The case for legal regulation of physicians' off-label prescribing

Notre Dame Law Review

Volumn 86, Issue 2, 2011, Pages 649-691

  Rosqfl, Philip M ^a   Coleman, Doriane Lambelet ^b  

^a DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b DUKE UNIVERSITY   (United States)

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[No Author keywords available]

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EID: 79959728971     PISSN: 07453515     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (282)

1. Drugs, or pharmaceuticals, generally include both small molecules generated by chemical manufacturing processes as well as "natural" products such as some antibiotics isolated from bacterial or fungal cultures. Biologics refer to thierapies uSat are purified natural products (generally of mammalian origin) such as some blood components as well as those therapeutics produced by genetic engineering and biotechnology that mimic or are identical to naturally occurring proteins. See Edward L. Korwek, What Are Biologics? A Comparative Legislative, Regulatory and Scientific Analysis, 62 FOOD & DRUG L. J. 257, 259-60 (2007) (providing background for statutory definitions of biologies).
2. See Off-Label Drug Use, AM. CANCER SOC'Y, http://www.cancer.org/docroot/ ETO/content/ETO-l-2x-Off-Label-Drug-Use.asp (last visited Feb. 11, 2011). The FDA does not establish a drug's safety and efficacy for general purposes, but only for the particular use or uses identified by its manufacturer for formal marketing purposes.
3. See id.
4. See id.
5. See infra note 15 and accompanying text (discussing other testing possibilities).
6. See Off-Label Drug Use, supra note 2;
7. see also William L. Christopher, Off-Label Drug Prescription: Filling the Regulatory Vacuum, 48 FOOD & DRUG LJ. 247, 248 (1993) (suggesting that off-label uses might include using approved drugs for nonapproved diseases or varying from the indicated dosage, regimen, or patient population);
8. Rebecca Dresser & Joel Frader, Off-Label Prescribing: A Call for Heightened Professional and Government Oversight, 37 J. L. MED. & ETHICS 476, 476-78 (2009) (describing physicians' discretion in prescribing drugs at dosages or using methods of administration not specified on the label).
9. See Kaspar J. Stoffelmayr, Comment, Products Liability and "Off-Label" Uses of Prescription Drugs, 63 U. CHI. L. REV. 275, 279 (1996). Recent regulations have been proposed which may erode this strict policy. (Pubitemid 126408715)
10. See Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices, FDA (Jan. 2009), http://www.fda.gov/RegulatoryInformation/Guidances/ucml25126.htm ("FDA recognizes that the public health can be served when health care professionals receive truthful and non-misleading scientific and medical information on unapproved uses of approved or cleared medical products. Accordingly, if a manufacturer follows the recommendations described in... this guidance, FDA does not intend to consider the distribution of such medical and scientific information... as establishing [prohibited] intent that the product be used for an unapproved new use."). Criticism of this "new" proposal and its potential for abuse by drug manufacturers predates this regulation by forty-seven years.
11. See Charles D. May, Selling Drugs by "Educating" Physicians, 36 J. MED. EDUC. 1, 22 (1961) (discouraging drug manufacturers' "artful attempts to enlist physicians in the sale of drugs by disguising promotion as 'education'");
12. see also Jim Edwards, FDA to Allow "Off-Label" Unapproved Drug Promotion, BNET (Jan. 13, 2009), http://industry.bnet.com/pharma/1000591/fda-to- allow-off-label-unapproved-drug-promotion (noting that this new approach is not about protecting patients from unsupported OLU but "about trying to reduce the amount of responsibility companies have for their own drugs", and that the result is that "you can expect a new flood of drug company sponsored, peer-reviewed literature to hit the market on off-label uses"); infra note 37 and accompanying text (discussing companies' financial sponsorship of ghost-written articles destined for peer-reviewed publications).
13. See Off-Label Drug Use, supra note 2. Once a drug is approved by the FDA, physicians are free to use it however they wish for the benefit of their (individual) patients. This includes the situations for which the drug was tested and approved, as well as others that the doctor, in her clinical judgment, believes would be appropriate.
14. See Christopher, supra note 5, at 248;
15. David A. Kessler, Regulating the Prescribing of Human Drugs for Nonapproved Uses Under the Food, Drug and Cosmetic Act, 15 HARV. J. ON LEGIS. 693, 698 (1978);
16. Paul W. Radensky et al., Potential Liability for Drug Companies, Health Care Providers, and Insurers: Off-Label Prescribing and Internet Advertising, in PHARMACEUTICAL LAW 239, 254 (Michael E. Clark ed., 2007).
17. See David C. Radley et al., Off-Label Prescribing Among Office-Based Physicians, 166 ARCHIVES INTERNAL MED. 1021, 1025 (2006) (providing the figure of twenty-one percent);
18. Steven R. Salbu, Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy, 51 FLA. L. REV. 181, 193 (1999) (reporting on "[o]ne estimate suggesting] that between twenty and sixty percent of all prescriptions are for off-label uses"). Some studies have estimated that the majority of prescriptions for anticancer drugs and drugs for children are for uses not approved by the FDA.
19. See Am. Acad, of Pediatrics, Uses of Drugs Not Described in the Package Insert (Off-Label Uses), 110 PEDIATRICS 181, 181 (2002);
20. Radley et al., supra, at 1022-26;
21. Michael Soares, "Off-Label" Indications for Oncology Drug Use and Compendia: History and Current Status, 1 J. ONCOLOGY PRAC. 102, 104 (2005).
22. Surrey M. Walton reviewed national OLU and concluded that a significant percentage of such prescribing lacked any significant evidentiary support. See Surrey M. Walton et al., Prioritizing Future Research on Off-Label Prescribing: Results of a Quantitative Evaluation, 28 PHARMACOTHERAPY 1443, 1443-51 (2008).
23. See Many People Think That Drugs Should Only Be Prescribed per FDA-Approved Use, Not for Off-Label Use, HARRIS INTERACTIVE (June 9, 2004), http://www.harrisi.org/news/allnewsbydate.asp?newsld=808 [hereinafter WSJ/Harris Poll] (reporting on the results of a poll conducted for the Wall Street Journal and concluding that "'[o]fflabel prescribing'... is probably not an issue which many people have diought about");
24. see also Margaret Z. Johns, Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest, 58 HASTINGS LJ. 967, 968 (2007) (discussing this poll); infra note 87 and accompanying text (discussing this point);
25. see also May, supra note 6;
26. Michelle M. Mello et al., Shifting Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals, 360 NEW ENG. J. MED. 1557 (2009).
