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Real-World Evidence in the Real World: Beyond the FDA

Published online by Cambridge University Press:  06 January 2021

Joan H. Krause
Affiliation:
UNC School of Law; Social Medicine, UNC School of Medicine; Health Policy & Management, UNC Gillings School of Global Public Health
Richard S. Saver
Affiliation:
UNC School of Law; Social Medicine, UNC School of Medicine; Health Policy & Management, UNC Gillings School of Global Public Health

Abstract

The 21st Century Cures Act (“Cures Act”) relies on the concept of real-world evidence (“RWE”) to improve the Food and Drug Administration (“FDA”) approval process. This has amplified interest and furthered momentum in applying RWE more broadly, beyond FDA regulation. In this article, we discuss the understandable appeal of RWE's pragmatic application and its many potential benefits. But we also caution that claims about RWE's wide-ranging, ameliorative impact on the health care system are likely overstated.

The real world of RWE is messy and uncertain. Successfully incorporating RWE into regular health care system decision-making, beyond the FDA, faces considerable obstacles and limitations. We review the reasons to be wary about RWE as a game-changer. These concerns including data reliability, insufficient incentives for stakeholders to generate and engage with high-quality RWE, and lack of comprehensive regulatory oversight. In addition, the push for RWE may impact the enforcement of the health care fraud and abuse laws, perhaps not in necessarily positive ways. Increased reliance on RWE may have significant implications for off-label fraud enforcement, further conflating the distinction between claims that are false for reimbursement rather than for scientific purposes.

Type
Articles
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2018

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Footnotes

I thank Lenore R. Livingston for her research assistance.

I thank MacKenzie D. Dickerman for her research assistance.

References

1 21st Century Cures Act, Pub. L. No. 114-255, 130 Stat. 1033 (2016).

2 See infra notes 3-6 and accompanying text.

3 See 21 U.S.C. § 355g(a)(1)-(2) (2016).

4 Id. § 355g(b). FDA expanded on the definition in its guidance about RWE and regulatory decisions for medical devices, describing RWE as “clinical evidence regarding the usage, and potential benefits or risks, of a medical product derived from analysis of [real-world data].” U.S. Food & Drug Admin., Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff 4 (2017), https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf [hereinafter FDA Guidance on Use of RWE]. The real-world data sources include electronic health records, disease registries, billing records, and numerous other data sources that can inform on health status. Id.

5 FDA Guidance on Use of RWE, supra note 4, at 4.

6 FDA Guidance on Use of RWE, supra note 4.

7 FDA's Sentinel Initiative, U.S. Food & Drug Admin., https://www.fda.gov/safety/fdassentinelinitiative/ucm2007250.htm [https://perma.cc/3768-Q8C6]; see also Bipartisan Policy Ctr., Using Real-World Evidence to Accelerate Safe and Effective Cures 5 (2016), https://bipartisanpolicy.org/wp-content/uploads/2016/06/BPC-Real-World-Evidence-Cures-Summary.pdf (last visited Feb. 25, 2018).

8 Daniel Blumenthal et al., Real-World Evidence Complements Randomized Controlled Trials in Clinical Decision Making, Health Aff. Blog (Sept. 27, 2017), https://www.healthaffairs.org/do/10.1377/hblog20170927.062176/full/. In a RCT, “participants are randomly assigned to receive either the treatment under investigation or, as a control, a placebo or the current standard treatment.” Tom Frieden, Why the ‘Gold Standard’ of Medical Research is No Longer Enough, Stat (Aug. 2, 2017), https://www.statnews.com/2017/08/02/randomized-controlled-trials-medical-research/ [https://perma.cc/RT3J-BFUD].

9 Frieden, supra note 8.

10 Van Spall, Harriette G.C. et al., Eligibility Criteria of Randomized Controlled Trials Published in High-Impact General Medical Journals: A Systematic Sampling Review, 297 JAMA 1233, 1237 (2007)CrossRefGoogle ScholarPubMed.

11 Blumenthal et al., supra note 8.

12 See, e.g., Existence of ‘Trial Effect’ in HIV Clinical Trials Confirmed, Sci. Daily (July 13, 2011), https://www.sciencedaily.com/releases/2011/07/110713182219.htm [https://perma.cc/3EQC-JDUR].

