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Contrasting Medical and Legal Standards of Evidence: A Precision Medicine Case Study

Published online by Cambridge University Press:  01 January 2021

Gary E. Marchant ,
Kathryn Scheckel  and
Doug Campos-Outcalt
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Abstract

As the health care system transitions to a precision medicine approach that tailors clinical care to the genetic profile of the individual patient, there is a potential tension between the clinical uptake of new technologies by providers and the legal system's expectation of the standard of care in applying such technologies. We examine this tension by comparing the type of evidence that physicians and courts are likely to rely on in determining a duty to recommend pharmacogenetic testing of patients prescribed the oral anti-coagulant drug warfarin. There is a large body of inconsistent evidence and factors for and against such testing, but physicians and courts are likely to weigh this evidence differently. The potential implications for medical malpractice risk are evaluated and discussed.

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Type
Independent Articles
Information
Journal of Law, Medicine & Ethics , Volume 44 , Issue 1: Part II: Harmonizing Privacy Laws to Enable International Biobank Research , Spring 2016 , pp. 194 - 204
Copyright
Copyright © American Society of Law, Medicine & Ethics 2016

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References

White House, Fact Sheet: President Obama’s Precision Medicine Initiative, January 20, 2015, available at <http://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
Marshall, E., “Waiting for the Revolution,” Science 331, no. 6017 (2011): 526-529, at 526; E. J. Stanek et al., “Adoption of Pharmacogenomic Testing by US Physicians: Results of a Nationwide Survey,” Clinical Pharmacology & Therapeutics 91, no. 3 (2012): 450-458, at 454.Google Scholar
Greer, A. L., “The State of the Art versus the State of the Science: The Diffusion of New Medical Technologies into Practice,” International Journal of Technology Assessment in Health Care 4, no. 1 (1988): 5-26, at 5.Google Scholar
Evans, J. P, Burke, W. and Khoury, M., “The Rules Remain the Same for Genomic Medicine: The Case against ‘Reverse Genetic Exceptionalism,’” Genetics in Medicine 12, no. 6 (2010): 342-343; A. C. J. W. Janssens and P. A. Deverka, “Useless Until Proven Effective: The Clinical Utility of Preemptive Pharmacogenetic Testing,” Clinical Pharmacology & Therapeutics 96, no. 7 (2014): 652–654.Google Scholar
Arkes, H. R., “The Consequences of the Hindsight Bias in Medical Decision Making,” Current Directions in Psychological Science 22, no. 5 (2013): 356–360.Google Scholar
De Ville, K., “Medical Malpractice in Twentieth Century United States: The Interaction of Technology, Law, and Culture,” International Journal of Technology Assessment in Health Care 14, no. 2 (1998): 196-211, at 200.CrossRefGoogle Scholar
Annas, G. J., “Is a Genetic Screening Test Ready When the Lawyers Say It Is?” The Hastings Center Report 15, no. 6 (1985): 16-18, at 18.Google Scholar
Roth, J. A. et al., “Genetic Risk Factors for Major Bleeding in Patients Treated with Warfarin in a Community Setting,” Clinical Pharmacology & Therapeutics 95, no. 6 (2014): 636-643, at 636; M. Pirmohamed et al., “Oral Anticoagulation: A Critique of Recent Advances and Controversies,” Trends in Pharmacologic Sciences 36, no. 3 (2015): 153–163.CrossRefGoogle Scholar
Choonara, I. A. et al., “The Relationship between Inhibition of Vitamin K1 2,3-Epoxide Reductase and Reduction of Clotting Factor Activity with Warfarin,” British Journal of Clinical Pharmacology 25, no. 1 (1998): 1-7, at 4–5.CrossRefGoogle Scholar
Flockhart, D. A. et al., ‘Pharmacogentic Testing of CYP2C9 and VKORC1 Alleles for Warfarin,” Genetics in Medicine 10, no. 2 (2008): 139-150, at 139.Google Scholar
In-hospital mortality of intracranial bleeding associated with warfarin is 42.3%, and many of those who survive are severely disabled. Dowlatshahi, D. et al., “Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal,” Stroke 43, no. 7 (2012): 1812-1817, at 1815.Google Scholar