27. See Johns, supra note 9, at 968 ("A majority of patients believe that doctors always prescribe drugs as approved by the FDA.");
28. id. at 1013 ("[T]he patient thinks the drug has been proven safe and effective for the prescribed treatment following rigorous scrutiny by the FDA, but with off-label uses it has not.");
29. WSJ/Harris Poll, supra note 9 ("A 51% to 31% majority believes, wrongly, that a doctor can prescribe drugs only for the diseases for which they have been approved... and that... [a] 48% to 31% plurality believes that doctors 'should not be allowed' to prescribe a drug for diseases for which that drug has not been approved by the FDA....").
30. See James M. Beck & Elizabeth D. Azari, FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53 FOOD & DRUG L. J. 71, 71-72, 76, 86-91 (1998);
31. WA. Meadows & B. D. Hollowell, 'Off-label' Drug Use: An EDA Regulatory Term, Not a Negative Implication of Its Medical Use, 20 INT'L J. IMPOTENCE RES. 135, 140 (2008).
32. See, e.g., Beck & Azari, supra note 11, at 87-89;
33. Meadows & Hollowell, supra note 11, at 139-40.
34. See Donna T. Chen et al., U. S. Physician Knowledge of the FDA-Approved Indications and Evidence Base for Commonly Prescribed Drugs: Results of a National Survey, 18 PHARMACOEPIDEMIOLOGY & DRUG SAFETY 1094, 1094-99 (2009). As one commentator notes, "[d]octors generally don't tell people that they're prescribing drugs pitched to them by pharmaceutical salespeople for unapproved treatments.... [In fact,] [m]ost physicians don't keep track of FDA-approved uses of drugs.... 'The great majority of doctors have no idea; they don't even understand the distinction between on-and offlabeling.'"
35. David Evans, Pfizer Broke the Law by Promoting Drugs for Unapproved Uses, 1BLOOMBERG (Nov. 9, 2009), http://www.bloomberg.com/apps/news?pid=news archive&sid=A4yVlnYxCGoA (quoting Peter Lurie).
36. Although not always using this particular phraseology, several previous commentators have established the equivalent of these categories, which track the push toward evidence-based medicine more generally. See, e.g.. Amy P. Abernethy et al., Systematic Review: Reliability of Compendia Methods for Off-Label Oncology Indications, 150 ANNALS INTERNAL MED. 336, 336-43 (2009);
37. Nicole Ansani et al., Designing a Strategy to Promote Safe, Innovative Off-Label Use of Medications, 21 AM. J. MED. QUALITY 255, 255-61 (2006);
38. Nicole Ansani et al., United States Medical Practice Summary: Innovative Off-Label Medication Use, 21 AM. J. MED. QUALITY 246, 246-54 (2006);
39. Madlen Gazarian et al., Off-Label Use of Medicines: Consensus Recommendations for Evaluating Appropriateness, 185 MED. J. AUSTL. 544, 546 (2006);
40. see also Lars Noah, Medicine's Epistemology: Mapping the Haphazard Diffusion of Knowledge in the Biomedical Community, 44 ARIZ. L. REV. 373, 381 (2002) (noting that "[b]y constructing a rough hierarchy that reflects the value of the different types of clinically-relevant information, evidence-based medicine attempts to improve decisionmaking by practicing physicians" and explaining that "[w]hen faced with a clinical problem, health care professionals should, in descending order of preference, look for guidance in systematic reviews of randomized controlled trials, the results of individual controlled clinical trials, observational (uncontrolled) studies, and anecdotal reports of clinical observations").
41. For instance, this could include the design and performance of high-quality, statistically valid clinical trials. There are also methods of slower, incremental accrual of validated evidence for and against an OLU, often compiled by such databases as the Cochrane Collaborative.
42. See M. C. Brouwers et al., Evidence-Based Health Care and the Cochrane Collaboration, 5 CLINICAL PERFORMANCE QUALITY HEALTH CARE, 195, 195-201 (1997).
43. See A. M. Gordon & B. K. Logan, Topiramate-Positive Death-Investigation and Impaired-Driving Cases in Washington State, 30 J. ANALYTICAL TOXICOLOGY 599 (2006) (discussing a study showing that topiramate (Topamax), a drug that was FDA-approved for use in seizure disorders (epilepsy), and which was very popular for OLU, was involved in a seemingly disproportionate number and percentage of cases referred to a state lab in Washington State, suggesting that excessive OLU was causally responsible);
44. Lisa A. Ladewski et al., Dissemination of Information on Potentially Fatal Adverse Drug Reactions for Cancer Drugs from 2000 to 2002, 21 J. CLINICAL ONCOLOCY 3859, 3859-64 (2003) (discussing a study showing that serious, including fatal, adverse drug reactions that were not known upon FDA approval for the original indication, can show up even years later; and calling for expanded and increased vigilance to accrue data on the potential danger of these drugs used both on-and off-label);
45. Gina Kolata, Drug that Stops Bleeding Shows Off-Label Dangers, N. Y. TIMES, Apr. 19, 2011, at Dl.
46. See infra note 71 (discussing the case of Rituximab or Rituxan in this regard).
47. See Kolata, supra note 16; infra notes 113-20 and accompanying text (discussing this doctrine and its history).
48. See Goldberg v. Boone, 912 A.2d 698, 716 (Md. 2006) ("' [A] claim for lack of informed consent focuses... on the adequacy of the explanation given by the physician in obtaining the patient's consent.' Therefore, the level of disclosure that is required to be given by the physician is 'measured by the patient's need, and that need is whatever is material to the decision. '" (second alteration in original) (citation omitted)
49. (quoting Dingle v. Belin, 749 A.2d 157, 165 (Md. 2002)));
50. see also id. (citing precedent for "the proposition that a physician must disclose to the patient all information that a reasonable person would need to make his or her decision of whether to undergo the procedure" and that "the standard for determining what information must be disclosed by a physician in Maryland is whether a reasonable person in the patient's position would consider the data significant to the decision whether to submit to a particular treatment or procedure" (internal quotation marks omitted)
51. (citing Reed v. Campagnolo, 630 A.2d 1145, 1152 (Md. 1993)
52. and Wachter v. United States, 877 F.2D 257, 260 (4th Cir. 1989))).