13 Marc Berger et al., Duke Margolis Ctr. for Health Policy, A Framework for Regulatory Use of Real-World Evidence 5 (2017), https://healthpolicy.duke.edu/sites/default/files/atoms/files/rwe_white_paper_2017.09.06.pdf.

14 Id.

15 Real World Evidence, Duke Clinical Research Inst., https://www.dcri.org/insights/real-world-evidence/ [https://perma.cc/VS65-KLQH].

16 Marc L. Berger & James Harnett, Are Real-World Data and Evidence Good Enough to Inform Health Care and Health Policy Decision-Making?, in Decision Making in a World of Comparative Effectiveness Research: A Practical Guide 97, 98 (Howard G. Birnbaum & Paul E. Greenberg eds., 2017).

17 Patel, Anushka et al., Reality and Truth: Balancing the Hope and the Hype of Real-World Evidence, 136 Circulation 260, 262 (2017)CrossRefGoogle ScholarPubMed; see Julie C. Locklear, What is Real-World Evidence, and Why Do We Need It?, Stat (Feb. 2, 2016), https://www.statnews.com/sponsor/2017/02/16/real-world-evidence-need-2/ [https://perma.cc/49ES-F33K].

18 Thomas Reinke, Real-World Evidence Faces Some Real-World Challenges, Managed Care (May 5, 2017), https://www.managedcaremag.com/archives/2017/5/real-world-evidence-faces-some-real-world-challenges [https://perma.cc/7SER-VV2J].

19 King, Spencer B. III, “Real-World Evidence?” Get Real!, 9 JACC: Cardiovascular Interventions 204, 205 (2016)Google Scholar; see infra notes 130-133 and accompanying text.

20 See Makady, Amr et al., Practical Implications of Using Real-World Evidence (RWE) in Comparative Effectiveness Research: Learnings from IMI-GetReal, 6 J. Comp. Effectiveness Res. 485, 487 (2017)CrossRefGoogle ScholarPubMed.

21 See, e.g., Jones, W. Schuyler et al., The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease, 68 J. Am. C. Cardiology 1898, 1900 (2016)CrossRefGoogle ScholarPubMed (describing the various characteristics of pragmatic RCTs).

22 In its guidance for use of RWE in regulatory decisions about medical devices, FDA explains that the real-world data to support RWE is data that informs on health status or relates to care delivery and that can be routinely collected from a wide variety of sources, including electronic health records, disease registries, and mobile devices. FDA Guidance on Use of RWE, supra note 4, at 4. Other definitions of “real-world data” are similarly broad. See, e.g., Duke Margolis Ctr. for Health Policy, supra note 17, at 4 (providing various definitions of real-world data).

23 Duke Margolis Ctr. for Health Policy, supra note 13, at 7.

24 See, e.g., Electronic Health Records (EHR) Incentive Programs, Ctrs. for Medicare & Medicaid Servs., https://www.cms.gov/Regulations-and-Guidance/Legislation/EHRIncentivePrograms/index.html?redirect=/EHRIncentivePrograms/ [https://perma.cc/F8D9-E2JP] (describing electronic health records incentive programs).

25 Zachary Brennan, Real World Evidence: FDA Commits to Advancing Its Use, Reg. Focus (Sept. 19, 2017), http://prod1.raps.org/Regulatory-Focus/News/2017/09/19/28491/Real-World-Evidence-FDA-Commits-to-Advancing-its-Use/ [https://perma.cc/3EWW-CK6G].

26 See Patel et al., supra note 17, at 261.

27 See White, Richard, Building Trust in Real-World Evidence and Comparative Effectiveness Research: The Need for Transparency, 6 J. Comp. Effectiveness Res. 5, 5 (2016)CrossRefGoogle ScholarPubMed (explaining the risk of significant bias if “treatment options are compared without adjustment for confounders such as patient demographics, disease severity, comorbidities and concomitant medications.”).