Fang, M. C., “Death and Disability from Warfarin-Associated Intracranial and Extracranial Hemorrhages,” American Journal of Medicine 120, no. 8 (2007): 700-705; L.-A. Linkins, “Bleeding Risks Associated with Vitamin K Antagonists,” Blood Reviews 27, no. 3 (2013): 111-118, at 112.Google Scholar
Wysowski, D. K., Nourjah, P. and Swartz, L., “Bleeding Complications with Warfarin Use: A Prevalent Adverse Effect Resulting in Regulatory Action,” Archives of Internal Medicine 167, no. 13 (2007): 1414–1419.CrossRefGoogle Scholar
Budnitz, D. S. et al., “Emergency Hospitalizations for Adverse Drug Events in Older Americans,” New England Journal of Medicine 365, no. 21 (2011): 2002-2012, at 2008.Google Scholar
Roth et al., supra note 8, at 636.Google Scholar
Sconce, E. A. et al., “The Impact of CYP2C9 and VKORC1 Genetic Polymorphism and Patient Characteristics Upon Warfarin Dose Requirements: Proposal for a New Dosing Regimen,” Blood 106, no. 7 (2005): 2329-2333, at 2332; C. Carnes, “What Is the Role of Pharmacogenetics in Optimization of Warfarin Dosing?” Trends in Cardiovascular Medicine 25, no. 1 (2015): 42–43.CrossRefGoogle Scholar
Flockhart et al., supra note 10, at 140.Google Scholar
Id.Google Scholar
Chatterjee, S. et al., “New Oral Anticoagulants and the Risk of Intracranial Hemorrhage: Traditional and Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials of New Oral Anticoagulants in Atrial Fibrillation,” JAMA-Neurology 70, no. 12 (2014): 1486-1490; A. Liew et al., “Assessment of Anticoagulation Intensity and Management of Bleeding with Old and New Oral Anticoagulants,” Canadian Journal of Cardiology 29, no. 7, Supp. (2013): S34-S44, at S34, S36.Google Scholar
Liew et al., supra note 19, at S34.Google Scholar
Rockoff, J. D. and Winslow, R., “New Medicines Emerge, but Few Blockbusters,” Wall Street Journal, December 15, 2013.Google Scholar
For example, Pradaxa resulted in the most reports of adverse effects of any drug monitored by FDA in 2012, and over 2400 lawsuits have been filed by alleged victims of Pradaxa bleeding side effects. Wright & Schulte LLC, New Order in Pradaxa Lawsuits Sets Dates for Jury Selection in First Federal Pradaxa Trial (May 5, 2014), available at <http://www.prweb.com/releases/2014/05/prweb11823340.htm> (last visited February 24, 2016). Xarelto has now surpassed Pradaxa in the number of serious adverse effects reported to FDA, and there are also multiple lawsuits pending against this alternative to warfarin. J. Steinberg, “Xarelto Plaintiffs Seek to Consolidate Injury Suits in Southern Illinois,” Product Safety & Liability Reporter (Bloomberg BNA) 42 (October 16, 2014): 1176.+(last+visited+February+24,+2016).+Xarelto+has+now+surpassed+Pradaxa+in+the+number+of+serious+adverse+effects+reported+to+FDA,+and+there+are+also+multiple+lawsuits+pending+against+this+alternative+to+warfarin.+J.+Steinberg,+“Xarelto+Plaintiffs+Seek+to+Consolidate+Injury+Suits+in+Southern+Illinois,”+Product+Safety+&+Liability+Reporter+(Bloomberg+BNA)+42+(October+16,+2014):+1176.>Google Scholar
Arepally, G. M. and Ortel, Thomas L., “Changing Practice of Anticoagulation: Will Target-Specific Anticoagulants Replace Warfarin?” Annual Review of Medicine 66 (2015): 241-253, at 246–248.Google Scholar
Johnson, J. A. and Cavallari, L. H., “Warfarin Pharmacogenetics,” Trends in Cardiovascular Medicine 25, no. 1 (2015): 33-41; D. S. Kazi and M. A. Hlatky, “Warfarin, Genes, and the (Health Care) Environment,” JAMA Internal Medicine 174, no. 8 (2014): 1338-1339, at 1338.Google Scholar
Linkins, supra note 12, at 111; Arepally and Ortel, supra note 23, at 242.Google Scholar
Limdi, N. A. et al., “Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic Complications in African-American and European-American Patients on Warfarin,” Clinical Pharmacology & Therapeutics 83, no. 2 (2008): 312-321; M. Wadelius et al., “The Largest Prospective Warfarin-Treated Cohort Supports Genetic Forecasting,” Blood 113, no. 4 (2009): 790-791; J. Yang, et al., “Influence of CYP2C9 and VKORC1 Genotypes on the Risk of Hemorrhagic Complications in Warfarin-Treated Patients: A Systematic Review and Meta-analysis,” International Journal of Cardiology 168, no. 4 (2013): 4234–4243.Google Scholar