53. See infra notes 78-85 and accompanying text (discussing this case law and noting that, in these cases, the courts themselves may not have been aware that many OLU are unsupported by evidence of safety and efficacy and thus that in some circumstances, a drug's FDA status may in fact be quite material to the patient's informed decision).
54. Compare Beck & Azari, supra note 11, at 71-72 (arguing that the FDA status of a drug is not material to a patient's medical decisionmaking and thus does not have to be disclosed)
55. with Johns, supra note 9, at 967-71 (arguing the contrary). Beck and Azari's is the most prominendy cited article on this issue, but even they agree that the underlying facts about risk and efficacy are often material ones; the only debatable issue, therefore, is whether (in their terms) FDA status is an appropriate "proxy" for safety and efficacy.
56. See Beck & Azari, supra note 11, at 72.
57. See, e.g., Beck & Azari, supra note 11, at 72 (arguing that forcing physicians to disclose "FDA regulatory status... would confound patient decisionmaking" and is not necessary to meeting informed consent requirements).
58. See Robert D. Mulford, Note, Experimentation on Human Beings, 20 STAN. L. REV. 99, 102 (1967) (noting that "[t]he concept of informed consent is central to any standard regulating research on human beings" and that it "was most strongly articulated" in the Nuremberg Code).
59. See infra notes 47-48 and accompanying text (setting out related definitions).
60. This is because the regulation of medical practice has-for the most part-remained outside of the federal government's regulatory jurisdiction. See infra Part I. A-B.
61. This is because the federal government has chosen to assume jurisdiction in this different context. See infra notes 77-81 and accompanying text (providing an example from the case law).
62. See Off-Label Use, supra note 2 (explaining that the reason "[m]any insurance companies will not pay for" an OLU is because it is considered "'experimental' or 'investigational'").
63. See, e.g., Salbu, supra note 8, at 196-98 (elaborating on this innovations argument);
64. cf. Christopher, supra note 5, at 247 (noting that, in general, "[t]he medical community argues that overregulation chills innovation and reduces medicine to 'cookbook' therapy").
65. See Dustin D. French et al., Letter to the Editor, How Well Do Psychotropic Medications Match Mental Health Diagnoses? A National View of Potential Off-Label Prescribing in VHA Nursing Homes, 36 AGE & AGEING 107, 107-08 (2007);
66. Kolata, supra note 16.
67. See Daria J. O'Reilly et al., The Unintended (and Costly) Effects Due to the Introduction of an Unrestricted Reimbursement Policy for Atypical Antipsychotic Medications in a Canadian Public Prescription Drug Program: 1996/97 to 2005/06, 16 CANADIAN J. CLINICAL PHARMACOLOGY 346, 352 (2009).
68. See A. P. Jonville-Béra et al., Are Incorrectly Used Drugs More Frequently Involved in Adverse Drug Reactions? A Prospective Study, 61 EUR. J. CLINICAL PHARMACOLOGY 232, 235 (2005) (finding that off-label uses cause adverse drug reactions);
69. Elin Kimland et al., Drug Related Problems and Off-Label Drug Treatment in Children as Seen at a Drug Information Centre, 166 EUR. J. PEDIATRICS 527, 527-28, 531 (2007) ("Adverse drug reactions [are] often associated with off-label drug treatment...."). An argument to the contrary is that permitting OLU is good "cost-containment" because it does not require society to incur the costs of expensive "FDA approval procedures."
70. See Salbu, supra note 8, at 195. This argument essentially provides that because ascertaining safety and efficacy is expensive, the project ought not (at least in some circumstances) be undertaken. Or, more specifically, it is that pharmaceutical companies ought not be made to bear the financial burdens of ascertaining the safety and efficacy of all of the uses to which their products will be put, including the uses they specifically promote. This argument is only valid if individuals and society are willing to bear the costs associated with unsafe and ineffective drugs.
71. There are a number of instances that meet these criteria. For example, the chemotherapy drug daunorubicin is FDA approved "for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults", Cerubidine (Daunorubicin Hydrochloride) Injection, Powder, for Solution [Bedford Laboratories], DAILYMED, http://dailymed.nlm.nih.gov/dailymed/ druglnfo.cfm?id=5821#nlm340 67-9 (last revised Nov. 2007), but is also a mainstay of treatment for the analogous disease in children.
72. See I. M. Hann et al., MRC Trials in Childhood Acute Myeloid Leukaemia, 83 ANNALS HEMATOLOGY S108, S108-12 (Feb. Supp. 2004).
73. See supra notes 21-25 and accompanying text (noting this argument).
74. Much of the argument of this Article relies on the use of the term "evidencebased medicine" as the platform from which the evaluation of the efficacy, safety, and utility of any therapeutic must be derived. Although it may be intuitively obvious that physicians would make decisions and clinical recommendations using the best available data to justify the action chosen, it has not been (and is not) always the case. Indeed, it is only in the last twenty years or so that academic medicine has formalized processes to teach students how to approach, find, and evaluate the relevant medical literature that forms the scientific grounding of modem medical practice. The origin of both the term "evidence-based medicine" and the approach it designates is somewhat vague, but appears to have emerged in the early 1990s.
75. See Jeffrey A. Claridge & Timothy C. Fabian, History and Development of Evidence-Based Medicine, 29 WORLD J. SURGERY 547, 547 (2005);
76. Gordon H. Guyatt et al., Users' Guides to the Medical Literature: II. How to Use an Article About Therapy or Prevention: Are the Results of the Study Valid?, 270 JAMA 2598, 2598-2601 (1993);
77. Andrew D. Oxman et al., Users' Guides to the Medical Literature: I. How to Get Started, 270 JAMA 2093, 2093-95 (1993).
78. David L. Sackett, in an influential editorial in the British Medical fournal, defined the term as follows: Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.... By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of
79. David L. Sackett et al., Editorial, Evidence Based Medicine: What It Is and What It Isn't, 312 BRIT. MED. J. 71, 71-72 (1996). Currently, coursework, lectures, and the like constitute components of the curricula of most, if not all, medical schools in the United States, and formal training in evidence-based data collection, analysis, and implementation is required by both the American Boards of Internal Medicine and Pediatrics.
