the clinical decision support mechanism.⁸⁷

Discussion

Given the barriers to clinical implementation, alternative strategies to deliver PGx at scale may be considered to improve population health. In a self-insured employer population, employers may find value in offering CMM enriched by PGx (PGx+CMM) services as a health and well-being benefit, considering their long-term interest and investment in employee health. As traditional payment models have examined costs and value on an individual level, a population-level strategy may diffuse costs across a group and reap value based on cases of positive outcome among the group.

Owing to current regulatory limitations leading to the absence of patient-initiated testing, the employee setting may offer an alternative channel to deliver PGx testing. Employers are well positioned to positively influence employee health and well-being while simultaneously addressing issues of economic, clinical, and humanistic public health outcomes. Employers may consider PGx+CMM health programming for employees as a means to improve employee health and reduce costs. Voluntary health-related genetic testing for employee populations may identify clinically actionable gene–drug interactions, engage individuals with their health and well-being, and promote safer and more effective medication use.⁸⁸

Benefit considerations vary greatly depending on whether an employer is implementing regular health insurance benefits or a wellness plan.⁶¹ In comparison with payors, employers are interested in employee engagement, well-being, and absenteeism in addition to costs when considering genomic services.⁶¹ In addition, employers and private insurers differ in their time spans of coverage (10+ years [or even 30 years for pension plans] for employers vs. only 1–2 years for private insurers).⁶¹ Thus, the impact of the intervention may be greater in the long term as PGx testing can be leveraged in future prescribing.

When considering the addition of a health care benefit, cost-effectiveness and savings are often evaluated. In addition, employers may be interested in data on avoidance of health episodes, shortening of episodes, and reduction of costs within episodes and consideration of the timeframe needed to achieve these outcomes.⁶¹ Employers are also interested in pilot studies that show the value of early interventions.⁶¹ Some employers are currently offering genetic testing to employees as a benefit in their wellness programs.⁸⁸

A 2019 analysis revealed 15 business-to-business corporate wellness vendors that offer genetic services,⁸⁸ of which 6 offered PGx. Interviews of 25 major employers, including top US self-insured employers (13), industry key opinion leaders (5), and disruptors (7), between September and November 2020 indicated a strong general conviction for precision medicine, especially among high-wage progressive employee populations. However, the surveyed employers felt there was a lack of clinical and economic evidence to convince them that PGx should be widely adopted.⁸⁹

In March 2019, the National Human Genome Research Institute (NHGRI) convened a group of employers (including 1 health care organization, 1 insurer, 1 genetic testing company, 1 retirement system, 1 university, 2 large multinational corporations, 4 biotechnology companies, and 5 hospital systems) to discuss the role of genomics in employee health.⁶¹ About 31% of participating employers were offering genomic testing as part of their wellness programs, with the main motivations being to reduce costs and improve employee health.⁶¹

Employee uptake of genomic testing was reported to be up to 25%.⁶¹ However, more insight into employee perspectives is needed to better understand barriers to program participation and determine what educational programs might be useful to drive employee engagement. For large self-insured employers, the employer is the payor and ultimately decides which tests, programs, and services to cover.⁶¹ The determination to offer tests and programs often depends on available evidence and value.

According to a recent survey by the business group on health,⁹⁰ employers are budgeting 4.3% of their health care dollars on well-being programs. Costs vary greatly depending upon the scope of offered programs—employers are spending between $150 and $1200 per employee per year on wellness programs. When allocating funds, employers may consider PGx programs among other preventative annual health programs, such as diabetes prevention,⁹¹ diabetes management, health screenings, health coaching, and tobacco cessation.⁹²

The same employers identified several barriers to implementation of a genetic testing program. Employers listed ethical, legal, and social issues, reliance on insurers, and concerns about the cost of testing as major reasons for not offering genomic testing.⁶¹ When implementing employee health programs, employers must provide a means for employees to opt-in and receive services, because in our fragmented health care system, an employee's individual physician may be naive to any employer-provided program.⁶¹

Moreover, employers identified the need to develop the downstream clinical infrastructure that translates genetic test results into the best patient care, as simply providing accredited tests is not enough.⁶¹ Enabling employers to use PGx testing in the framework of clinical care and CMM would address each of the barriers mentioned. Furthermore, implementation of a PGx+CMM program requires selection of the right messaging to eligible participants—others have noted that PGx initiatives have been sidetracked by concerns about genetic testing.⁸⁷

Employer-sponsored PGx testing programs must consider privacy concerns regarding employee genetic data. Program compliance with Health Insurance Portability and Accountability Act (HIPAA) and the Genetic Information Non-discrimination Act (GINA) is required.⁸⁸ According to GINA, all wellness programs must be voluntary. In addition, GINA prohibits employers from having access to data unless it is aggregated and deidentified.⁸⁸ Employees need to be educated about HIPAA, GINA, and their rights to privacy before implementing any wellness programs involving genetics, to reduce fears about employers' access to employee medical and genetic information.

As self-insured employers are major decision makers, payors, and implementers of health services, their funding of clinical pharmacy services as part of a CMM program for their insured employee population provides another avenue to overcome barriers to deliver valuable health care services to employees. Several institutions have successfully implemented PGx that include pre-emptive models⁹³ in clinical settings. These include the University of Colorado,⁸⁷ University of Florida,⁶⁴ Indiana Institute of Personalized Medicine,⁵² and other members of the Translational Pharmacogenetic Program (Mayo Clinic, Ohio State University, St. Jude Children's Research Hospital, University of Maryland, and Vanderbilt University Medical Center, University of Chicago, and Brigham and Women's Hospital).⁹⁴

These early adopters suggested that, to gain the maximal value, PGx information needs to be in a user-friendly format, used in a pre-emptive manner, and stored in the patient health record for future use.^52,64 In the employer setting where employers have discretion in formulating and funding health and well-being programs, additional considerations include legality, communications, and motivations (eg, productivity, cost savings, recruitment, retention).

Conclusion

PGx-enriched CMM (PGx+CMM) has the potential to improve health outcomes and medication safety while reducing costs. Employers, patients, and health care providers express interest in PGx testing to predict medication effectiveness and side effects, yet, delivering PGx+CMM to the populations who could benefit has been impeded by confidence gaps, fragmented infrastructure, and a lack of insurance coverage and reimbursement.

However, many of these barriers do not exist in the paradigm of self-insured, employer-sponsored health plans, and thus a PGx+CMM program could facilitate driving value where improved health and reduced costs are desired. Ultimately, PGx-enriched CMM programs have the potential to improve employee health and clinical outcomes and to decrease costs for employers.

Footnotes

Authors' Contributions

All listed authors contributed to the preparation of this review article and approved the final submission.

Author Disclosure Statement

Dr. Fragala, Dr. Lorenz, and Dr. Goldberg are employed by and receive a salary from Quest Diagnostics. Dr. Fragala and Dr. Goldberg have stock ownership in Quest Diagnostics. Dr. Shaman is employed by, receives a salary from, and has an equity interest in Coriell Life Sciences.

Funding Information

No funding was received for this article.

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