28 Patel et al., supra note 17, at 261.

29 Brett Davis et al., Deloitte Ctr. for Health Sols., Getting Real With Real-World Evidence 1 (2017), https://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-ls-2017-real-world-evidence-survey-031617.pdf.

30 Id. at 9.

31 See Makady et al., supra note 20, at 488 (“[P]atient-level data is subject to strict privacy rules ….”); see generally FDA Guidance on Use of RWE, supra note 4, at 15-16 (explaining how the FDA will consider patient data privacy when reviewing sources of RWD).

32 See Davis et al., supra note 29, at 10 (“Researchers often have to clean RWD, especially from nontraditional sources, since most of it is not collected for research purposes.”).

33 Id.

34 Id.

35 Cf. Yale Collaboration for Research Integrity & Transparency, Public Comment on the Food and Drug Administration's Draft Guidance “Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices” 6 (Oct. 24, 2016), https://law.yale.edu/system/files/area/center/crit/document/rwe_comment_from_yale_collaboration_for_research_integrity_and_transparency.pdf (“Previous work has shown that participants in postmarketing [RWE] studies for carotid artery stenting have different characteristics and lower mortality than nonparticipants and, thus, results for post-marketing studies may not be reliably extrapolated to the real-world population of patients receiving the device.”).

36 White, supra note 27, at 6.

37 Sherman, Rachel E. et al., Real-World Evidence—What is It and What Can It Tell Us?, 375 New Eng. J. Med. 2293, 2293 (2016)CrossRefGoogle ScholarPubMed.

38 See Thomas E. Hubbard & Rebecca Paradis, Real World Evidence: A New Era for Health Care Innovation 2, Sept. 2015, https://www.nehi.net/writable/publication_files/file/rwe_issue_brief_final.pdf.

39 White, supra note 27, at 6.

40 See id. at 5 (“The observational nature of RWE means that, unlike RCTs, patients cannot be randomized to different treatment options ….”).

41 See id. at 5.

42 See generally Schilsky, Richard L., Finding the Evidence in Real-World Evidence: Moving from Data to Information to Knowledge, 224 J. Am. C. Surgeons 1, 3 (2017)CrossRefGoogle Scholar.

43 Id.

44 White, supra note 27, at 6; see infra notes 134-136 and accompanying text.

45 FDA Guidance on Use of RWE, supra note 4, at 8.

46 Clinical Trials Registration and Results Information Submission, 81 Fed. Reg. 64982, 64982-83 (Sept. 21, 2016).

47 See, e.g., Anderson, Monique L. et al., Compliance with Results Reporting at ClinicalTrials.gov, 372 New Eng. J. Med. 1031, 1031 (2015)CrossRefGoogle ScholarPubMed; Chris Cai, New Rule on Clinical Trial Reporting Doesn't Go Far Enough, Stat (Jan. 17, 2017), https://www.statnews.com/2017/01/17/clinical-trial-reporting-new-rule/ [https://perma.cc/BK2H-PXFK].

48 Duke Margolis Ctr. for Health Policy, supra note 13, at 13.

49 Schilsky, supra note 42, at 6.

50 Blumenthal et al., supra note 8.

51 See, e.g., FDA Guidance on Use of RWE, supra note 4, at 12 (“Whether evidence is sufficiently relevant and reliable for use will, in part, depend on the level of quality necessary to make a particular regulatory decision.”).

52 See id. at 9.

53 See Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, FDA (Feb. 23, 2018), https://www.fda.gov/ForPatients/Approvals/Fast/ucm20041766.htm [https://perma.cc/26DS-DQ2V].

54 Sherman et al., supra note 37, at 2295.

55 Id.

56 See supra notes 37-39 and accompanying text.

57 Reinke, supra note 18.

58 Duke Margolis Ctr. for Health Policy, supra note 13, at 13.

59 See Saver, Richard S., Health Care Reform's Wild Card: The Uncertain Effectiveness of Comparative Effectiveness Research, 159 U. Pa. L. Rev. 2147, 2147 (2011)Google Scholar [hereinafter Saver, Health Care Reform's Wild Card].

60 Id. at 2151.

61 42 U.S.C. § 1320e(b)(3) (2010).