80. See, e.g., David B. Rueben, Chair's Message, AM. BOARD INTERNAL MED., http://abim.org/about/board-of-directors/chairs-message.aspx (last visited Feb. 15, 2011) (stating that the board is focusing on data collection and evidence-based medicine). Thus, it is fair to say that American physicians should be expected to be expert arbiters of the available scientific literature evidence base (or lack of it) in supporting any particular therapeutic modality.
81. See supra note 6 and accompanying text.
82. As one commentator noted, "Companies regard the risk of multimillion-dollar penalties [in this context] as just another cost of doing business." Evans, supra note 13. Specifically, "[a]s large as the penalties are for drug companies caught breaking the off-label law, the fines are tiny compared with the firms' annual revenues."
83. Id. For example, "[t]he $2.3 billion in fines and penalties Pfizer paid for marketing Bextra and three other drugs... amount to just 14 percent of its $16.8 billion in revenue from selling those medicines from 2001 to 2008."
84. Id.
85. See infra Part II. A (setting out this argument).
86. See Jeffrey R. Lacasse & Jonathan Leo, Ghostwriting at Elite Academic Medical Centers in the United States, PLOS MED., Feb. 2010, http://www.plosmedicine.org/article/info:doi%2F10.1371%2Fjournal.pmed.1000230;
87. Stephanie Saul, Merck Wrote Drug Studies for Doctors, N. Y. TIMES, Apr. 16, 2008, at C1;
88. Natasha Singer, Medical Papers by Ghostwriters Pushed Therapy, N. Y. TIMES, Aug. 5, 2009, at A1.
89. See Dresser & Frader, supra note 5. This call revives an earlier theme in the literature. See Arthur S. Levine, Clinical Trials and the Community Physician, 51 CANCER 2498, 2498-2502 (1983) (addressing and promoting the introduction of protocols in community hospitals for testing new therapeutic techniques);
90. Robert J. Levine, The Boundaries Between Biomedical or Behavioral Research and the Accepted and Routine Practice of Medicine, in NAT'L COMM'N FOR THE PROT. OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH, THE BELMONT REPORT: ETHICAL PRINCIPLES AND GUIDELINES FOR THE PROTECTION OF HUMAN SUBJECTS OF RESEARCH app. I, at 1-1 to 1-44 (1978) [hereinafter THE BELMONT REPORT];
91. Legal Implications of the Boundaries Between Biomedical Research Involving Human Subjects and the Accepted or Routine Practice of Medicine, in THE BELMONT REPORT, supra, app. II, at 16-44 to 16-45.
92. See Celia Davies, Editorial, Getting Health Professionals to Work Together, 320 BRIT. MED. J. 1021, 1021-22 (2000) (discussing research displaying the need for more collaboration on the part of doctors and hospital staff).
93. See generally Edmund D. Pellegrino, Patient and Physician Autonomy: Conflicting Rights and Obligations in the Physician-Patient Relationship, 10 J. CONTEMP. HEALTH L. & POL'Y 47, 58-63 (1994) (discussing physicians' traditional discretion).
94. See infra Part I (describing the dearth of effective regulation in additional detail).
95. See, e.g., Christopher, supra note 5, at 247 (noting that "physicians attack some attempts to regulate medicine with the vigor of an artist resisting censorship" and that "[t]he medical community argues that overregulation chills innovation and reduces medicine to 'cookbook' therapy").
96. See Veronica Henry, Problems with Pharmaceutical Regulation in the United States, 14 J. LEGAL MED. 617, 618-20 (1993);
97. Katherine A. Helm, Note, Protecting Public Health from Outside the Physician's Office: A Century of FDA Regulation from Drug Safety Labeling to Off-Label Drug Promotion, 18 FORDHAM INTELL. PROP. MEDIA & ENT. L. J. 117, 125 (2007).
98. See Salbu, supra note 8, at 190-91. As one court recently wrote with respect to OLU in particular, [t]he FDA has always recognized that the [Food, Drug, and Cosmetics] Act does not... limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may choose to prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. The FDA also observes that accepted medical practice often include [s] drug use that is not reflected in approved drug labeling.
99. Blazoski v. Cook, 787 A.2d 910, 919 (NJ. Super. Ct. App. Div. 2002) (first alteration in original)
100. (quoting Morlino v. Med. Ctr. of Ocean Cnty., 706 A.2d 721, 730 (N. J. 1998));
101. see also id. at 918 ("'[0]ff-label' usage of medical devices 'is an accepted and necessary corollary of the FDA's mission to regulate in this area without direcdy interfering with the practice of medicine.'" (alteration in original) (quoting Buckman Co. v. Plaintiffs' Legal Comm., 531 U. S. 341, 350 (2001))). The two exceptions to this rule are clinical trials with patient/subjects
102. see 21 C. F. R. § 50 (2010);
103. id. § 56; 45 C. F. R. § 46 (2010), and the regulation of narcotics, amphetamines, and hallucinogens
104. see Controlled Substances Act, 21 U. S. C. §§ 801-904 (2006).
105. See infra notes 72-77 and accompanying text (discussing the effects of such aftermarket actions on medical malpractice actions).
106. See 45 C. F. R. § 46. 102 (g) - (j) (defining Institutional Review Boards and their approval process);
107. Office of Human Subjects Research, OHSR Information Sheets/Forms, NAT'L INSTS. HEALTH (NOV. 20, 2006), http://ohsr.od.nih.gov/info/sheetl.html (discussing the OHSR's responsibilities).
108. See 45 C. F. R. § 46. 102 (d). A "human subject" for purposes of this policy is defined as "a living individual about whom an investigator (whether professional or student) conducting research obtains (1) [d]ata through intervention or interaction with the individual, or (2) [i]dentifiable private information. "
109. Id. § 46.102 (f). " (G]eneralizable knowledge" is "knowledge related to health that can be applied to populations outside the population being studied. That is, participants in a research project may or may not benefit direcdy from the study, but a larger group is expected to gain from the knowledge obtained in the study."