Johnson and Cavallari, supra note 24.Google Scholar
Roth et al., supra note 8, at 639.Google Scholar
FDA, “FDA Approves Updated Warfarin (Coumadin) Prescribing Information; New Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients,” August 6, 2007, available at <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
FDA, “Label for Coumadin® Tablets (Warfarin Sodium Tablets, USP),” at 4, available at <http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
The International Warfarin Pharmacogenetics Consortium, “Estimation of the Warfarin Dose with Clinical and Pharmaccogenetic Data,” New England Journal of Medicine 360, no. 8 (2009): 753-764; B. S. Finkelman et al., “Genetic Warfarin Dosing: Tables Versus Algorithms,” Journal of the American College of Cardiology 57, no. 5 (2011): 612–618.Google Scholar
FDA, Nanosphere 501(k) Summary (2007), available at <https://www.accessdata.fda.gov/cdrh_docs/pdf7/K070597.pdf> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
FDA, “Transcript of FDA Press Conference on Warfarin,” August 16, 2007, at 6, available at <http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/ucm123583.pdf> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
Mello, M. M., “Of Swords and Shields: The Use of Clinical Practice Guidelines in Medical Malpractice Litigation,” University of Pennsylvania Law Review 149, no. 3 (2001): 645-710, at 662–667.CrossRefGoogle Scholar
Holbrook, A. et al., “Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence Based Clinical Practice Guidelines,” Chest 141, no. 2, Suppl. (2012): e152S-184S, at 159s-161s.Google Scholar
PharmGKB, “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Information for Warfarin and CYP2C9, VKORC1,” available at <https://www.pharmgkb.org/guideline/PA166104949> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
Anderson, J. L., et al., “Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation,” Circulation 116, no. 22 (2007): 2563–2570.CrossRefGoogle Scholar
Burmester, J. K. et al., “A Randomized Control Trial of Geno-type-Based Coumadin Initiation,” Genetics in Medicine 13, no. 6 (2011): 509–518.CrossRefGoogle Scholar
Kimmel, S. E. et al., “A Pharmacogenetic Versus Clinical Algorithm for Warfarin Dosing,” NEJM 369, no. 24 (2013): 2283–2293.CrossRefGoogle Scholar
Cavallari, L. H. and Nutescu, E. A., “Warfarin Pharmacogenetics: To Genotype or Not to Genotype, That Is the Question,” Clinical Pharmacology & Therapeutics 96, no. 1 (2014): 22-24, at 22–23.Google Scholar
Id., at 23.Google Scholar
Id.Google Scholar
Id.Google Scholar
Johnson and Cavallari, supra note 24.Google Scholar
Pirmohamed, M. et al., “A Randomized Trial of Genotype Guided Dosing for Warfarin,” NEJM 369, no. 24 (2013): 2294–2303.Google Scholar
See, e.g., Johnson and Cavallari, supra note 24.Google Scholar
Scott, S. A and Lubitz, S. A., “Warfarin Pharmacogenetic Trials: Is There a Future for Pharmacogenetic-Guided Dosing?” Pharmacogenomics 15, no. 6 (2014): 719-722, at 720.Google Scholar
Id., at 721.Google Scholar
Do, E. J. et al., “Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT): Rationale and Study Design,” Pharmacogenomics Journal 12, no. 5 (2012): 417–424.CrossRefGoogle Scholar
See Pirmohamed et al., supra note 8, at 156–157.Google Scholar
Anderson, J. L. et al., “A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II),” Circulation 125, no. 16 (2012): 1997–2005.Google Scholar
Epstein, R. S. et al., “Warfarin Genotyping Reduces Hospitalization Rates: Results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study),” Journal of the American College of Cardiology 55, no. 25 (2010): 2804–2812.CrossRefGoogle Scholar
Mega, J. L. et al., “Genetics and the Clinical Response to Warfarin and Edoxaban: Findings from the Randomised, Double-Blind ENGAGE AF_TIMI 48 Trial,” The Lancet 385, no. 9984 (2015): 2280–2287.CrossRefGoogle Scholar
