Ethical Conflicts in Industry-Sponsored Genetic Testing for Underserved Health Systems

Photo ID 64616115 © Sergunt | Dreamstime.com Abstract Genetic testing is essential for diagnosing and managing many rare diseases. Testing for high-risk alleles can predict disease decades before symptoms arise and treatment may be too late. However, cost, limited specialist availability, and health system capacity make patients’ access to this testing unequal. Industry-sponsored genetic testing (IST), in which commercial entities provide molecular diagnostics to patients free of cost, has been proposed as a means of addressing this diagnostic inequity. Because of ethical concerns, many health systems have been reluctant to adopt IST even when it is available, particularly when sponsors are developing related therapeutics. This article examines the ethical and practical challenges associated with implementing IST in a clinic setting. Using hereditary variant transthyretin amyloidosis (ATTRv) as a case example, we assess when and how IST can expand access without undermining professional integrity, patient trust, or equitable care. We discuss recurrent ethical concerns surrounding IST, including conflicts of interest, data stewardship, fragmentation of medical records, inadequate education, clinician autonomy, and the risk of inappropriate testing in nonspecialist settings. We propose that IST is neither inherently ethical nor unethical, but rather that there are five conditions under which it may be incorporated appropriately into clinical practice. We conclude that adopting IST may offer a pragmatic solution to access issues in rare disease care, but it should not replace services that non-industry-sponsored, well-resourced, multidisciplinary care teams provide under clinical supervision. Sustainable and equitable diagnostic support will require broader structural transformations. Introduction Genetic testing is increasingly able to identify genetic variants that contribute to rare diseases. However, results from these tests can be confusing and challenging for patients to access, which is made more difficult by the well-recognized shortage of genetics specialists across the country.[i] In some regions, patients may be completely unable to receive the diagnostic services they require and deserve, even when testing would otherwise be covered by the health system. Industry-sponsored testing (IST)—sequencing and analysis that a commercial entity, such as a pharmaceutical company, provides without cost to the patient—is widely available and has been proposed as one strategy to address “diagnostic deserts” in underserved health systems.[ii] However, despite the availability of IST and these health systems’ capability to treat affected patients who have been tested, many healthcare providers have not adopted IST even where no public alternative exists. Reasons for this lack of adoption include staffing constraints, legal concerns, scope-of-practice limits, logistical and resource constraints, and ethical questions. Another reason for this lack of adoption may be that providers may attempt to follow institutional mandates by forgoing all gifts from industry. This adherence to policy reflects a legitimate ethical concern, but categorical refusal may limit patients’ access and clinicians’ ability to exercise beneficence in strict pursuit of institutional independence from industry. This leaves patients to self-advocate, pay out of pocket, endure misdiagnosis, or receive no diagnosis at all, potentially leading to worse health outcomes. It can also force clinicians to refer their patients to other health systems, interrupting continuity of care and imposing new barriers. Moreover, patients may choose not to complete a referral due to issues with insurance coverage, logistical requirements, physical burdens of traveling while ill, and diagnostic fatigue, among other reasons.[iii] Systems administrators, genetics specialists, and ethicists struggle to weigh the issues with the potential risks and benefits represented by IST. Very little has been written on the topic,[iv] but some reports suggest IST may increase uptake of clinically indicated testing[v] while other data demonstrate limitations in no-cost testing for improving uptake based on patient population demographics.[vi] Given the paucity of information, we use the case of hereditary variant transthyretin amyloidosis (ATTRv) to explore the ethical concerns of IST partnerships and the conditions under which those concerns may be overcome. Case Example Amyloidosis is a disorder in which amyloid protein accumulates pathologically in the body causing organ dysfunction. This protein accumulation is involved in the pathophysiology of many degenerative disorders.