110. 2 Organizational Policy on the Definition of Research as It Applies to Clinical Practice and Public Health Activities, JOHNS HOPKINS MED. (Sept. 2007), http://www.hopkinsmedicine.org/institutional-review-board/guidelines-policies/ organization-policies/102-2.html.
111. 45 C. F. R. §46. 102 (e).
112. In addition to OLU, well-known examples of experimental or innovative activity that falls outside of the jurisdiction of the OHSR include some types of stem cell and recombinant DNA research. See id. § 46.101 (a) - (i) (describing research to which this policy applies). However, all clinical research using human subjects is regulated by the OHSR, no matter what the funding source (private or government).
113. See id. § 46.101 (a).
114. See supra notes 47-49 (distinguishing "human subjects research" from innovative medical practice on the basis that the former is to obtain generalizable knowledge and the latter is to cure or alleviate an individual patient's condition).
115. See supra note 42.
116. See, e.g., Doriane Lambelet Coleman, The Legal Ethics of Pediatric Research, 57 DUKE LJ. 517, 530-31 (2007) (describing experiments on children as padents).
117. Physician-padent relationships that involve, in addidon to diagnosis and treatment, formal enrollment of the padents in studies designed to test the merits of OLU are the exception to this proposition. These patients and their physicians acting as investigators are subject to the federal regulations governing human subjects research. See 21 C. F. R. § 50. 1 (a) (2010);
118. id. § 56.101; 45 C. F. R. § 46. 101 (a) - (i). The difference for these patients is that the intent of the studies is not to cure or alleviate their particular symptoms, but rather to gather generalizable knowledge about their condition.
119. Our use of the term "experimental" refers not to a research endeavor, one aimed towards generating knowledge applicable to others, but rather to one in which the outcome is unknown and cannot be predicted with a high degree of confidence.
120. See supra note 41 and accompanying text.
121. Dent v. West Virginia, 129 U. S. 114, 121-23 (1889).
122. The Court also held that such a licensing requirement could not be construed as a restraint of trade. Id.
123. See ABRAHAM FLEXNER, MEDICAL EDUCATION IN THE UNITED STATES AND CANADA passim (1910);
124. Andrew H. Beck, The Flexner Report and the Standardization of American Medical Education, 291 JAMA 2139, 2139-40 (2004).
125. Indeed, this was probably the first official endorsement of "evidence-based medicine." See supra note 33.
126. See FSMB Mission & Goals, FED'N STATE MED. BOARDS, http://www.fsmb.org/mission. html (last visited Feb. 12, 2011);
127. FSMB History, FED'N STATE MED. BOARDS, http://www.fsmb.org/history.html (last visited Feb. 12, 2011);
128. Policy Documents, FED'N STATE MED. BOARDS, http://www.fsmb.org/grpol- policydocs.html (last visited Feb. 12, 2011).
129. See Continuing Medical Education (CME) FAQs, N. C. MED. BOARD, http://ncmed board.org/faqs/list/category/continuing-medical-educadon-cme (last visited Feb. 12, 2011).
130. See State of the States: Physician Regulation 2009, FED'N STATE MED. BOARDS, 6, http://www.fsmb.org/pdf/2009-state-of-states.pdf (last visited Feb. 12, 2011) ("While medical boards sometimes find it necessary to suspend or revoke licenses, regulators have found many problems can be resolved with additional education or training in appropriate areas.... This compromise protects the public while maintaining a valuable community resource in the physician. ").
131. For information on licensure requirements, see Becoming a Physician: Medical Licensure, AM. MED. ASS'N, http://www.ama-assn.org/ama/pub/education- careers/becoming-physician/medical-licensure.shtml (last visited Feb. 12, 2011).
132. See DAN B. DOBBS, THE LAW OF TORTS 633 (2001).
133. As Professor Dobbs explains: The standard of care is not the reasonable person standard used in most negligence cases. The reasonable person standard asks the trier to weigh the reasonableness, that is at least in part to weigh the risks and utilities of the defendant's conduct; but the professional standard asks the trier only to determine whether the defendant's conduct conformed to the medical standard or medical custom in the relevant community. Thus under the traditional rule, as long as a doctor follows the medical standard or custom, he is not negligent, regardless of how risky the custom or how unnecessary. Id.
134. This number is the result of a Wesdaw search in February 2010 according to the following criteria: the database was "allstates" and the search terms were "medical w/1 malpractice & off w/I label." The same result was obtained when the search terms were changed to "medical w/1 malpractice & off-label." The cases that we describe as arguably restrictive of physicians' off-label practices are those described in notes 67-72 and accompanying text. These involve the decision of some courts to permit malpractice plaintiffs to introduce physician package inserts into evidence to establish the standard of care.
135. H-120.988 Patient Access to Treatments Prescribed by Their Physicians, AM. MED. ASS'N, https://ss13.ama-assn.org/apps/ecomm/PolicyFinderForrn. pl?site=www.amaassn.org&uri=/amal/pub/upload/mm/PolicyFinder/policyfiles/ HnE/H-120.988. HTM (last visited Feb. 12, 2011).
136. See Silberstein v. Berwald, 460 S. W.2d 707, 709 (Mo. 1970).
137. See, e.g., State Bd. of Registration for the Healing Arts v. McDonagh, 123 S. W.3d 146, 164 (Mo. 2003) (noting in the context of a case challenging a physician's off-label use of chelation therapy that "[p]hysicians are afforded considerable leeway in the use of professional judgment to decide on appropriate treatments, especially when applying the negligence standard.
138. For instance, [another] medical negligence case, holds that 'as long as there is room for an honest difference of opinion among competent physicians, a physician who uses his own best judgment cannot be convicted of negligence, even though it may afterward develop that he was mistaken. '" (quoting Haase v. Garfinkel, 418 S. W.2d. 108, 114 (Mo. 1967))).
139. See id. at 150 (quoting from the AMA's position statement on the off-label use of chelation therapy, which also included the admonitions that " (1) [t]here is no scientific documentation that the use of chelation therapy is effective in the treatment of cardiovascular disease, atherosclerosis, rheumatoid arthritis, and cancer; [and] (2) chelation therapy
140. H-175.994 Chelations Therapy, AM. MED. ASS'N (2004), https://ss13.ama- assn.org/apps/ecomm/PolicyFinderform. pl?site=www.ama-assn.org&uri=/amal/ pub/upload/mm/PolicyFinder/policyfiles/HnE/H-175.994. HTM;
141. * 17 (Tex. Dist. Ct. June 7, 1999) ("Once a device has been cleared for labeling for one use, physicians in their private practice may use it in any manner they deem medically appropriate, including uses being studied pursuant to an IDE.").