Wen, M. S. et al., “Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes,” Clinical Pharmacology & Therapeutics 84, no. 1 (2008): 83-89; P. A. Lenzini et al., “Laboratory and Clinical Outcomes of Pharmacogenetic vs. Clinical Protocols for Warfarin Initiation in Orthopedic Patients,” Journal of Thrombosis and Haemostasis 6, no. 10 (2008): 1655-1662; G. A. McMillin et al., “Gene-Based Warfarin Dosing Compared with Standard of Care Practices in an Orthopedic Surgery Population: A Prospective, Parallel Cohort Study,” Therapeutic Drug Monitoring 32, no. 3 (2010): 338–345.Google Scholar
Stergiopoulos, K. and Brown, D. L., “Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues: Meta-analysis of Randomized Clinical Trials,” JAMA Internal Medicine 174, no. 8 (2014): 1330–1338.CrossRefGoogle Scholar
Liao, Z. et al., “Meta-analysis of Randomized Controlled Trials Reveals an Improved Clinical Outcome of Using Geno-type Plus Clinical Algorithm for Warfarin Dosing,” Journal of Thrombosis and Thrombolysis 39, no. 2 (2015): 228–234.Google Scholar
Meckley, L. M. et al., “A Policy Model to Evaluate the Benefits, Risks and Costs of Warfarin Pharmacogenomic Testing,” Pharmacogenomics 28, no. 1 (2010): 61-74, at 70–71.Google Scholar
Eckman, M. H. et al., “Cost-Effectiveness of Using Pharmaco-genetic Information in Warfarin Dosing for Patients with Nonvalvular Atrial Fibrillation,” Annals of Internal Medicine 150, no. 2 (2009): 73-83, at 80.Google Scholar
Id., at 78.Google Scholar
Leey, J. A. et al., “Cost-Effectiveness of Genotype-Guided Warfarin Therapy for Anticoagulation in Elderly Patients with Atrial Fibrillation,” American Journal of Geriatric Pharmaco-therapy 7, no. 4 (2009): 197–203.CrossRefGoogle Scholar
Sweezy, T. and Mousa, S. A., “Genotype-Guided Use of Oral Antithrombotic Therapy: A Pharmacoeconomic Perspective,” Personalized Medicine 11, no. 2 (2014): 223–235.Google Scholar
Id.Google Scholar
Neumann, P. J., Cohen, J. T. and Weinstein, M. C., “Updating Cost-Effectiveness — The Curious Resilience of the $50,000-per-QALY Threshold,” NEJM 371, no. 9 (2014): 796–797.Google Scholar
FDA News Release, FDA Approves Updated Warfarin (Coumadin) Prescribing InformationNew Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients, Press Release, August 16, 2007, available at <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
FDA Warfarin Press Conference Transcript, supra note 33, at 2 (statement of Larry Lesko, FDA) (emphasis added).Google Scholar
Id., at 30.Google Scholar
Centers for Medicare & Medicaid Services, “National Coverage Determination (NCD) for Pharmacogenomic Testing for Warfarin Response (90.1),” 2009, available at <http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=333&bc=AgAAQAAAAAAA&ncdver=1> (last visited February 24, 2016).+(last+visited+February+24,+2016).>Google Scholar
Kazi and Hlatky, supra note 24, at 1338.Google Scholar
Sweezy and Mousa, supra note 60; Kazi and Hlatky, supra note 24, at 1338.Google Scholar
Nutescu, E. A. et al., “Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service,” Pharmacotherapy 33, no. 11 (2013): 1156–1164.Google Scholar
See, e.g., Johnson and Cavallari, supra note 24; Kazi and Hlatky, supra note 24, at 1338.Google Scholar
Scott and Lubitz, supra note 47, at 721; Maitland-van der Zee, A. H. et al., “Patients Benefit from Genetics-Guided Coumarin Anticoagulant Therapy,” Clinical Pharmacology & Therapeutics 96, no. 1 (2014): 15-17; Pirmohamed et al., supra note 8, at 161.Google Scholar
Cavallari and Nutescu, supra note 40, at 24.Google Scholar
Johnson and Cavallari, supra note 24.Google Scholar
Kazi and Hlatky, supra note 24, at 1338.Google Scholar
Limdi, N. A. et al., “Race Influences Warfarin Dose Changes Associated with Genetic Factors,” Blood 126, no. 4 (2015): 539–545.Google Scholar
See Peters, P. G. Jr., “The Role of the Jury in Modern Malpractice Law,” Iowa Law Review 87, no. 3 (2002): 909-969, at 914.Google Scholar
See, e.g., O’Neill, A. W. et al., “GM Ordered to Pay $4.9 Billion in Crash Verdict,” Los Angeles Times, July 10, 1999.Google Scholar
Arkes, supra note 5, at 358.Google Scholar
E.g., Jeffries v. United States, No. C08-1514RSL (W.D. Wash., Oct. 28, 2009), 30 No. 1 Verdicts, Settlements & Tactics art 12 ($3.8 million verdict for negligent provision of anti-coagulation therapy); “388,000 Awarded to Family of Patient Who Died after Failure to Monitor Administration of Coumadin,” Physician Risk Management, July 1, 2013.Google Scholar