[vii] One form of amyloidosis is caused by transthyretin (TTR) protein, a normal protein predominantly made by the liver that transports thyroid hormone and retinol (vitamin A). ATTR has been associated with heart conditions, such as congestive heart failure, atrial fibrillation, and conduction abnormalities leading to the need for pacemakers. ATTR is also associated with musculoskeletal complaints including bilateral carpal tunnel syndrome, trigger finger, biceps tendon rupture, and joint arthritis, often requiring joint replacement at earlier ages. Neurological signs of ATTR include peripheral neuropathy, gait imbalances, and autonomic nervous system dysfunction. Early recognition of these symptoms as part of a systemic syndrome is critical, as treatment of the underlying amyloid protein deposition is required to manage these sequelae but does not reverse all the damage already done. ATTR can be subdivided into wild type (ATTRwt, formerly called senile ATTR), characterized by age-related protein misfolding, and hereditary variant (ATTRv), characterized by disease-causing genetic variants in the TTR gene. Once amyloidosis has been diagnosed, only genetic testing can distinguish ATTRwt from ATTRv. A correct, specific diagnosis between ATTRwt and ATTRv is critical, as ATTRv may have earlier onset and more systemic signs and symptoms. However, interpreting genetic results for this testing is complicated. Over 130 pathogenic variants within the TTR gene are associated with ATTRv, and each variant manifests differently across populations. Moreover, patients who are homozygous for a pathogenic variant may exhibit more severe symptoms at an earlier age. While treatment and prognosis are often dictated by the amount of cardiac and neurologic involvement, early genetic testing remains important as certain treatments may only be indicated for either ATTRv or ATTRwt. Different genetic variants are also associated with differing degrees of phenotypic penetrance: some primarily cause either cardiomyopathy or neuropathy while other genetic variants have mixed phenotypes. If a pathogenic variant is present, cascade genetic testing is recommended for first-degree family members, as there may be up to a 50 percent chance that they will be afflicted. Finally, genotyping may identify relatives at high risk of disease before they develop life-limiting cardiomyopathy and prevent irreversible disease progression. While expert opinion and guidelines recommend genetic testing for all patients diagnosed with ATTR[viii] regardless of patient demographics or severity of disease involvement, there are several reasons why genetic testing may not be performed. Patients affected by ATTR amyloidosis may be followed by a diverse team of clinicians. Currently, they are typically treated by advanced heart failure cardiologists and neurologists and are seen at tertiary academic centers of excellence, but this access and diagnostic bottleneck is improving. As the diagnostic pathway has been simplified and several FDA-approved treatments have become available, patients with amyloidosis are increasingly seen in community hospitals and placed under the care of nonspecialists. Because ATTR is a systemic condition, many other specialists may be involved in their care, including gastroenterologists, nephrologists, and orthopedists. In addition, genetics specialists may encounter the disease when screening for unrelated conditions and incidentally find an ATTR disease-causing variant. Industry-sponsored genetic test kits are available for use in diagnosing ATTRv. One example is the NavigATTR Sponsored Testing Program offered through PreventionGenetics, a program sponsored by AstraZeneca and Ionis Pharmaceuticals.[ix] Historically, these tests have not been widely recommended because of these programs’ relationship with their industry sponsors and concerns that the genetic information provided would be limited. However, IST kits offer an alternative route for diagnosis when this may not otherwise be available to affected patient populations. These IST kits are convenient to use and require only a cheek swab and postal drop-box. Some existing gaps in care stem from concerns about the ethics of industry partnerships rather than practical barriers to testing. The arguments for and against IST are outlined in Table 1 and discussed in detail below. See Table 1 (available in PDF version only) Health Systems’ Objections to Industry-Sponsored Testing Health systems may worry that integrating IST into ATTR workups involves a conflict of interest, particularly when testing is funded by companies developing ATTR therapeutics. Patients’ and providers’ distrust of industry involvement in medicine remains strong[x] and some administrators may worry that financial gain could motivate the sponsor’s offer. Even the mere appearance of such conflict can undermine the therapeutic relationship between patients and medical organizations.[xi] However, a commercial interest does not necessarily mean the relevant parties' interests are opposed. A sponsor seeking to identify patients who could benefit from a therapy may in fact share the clinician’s interest in diagnosis and the patient’s interest in receiving appropriate treatment. That said, a sponsor additionally benefi