142. McDonagh, 123 S. W.2d at 159.
143. See id. at 165 (noting, in response to the claim that a physician failed to abide by AMA guidelines, that "medicine is not readily regulated by a standard cookbook or set of rules").
144. The court in McDonagh even went so far as to suggest that physicians could properly use a therapy off-label that was generally held to be ineffective so long as it was otherwise harmless and patients could be healed by believing in its curative properties: Medicine is an art, as well as a science, as its practitioners are taught. It is also a dynamic field, where beliefs about what is conventional therapy can change over time. What is effective treatment is often a combination, not just of art and science, but of belief. The patient may get better if the patient is convinced of the usefulness of the therapy. Id. at 166.
145. See Philip M. Rosoff, Can Underpowered Clinical Trials Be Justified?, IRB: ETHICS HUM. RES., May-June 2004, at 16, 16. The story of bone marrow transplants and breast cancer is illustrative. In 1986 doctors reported using very high doses of chemotherapy to eliminate residual cancer in patients with advanced disease and "rescuing" them with using dieir own bone marrow. The initial, noncontrolled, results were impressive, thus providing proof of principle in terms of both feasibility and potential efficacy.
146. See J. Paul Eder et al., High-Dose Combination Alkylating Agent Chemotherapy with Autologous Bone Marrow Support for Metastatic Breast Cancer, 4 J. CLINICAL ONCOLOGY 1592, 1592 (1986);
147. W. P. Peters et al., High-Dose Combination Alkylating Agents with Autologous Bone Marrow Support: A Phase 1 Trial, 4 J. CLINICAL ONCOLOGY 646, 652-53 (1986).
148. The data were impressive enough that others adopted the approach and it became the "standard of care." Public pressure built to provide this "miracle" therapy to women and have insurance companies pay for it. See RICHARD A. RETTIG ET AL., FALSE HOPE passim (2007).
149. This practice was so accepted that a number of patients successfully sued their insurance companies when they were denied coverage for autologous transplantation for breast cancer. See, e.g., Henderson v. Bodine Aluminum, Inc., 70 F.3d 958, 961 (8th Cir. 1995) (granting plaintiff's requested injunctive relief on the basis that her insurance "plan covers HDCT for other types of cancer for which it is an accepted treatment, and... she has shown considerable unrebutted evidence that HDCT is an accepted breast cancer treatment with significandy higher success rates than standard chemotherapy"). Unfortunately, when Phase 3 randomized trials were eventually performed some years later, the results of these trials demonstrated that the benefit of autotransplantation for advanced breast cancer was marginal at best.
150. See Martin S. Tallman et al., Conventional Adjuvant Chemotherapy with or Without High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in High-Risk Breast Cancer, 349 NEW ENG. J. MED. 17, 17 (2003);
151. Sjoerd Rodenhuis et al., High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for High-Risk Breast Cancer, 349 NEW ENG. J. MED. 7, 14-15 (2003);
152. C. Farquhar et al., High Dose Chemotherapy and Autologous Bone Marrow or Stem Cell Transplantation Versus Conventional Chemotherapy for Women with Metastatic Breast Cancer, 1 COCHRANE DATABASE SYSTEMATIC REVS., 2005, at 2 (D. O. I.: 10.1002/14651858.CD0031342);
153. Gerald J. Elfenbein, Editorial, Stem-Cell Transplantation for High-Risk Breast Cancer, 349 NEW ENG. J. MED. 80, 80-82 (2003);
154. ®) is similarly illustrative. This drug is a product of genetic engineering and is FDA approved for use in non-Hodgkin's lymphoma.
155. See Rituxan (Nituximab) Injection, Solution [Genentech, Inc.], DAILY MED, http://dailymed. nlm.nih.gov/dailymed/druglnfo.cfm?id=16017 (last revised Jan. 2010).
156. However, it is now prescribed for a wide variety of unapproved uses. See Richard Imrich et al., Autoimmune Autonomic Ganglionopathy: Treatment by Plasma Exchanges and Rituximab, 19 CLINICAL AUTONOMIC RES. 259, 259-62 (2009);
157. A.Ø. Jensen et al., Treatment of Treatment-Resistant Autoimmune Blistering Skin Disorders with Rituximab, 160 BRIT. J. DERMATOLOGY 1359, 1359-61 (2009);
158. C. Lebrun et al., Successful Treatment of Refractory Generalized Myasthenia Gravis with Rituximab, 16 EUR. J. NEUROLOGY 246, 246-49 (2009);
159. Brigitta U. Mueller et al., One Year Follow-Up of Children and Adolescents with Chronic Immune Thrombocytopenic Purpura (ITP) Treated with Rituximab, 52 PEDIATRIC BLOOD CANCER 259, 259-61 (2009);
160. V. Torrente-Segarra et al., Clinical, Biological and Ultrasonographic Remission in a Patient with Musculoskeletal Systemic Lupus Erythematosus with Rituximab, 18 LUPUS 270, 270-72 (2009). There have been several alerts from the FDA after reports of severe and occasionally fatal reactions to this drug, finally resulting in a so-called "black box" warning (added to the required drug information package insert data sheet).
161. Most of these warnings came after unexpected side effects occurred in patients receiving rituximab for OLU. See Rituximab (Marketed as Rituxan) Information: FDA Alert [12/18/2006], http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ucml09106.htm (last updated Jan. 21, 2010).
162. See supra note 31 and accompanying text.
163. See, e.g., Richardson v. Miller, 44 S. W.3d 1, 15-17 (Tenn. Ct. App. 2000) ("The great weight of authority is that a drug's labeling or its parallel PDR reference is admissible, as long as it is accompanied by other expert evidence regarding the standard of care."). This requirement has been established indirecdy, as a result of the evidentiary value of package inserts to establish the standard of care. This point is discussed in additional detail in the text.