62 Id. § 1320e(b)(1), (c).

63 Makady et al., supra note 20, at 486.

64 See id.

65 See generally Saver, Health Care Reform's Wild Card, supra note 59, at 2175-98 (discussing several of the reasons physicians may be hesitant to rely on CER information).

66 Id.

67 Mushlin, Alvin I. & Ghomrawi, Hassan M.K., Comparative Effectiveness Research: A Cornerstone of Healthcare Reform?, 121 Transactions Am. Clinical & Climatological Ass'n 141, 141 (2010)Google ScholarPubMed (explaining that CER has “existed for a long time” but has had various names throughout its time).

68 See Ali Riaz et al., Comparative Effectiveness Research in the United States: A Catalyst for Innovation, 4 Am. Health Drug Benefits 68, 68-69 (2011).

69 Saver, Health Care Reform's Wild Card, supra note 59, at 2158.

70 Id.

71 See, e.g., Berger, Marc L. et al., A Questionnaire to Assess the Relevance and Credibility of Observational Studies to Inform Health Care Decision Making: An ISPOR-AMCP-NPC Good Practice Task Force Report, 17 Value Health 143, 143 (2014)CrossRefGoogle ScholarPubMed.

72 Jennifer Graff, Opinion, The Use of Real-World Evidence in Health Care Decision-Making, Morning Consult (Sept. 13, 2017), https://morningconsult.com/opinions/understanding-use-real-world-evidence-health-care-decision-making/ [https://perma.cc/M4Z5-Q8ZY].

73 See, e.g., Health Insurance Portability and Accountability Act of 1996, Pub. L. No. 104-191, §§ 241-49, 119 Stat. 2016-21 (codified at 18 U.S.C. §§ 24, 1347, 669, 1035, 1518, 1956(c)(7), 1345(a)(1)-(2), 3486, 982(a)) (revising criminal law provisions relating to health care fraud).

74 42 U.S.C. §§ 1320a-7, 1320a-7a, 1320a-7b, 1320a-7d (2012) (expanding administrative penalties); id. § 1320a-7c (establishing the Health Care Fraud and Abuse Control Program).

75 21st Century Cures Act, Pub. L. No. 114-255, § 5003, 130 Stat. 1188 (2016) (codified at 42 U.S.C. § 1320a-7a(o)-(s) (2016)).

76 31 U.S.C. §§ 3729-3733 (2009).

77 42 U.S.C. § 1320a-7a(o) (2016).

78 Dep't of Health & Human Servs. & Dep't of Justice, Health Care Fraud and Abuse Control Program Annual Report for Fiscal Year 2016 1 (2017), https://oig.hhs.gov/publications/docs/hcfac/FY2016-hcfac.pdf.

79 Id.

80 Sammy Almashat et al., Twenty-Five Years of Pharmaceutical Industry Criminal and Civil Penalties: 1991 Through 2015, Public Citizen 10 (Mar. 2016), https://www.citizen.org/sites/default/files/2311_0.pdf.

81 Id. at 55-56.

82 See Act of Mar. 2, 1863, ch. 67, 12 Stat. 696; see also S. Rep. No. 99-345, at 6 (1986), reprinted in 1986 U.S.C.C.A.N. 5266, 5273.

83 31 U.S.C. § 3729(a)(1)(A) (2009); id. § 2739(b).

84 31 U.S.C. § 3729(b)(1) (2009). One reason the FCA has been so effective is the law's qui tam provision, which permits private “relators” (including competitors, employees, and patients) to sue on the government's behalf and receive a portion of the proceeds. See id. § 3730(d).

85 28 C.F.R. § 85.5 (2018).

86 See, e.g., United States ex rel. Conner v. Salina Reg'l Health Ctr., Inc., 543 F.3d 1211, 1217 (10th Cir. 2008).

87 United States ex rel. Mikes v. Straus, 274 F.3d 687, 698-99 (2d Cir. 2001), abrogated by Universal Health Servs., Inc. v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016) (affirming validity of the implied certification theory). For a thorough discussion of the certification theories, see Krause, Joan H., Reflections on Certification, Interpretation, and the Quest for Fraud that “Counts” Under the False Claims Act, 2017 U. Ill. L. Rev. 1811 (2017)Google Scholar.

88 See generally Escobar, 136 S. Ct. at 2000-02 (alleging that mental health clinic's Medicaid claims contained implied representations of compliance with regulations, but in reality clinic had violated state licensing and supervision rules).

89 See id.

90 42 U.S.C. § 1320a-7b(b) (2015).

91 Id.; see also id. §§ 1320a-7(a) (mandatory exclusion upon conviction), 1320a-7(b)(7) (permissive exclusion), 1320a-7a (civil monetary penalties); Bipartisan Budget Act of 2018, H.R. 1892, § 50412.

92 42 U.S.C. § 1320a-7b(g) (2015).

93 See, e.g., Press Release, U.S. Dep't of Justice, Amgen Inc. Pleads Guilty to Federal Charge in Brooklyn, NY.; Pays $762 Million to Resolve Criminal Liability and False Claims Act Allegations (Dec. 19, 2012), http://www.justice.gov/opa/pr/amgen-inc-pleads-guilty-federal-charge-brooklyn-ny-pays-762-million-resolve-criminal [https://perma.cc/Q9LW-FYF4] (alleging that manufacturer offered kickbacks designed to influence physicians' prescribing decisions).

94 For a detailed analysis, see Krause, Joan H., Truth, Falsity, and Fraud: Off-Label Drug Settlements and the Future of the Civil False Claims Act, 71 Food & Drug L.J. 401 (2016)Google ScholarPubMed [hereinafter Krause, Truth, Falsity, and Fraud].

95 21 U.S.C. §§ 331(a), 352(a), 352(f) (2016).

96 21 C.F.R. § 310.3(h)(4) (2018) (explaining that a drug may be “new” with regard to the treatment of one condition, even if approved to treat another).

97 See, e.g., Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices; Request for Comments, 59 Fed. Reg. 59,820, 59,821 (proposed Nov. 18, 1994).

98 Radley, David C. et al., Off-Label Prescribing Among Office-Based Prescriptions, 166 Arch. Internal Med. 1021, 1021 (2006)CrossRefGoogle Scholar; see also American Society of Clinical Oncology, Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications, 24 J. Clinical Oncology 3206, 3206 (2006) (estimating that approximately half the uses for cancer drugs are off-label); see generally Joseph, John N. et al., Enforcement Related to Off-Label Marketing and Use of Drugs and Devices: Where Have We Been and Where Are We Going?, 2 J. Health & Life Sci. L. 73, 79-80 (2009)Google ScholarPubMed (describing common off-label use of older drugs).

99 Radley et al., supra note 98, at 1022-23.

100 Eguale, Tewodros et al., Association of Off-Label Drug Use and Adverse Drug Events in an Adult Population, 176 JAMA Internal Med. 55, 58 (2016)CrossRefGoogle Scholar.

101 See United States v. Caronia, 703 F.3d 149, 160 (2d Cir. 2012); see also Washington Legal Found. v. Henney, 56 F. Supp. 2d 81, 86-87 (D.D.C. 1999) (finding that restrictions on a manufacturer's ability to share information about off-label uses of pharmaceutical drugs unconstitutionally restricts protected commercial speech).

102 Caronia, 703 F.3d at 168-69.

103 United States ex rel. Polansky v. Pfizer, Inc., 822 F.3d 613, 615 n.2 (2d Cir. 2016) (emphasis added).

104 See, e.g., 42 U.S.C. § 1396r-8(d)(1) (2016) (permitting states to limit Medicaid drug coverage); see also, e.g., Ctrs. for Medicare & Medicaid Servs., Medicare Benefit Policy Manual § 30 (Rev. 234, Mar. 10, 2017), http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c01.pdf (explaining Medicare Part A coverage of drugs in the hospital setting).

105 See, e.g., 42 U.S.C. §§ 1396b(i)(1), 1396r-8(k)(3), 1396r-8(k)(6) (2018) (defining a medically accepted indication as a use approved by the FDA or “which is supported by one or more citations included or approved for inclusion in” the specified compendia); id. § 1395w-102(e)(4)(A)(ii) (applying same definitions to Medicare Part D).