164. See id.
165. See Arnold v. Lee, 720 N. W.2d 194
166. *6 (Iowa Ct. App. May 24 2006) (unpublished table decision) (upholding district court's refusal to admit package insert into evidence because of the "risk for unfair prejudice"). Jurisdictions that permit the introduction of package inserts to establish the standard of care are also concerned with their potential to mislead juries about the propriety of off-label uses, but this concern is addressed not by prohibiting their use as evidence but by requiring the simultaneous production of an expert to establish that the inserts do in fact reflect the standard of care.
167. See, e.g., Richardson, 44 S. W.3d at 15-17.
168. *3.
169. It is unclear which approach reflects the majority view. Jurisdictions in both camps purport to do so.
170. Compare id. ("[W]e find that a slight majority do not allow the insert for the truth of the matters asserted within. ")
171. with Richardson, 44 S. W.3d at 15 ("Virtually every court addressing this question has concluded that the drug's labeling and PDR reference are relevant to the standard of care issue.").
172. See, e.g., Blazoski v. Cook, 787 A.2d 910, 918 (N. J. Super. Ct. App. Div. 2002) ("The majority view... represented by the recent decision of the Pennsylvania Supreme Court... is that the doctrine of informed consent does not require surgeons to advise patients of the FDA investigational status of pedicle screws.");
173. Johns, supra note 9, at 1013 ("[R]esearch has disclosed no case holding that the doctrine of informed consent requires a doctor to disclose that a prescription is off label.").
174. Blazoski, 787 A.2d at 917.
175. Id. at 919
176. (quoting Southard v. Temple Univ. Hosp., 781 A.2d 101, 107 (Pa. 2001)). Of course, this rationale avoids the inconvenient truths that approved, i.e., "on-label", uses are such precisely and only because they have been determined to be safe and effective, and that safety and efficacy are central to medical decisionmaking.
177. Id. (first alteration in original)
178. (quoting Klein v. Biscup, 673 N. E.2d 225, 231 (Ohio Ct. App. 1996)).
179. Id. at 913.
180. Id. at 914.
181. Id.
182. Id. at 921
183. (citing Southard, 781 A.2d at 107-08).
184. See, e.g., id. at 917 (noting that "[t]he doctor's duty of disclosure is measured by the 'prudent patient'" and not the "physician's judgment").
185. We base our view in part on intuition and anecdotal experience, and in part on supportive reports.
186. See supra notes 9-10 and accompanying text (describing these reports).
187. The Blazoski case provides some additional evidence that its materiality finding was normative rather than fact based. Specifically, the court also rationalized its decision on "sound policy reasons" including that "[r]equiring disclosure may necessitate a pre-surgery discourse by the physician on the mechanics of the FDA approval process which may dilute the significance of material, medical risks related to the procedure."
188. Blazoski, 787 A.2d at 9920. In this context, the court quoted the following language from a related law review article: Patients... would be distracted from learning about the nature, risks, and benefits of their treatments by regulatory information of de minimus value. Such information would accentuate the errant notion that all off-label use is by definition inherently risky, novel, or investigational. By implying risk or novelty when there is none, these disclosures could frighten patients away from the very therapies that actually are best for the treatment of their conditions.
189. Id. (alteration in original)
190. (quoting Beck & Azari, supra note 11, at 101).
191. For example, Dr. J. Jemsek was sanctioned by the North Carolina Medical Board for continually misdiagnosing patients as having chronic Lyme Disease and prescribing long-term intravenous antibiotics.
192. See Board Orders/Consent Orders/Other Board Actions: July-August 2006, N. C. MED. BOARD, 2-3 (2006), http://www.ncmed board.org/images/uploads/ disciplinary-reports/ba57.pdf.
193. See AM. MED. ASS'N, CODE OF MEDICAL ETHICS OF THE AMERICAN MEDICAL ASSOCIATION (1847), available at http://www.ama-assn.org/amal/pub/upload/mm/369/ 1847code.pdf.
194. The AMA currently counts 236, 153 members: this is fewer than thirty percent of the listed physicians in the United States. Indeed, this may be a gross overestimate. This number was current as of 2009 when it was obtained from the AMA. However, it also includes students and retired doctors, so it is unclear the exact percentage of practicing physicians who are members of the AMA. That the AMA membership rep resents a small minority of active doctors remains a valid point.
195. See COUNCIL ON LONG RANGE PLANNING & DEV., AM. MED. ASS'N, REPORT NO. 3-A-09, DEMOGRAPHIC CHARACTERISTICS OF THE HOUSE OF DELEGATES AND AMA LEADERSHIP (2009), available at http://www.ama-assn.org/amal/pub/upload/mm/41/ clrdp-report-3-a09-demographic.pdf.
196. See Doctor Finder, AM. MED. ASS'N, https://webapps.ama-assn.org/ doctorfinder/home.jsp (last visited Feb. 12, 2011).
197. Principles of Medical Ethics, AM. MED. ASS'N (rev. ed. 2001), http://www.amaassn.org/ama/pub/physician-resources/medical-ethics/ code-medical-ethics/principles-medical-ethics.shtml.
198. Id.
199. H-120.988 Patient Access to Treatments Prescribed by Their Physicians, supra note 65.
200. Id. The compendia referred to in the policy are the AMA's own Drug Evaluations, the United States Pharmacopeia-Drug Information, Volume I, and the American Hospital Formulary Service-Drug Information. It notes that the first two compendia "currently are being merged as the result of an alliance between the American Medical Association and the United States Pharmacopeia."
201. Id. Although the policy statement purports to derive the AMA's commitment to physicians' reliance on "sound scientific evidence and sound medical opinion" from the law, it is in fact only an ethical requirement.
202. Id. To the extent the law is implicated in this aspect of the policy statement, it is only in the permission it indirectly gives doctors to "use an FDA-approved drug product... for an unlabeled indication. "
203. Id. These compendia, while seemingly reliable and unimpeachable sources of unvarnished and trustworthy information about drugs and their uses that are supported by high-quality information, are actually extensively open to exploitation and undue influence by the drug companies.