106 United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39, 52 (D. Mass. 2001).

107 See 31 U.S.C. § 3729(a)(1)(A)-(B) (2018).

108 See id.

109 There has been no definitive ruling on whether such suits implicate the First Amendment, although some courts have expressed skepticism regarding the underlying FCA theory. See, e.g., United States ex rel. Solis v. Millennium Pharms., Inc., No. 2:09-cv-03010-MCE-EFB, 2015 WL 1469166, at *7 (E.D. Cal. Mar. 30, 2015) (denying motion to dismiss off-label FCA allegations). Cf. United States ex rel. Polansky v. Pfizer, Inc., 822 F.3d 613, 619-20 (2d Cir. 2016) (affirming dismissal of FCA claims; expressing skepticism that “anyone could be identified who actually submitted a false claim” under the facts, but acknowledging that a relator might be able to satisfy pleading requirements “in a case in which it would be obvious to anyone that the use promoted is one that is not approved ….”).

110 Sammy Almashat & Sidney Wolfe, Pharmaceutical Industry Criminal and Civil Penalties: An Update, Public Citizen 45 (Sept. 2012), http://www.citizen.org/documents/2073.pdf.

111 See Krause, Truth, Falsity, and Fraud, supra note 94, at 417-18, tbl.1.

112 See Almashat & Wolfe, supra note 110, at 5, 13-17 (discussing possible factors for decline in settlements); see also John Bentivoglio et al., Recent Settlements Suggest Off-Label Cases Aren't Extinct, Law360 (Aug. 30, 2017, 12:30PM), https://www.law360.com/articles/958949/recent-settlements-suggest-off-label-cases-aren-t-extinct.

113 See Krause, Truth, Falsity, and Fraud, supra note 94, at 427-30; see, e.g., Press Release, U.S. Dep't of Justice, Pharmaceutical Companies to Pay $67 Million to Resolve False Claims Act Allegations Relating to Tarceva (June 6, 2016), https://www.justice.gov/opa/pr/pharmaceutical-companies-pay-67-million-resolve-false-claims-act-allegations-relating-tarceva [https://perma.cc/XE34-SACP].

114 The Cures Act did expand an existing exception permitting “health care economic information” about off-label uses to be shared with certain entities involved in drug coverage and reimbursement decisions in limited circumstances, but that provision is not relevant to most physician interactions. See 21 U.S.C. § 352(a) (2016); see also Halabi, Sam F., Off-Label Marketing's Audiences: The 21st Century Cures Act and the Relaxation of Standards for Evidence-Based Therapeutic and Cost-Comparative Claims, 44 Am. J.L. & Med. 181 (2018)CrossRefGoogle ScholarPubMed.

115 See supra note 19 and accompanying text.

116 Ctrs. for Medicare & Medicaid Servs., Medicare Fee-For-Service 2016 Improper Payments Report 1 (July 27, 2017), https://www.cms.gov/Research-Statistics-Data-and-Systems/Monitoring-Programs/Medicare-FFS-Compliance-Programs/CERT/Downloads/MedicareFeeforService2016ImproperPaymentsReport.pdf [hereinafter CMS Improper Payments Report 2016]; see also Krause, Joan H., Following the Money in Health Care Fraud: Reflections on a Modern-Day Yellow Brick Road, 36 Am. J.L. & Med. 343, 345-49 (2010)CrossRefGoogle ScholarPubMed (analyzing error rates).

117 CMS Improper Payments Report 2016, supra note 116, at 14.

118 Id. at 1. See also Malcolm K. Sparrow, License to Steal: How Fraud Bleeds America's Health Care System 2 (Westview Press updated ed. 2000) (“What you see is not the problem. It's what we don't see that really does the damage ….”).

119 See, e.g., Hill, Kevin P. et al., The ADVANTAGE Seeding Trial: A Review of Internal Documents, 149 Annals Internal Med. 251, 251 (2008)CrossRefGoogle ScholarPubMed (describing seeding trial for Vioxx); Krumholz, Samuel et al., Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial, 171 JAMA Arch. Internal Med. 1100, 1100 (2011)Google ScholarPubMed (describing seeding trials); see generally Sergio Sismondo, Ghost Management: How Much of the Medical Literature is Shaped Behind the Scenes by the Pharmaceutical Industry?, 4 PLoS Med. 1429 (2007).

120 See, e.g., FDA Guidance on Use of RWE, supra note 4, at 13-14 (describing criteria for relevance and reliability of RWE in the medical device context); see generally Jarow, Jonathan P. et al.,Multidimensional Evidence Generation and FDA Regulatory Decision Making: Defining and Using “Real-World” Data, 318 JAMA 703 (2017)CrossRefGoogle ScholarPubMed(describing types of data sources that might qualify); Kesselheim, Aaron S. & Mello, Michelle M., Prospects for Regulation of Off-Label Drug Promotion in an Era of Expanding Commercial Speech Protection, 92 N.C. L. Rev. 1539, 1585 (2014)Google Scholar (raising concern that manufacturers might produce studies of dubious quality to support off-label uses); see generally Hubbard & Paradis, supra note 38.

121 See, e.g., United States ex rel. Solis v. Millennium Pharms., Inc., No. 2:09-cv-03010-MCEEFB, 2015 WL 1469166, at *6 (E.D. Cal. Mar. 30, 2015) (alleging manufacturer violated Anti-Kickback Statute and FCA by funding grants, paying excessive fees to speakers, honoraria, meals, attendance at CME events controlled by the company, and funding advisory boards and preceptorship opportunities, all to entice physicians to write off-label prescriptions).

122 See, e.g., United States ex rel. Franklin v. Parke-Davis, 147 F. Supp. 2d 39, 52-53 (D. Mass. 2001) (describing FCA liability theory).

123 See Ctrs. for Medicare & Medicaid Servs., Medicare Prescription Drug Benefit Manual § 20.1 (Rev. 18, Jan. 15, 2016), https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Part-D-Benefits-Manual-Chapter-6.pdf [hereinafter CMS Medicare Prescription Drug Benefit Manual] (describing classes of drugs excluded from Part D coverage, including drugs used to treat anorexia, weight loss, or weight gain; fertility drugs; and drugs used for cosmetic purposes or hair growth).

124 See, e.g., Franklin, 147 F. Supp. 2d at 52-53 (refusing to dismiss Medicaid off-label allegations, but noting “a much closer question” would have been raised if the allegations involved unlawful but truthful company statements).

125 Wang v. FMC Corp. 975 F.2d 1412, 1421 (9th Cir. 1992), overruled by United States ex rel. Hartpence v. Kinetic Concepts, Inc., 792 F.3d 1121 (9th Cir. 2015); see also Krause, Truth, Falsity, and Fraud, supra note 94, at 431-37.

126 21 U.S.C. § 355(d) (2017).

127 See Kesselheim & Mello, supra note 120, at 1583 (noting evidentiary difficulties in proving promotional statements are false and misleading).

128 See, e.g., Johnson, Sandra H., Polluting Medical Judgment? False Assumptions in the Pursuit of False Claims Regarding Off-Label Prescribing, 9 Minn. J.L. & Tech. 61, 117 (2008)Google Scholar (“The absence of clinical trials does not mean that [the drug] Neurontin … is not effective in treating these highly similar pain states just as FDA approval in 2002 did not make the drug effective for treating pain.”).

129 Washington Legal Found. v. Friedman, 13 F. Supp. 2d 51, 67 (D.D.C. 1998).

130 See, e.g., Kesselheim & Mello, supra note 120, at 1598-1603 (encouraging expanded acceptance of “substantial clinical experience” to support certain drug advertisements and encouraging expansion of “substantial evidence” to encompass certain observational research); Krause, Truth, Falsity, and Fraud, supra note 94, at 435 (discussing other standards); 21 U.S.C. § 352(a) (2016) (permitting “[h]ealth care economic information provided to a payor, formulary committee, or other similar entity” to be “based on competent and reliable scientific evidence ….”).

131 See generally Krause, Truth, Falsity, and Fraud, supra note 107.