204. See ROSS MCKINNEY ET AL., WHITE PAPER: POTENTIAL CONFLICT OF INTEREST IN THE PRODUCTION OF DRUG COMPENDIA 6-7, 55-58 (2009), available at http://www.cms.gov/determinationprocess/downloads/id64TA.pdf;
205. Abernethy et al., supra note 14, at 336.
206. The reliability of compendia for accurate and unbiased information may be improved by a provision included in the Medicare Improvements for Patients and Providers Act of 2008, Pub. L. No. 110-275, § 182(b), 122 Stat. 2494, 2583
207. (amending 42 U. S. C. § 1395 x (t) (2) (B) (2006 & Supp. IV 2010)), which explicitly requires these databases to openly declare any conflicts of interest and publicize their methods.
208. See Katherine Tillman et al., Compendia and Anticancer Therapy Under Medicare, 150 ANNALS INTERNAL MED. 348, 349 (2009). However, the open declaration of potential conflicts of interest is not always a reliable deterrent to avoiding them.
209. See supra notes 43-45 and accompanying text.
210. See supra notes 6, 34-37 and accompanying text (describing this focus).
211. See supra notes 6-8, 34-37 and accompanying text (discussing this failure).
212. See supra notes 34-37 and accompanying text (noting this point).
213. See supra notes 40-42 and accompanying text (providing additional background).
214. See, e.g., Am. Soc'y of Clinical Oncology, Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications, 24 J. CLINICAL ONCOLOGY 3206, 3206-07 (2006) (supporting a requirement that "Medicare contractors... take into account peerreviewed literature" in order to expand coverage for off-label uses);
215. Asco Supports Government Report: "Off-Label Drugs: Reimbursement Policies Constrain Physicians in Choice of Cancer Therapies", 5 ONCOLOGY Oct. 1991, at 29, 29-30, 33.
216. See, e.g., Christopher, supra note 5, at 247.
217. See supra notes 40-42 (describing this argument).
218. See Council on Ethical & Judicial Affairs, Fundamental Elements of the Patient-Physician Relationship, AM. MED. ASS'N (1990), http://www.ama-assn. org/amal/pub/upload/mm/code-medical-ethics/lOOla.pdf;
219. Council on Ethical & Judicial Affairs, The Patient-Physician Relationship, AM. MED. ASS'N (2001), http://www.ama-assn.org/amal/pub/upload/mm/ code-medical-ethics/10015a.pdf.
220. KATHRYN MONTGOMERY, HOW DOCTORS THINK 53 (2006).
221. See supra note 22 and accompanying text (describing this point).
222. For instance, the AMA notoriously lodged vociferous objections to the creation of Medicare, in part arguing that it heralded the death knell of the doctor-patient relationship and its companion, physician autonomy.
223. See PAUL STARR, THE SOCIAL TRANSFORMATION OF AMERICAN MEDICINE 368 (1982).
224. See supra notes 14-17, 33-39 and accompanying text (describing evidentiary standards and regulations on pharmaceutical marketing).
225. Importantly, others who have discussed this problem and come to similar conclusions have suggested nonbinding directives for physicians to attempt to control the most egregious practices of OLU. However, while we are extending this analysis by calling for new statutory regulation of problematic OLU as a mechanism for managing physicians' abuses of the current system, the content of these proposed regulations would be similar, if not identical to what others have recommended for nonbinding practice guidelines.
226. See, e.g., Dresser & Frader, supra note 5, 476-77.
227. See, e.g., Johns, supra note 9, at 1023-24.
228. See supra notes 10-11 and accompanying text (discussing this misimpression).
229. See Beck & Azari, supra note 11, at 72.
230. See id.
231. see also supra notes 73-80 and accompanying text (describing the related case law).
232. Beck & Azari, supra note 11, at 84.
233. See supra notes 2-5 (explaining that on-label means that the FDA put a drug through rigorous testing for safety and efficacy and off-label means it did not).
234. See supra notes 14-15 and accompanying text (discussing the different levels of evidentiary support for OLU).
235. See supra note 20 and accompanying text (setting out Beck and Azari's argument that FDA status is not a "proxy" for safety and efficacy).
236. ** of their article.
237. **. Notably, they also acknowledge that safety and efficacy are medically material information, as is the fact that a prescription would be for an innovative use.
238. See id. at 72.
239. See Mohr v. Williams, 104 N. W. 12, 14 (Minn. 1905) ("Under a free government, at least, the free citizen's first and greatest right, which underlies all others-the right to the inviolability of his person; in other words, the right to himself-is the subject of universal acquiescence, and this right necessarily forbids a physician or surgeon, however skillful or eminent, who has been asked to examine, diagnose, advise, and prescribe... to violate, without permission, the bodily integrity of his patient... without his consent or knowledge." (quoting Pratt v. Davis, 118 111. App. 161, 166 (1905)))
240. overruled by Genzel v. Halvorson, 80 N. W.2d 854 (Minn. 1957);
241. id. at 14-15 ("The patient must be the final arbiter as to whether he will take his chances with [the proposed treatment], or take his chances of living without it. Such is the natural right of the individual, which the law recognizes as a legal one."
242. (quoting 1 EDGAR B. KINKEAD, COMMENTARIES ON THE LAW OF TORTS § 375 (1901)));
243. Schloendorff v. Soc'y of N. Y. Hosp., 105 N. E. 92, 93 (N. Y. 1914) ("Every human being of adult years and sound mind has a right to determine what shall be done with his own body.")
244. abrogated by Bing v. Thunig, 143 N. E.2d 3 (N. Y. 1957). Few would argue that one of the singularly significant outcomes of the Nuremberg Trials and the subsequent Belmont Report was to emphasize the exceptional, if not unique, importance of informed consent to the practice of medicine and clinical research.
245. See THE BELMONT REPORT, supra note 38. In their influential history of informed consent, Faden and Beauchamp note the historical transition of doctors' behavior and attitude in requesting permission to do something to (and for) patients
246. Until recendy... the justification of practices of disclosure and consentseeking were stricdy governed by what we shall call a beneficence model rather than an autonomy model of the physician's responsibility for the patient. The "autonomy model", as we use the term, is the view that the physician's responsibilities of disclosure and consent-seeking are established primarily (perhaps exclusively) by the principle of respect for autonomy. The "beneficence model", as we use the term, depicts the physician's responsibilides of disclosure and consent-seeking as established by the principle of beneficence, in particular through the idea that the physician's primary obligadon (surpassing obligadons of respect for autonomy) is to provide medical benefits. The management of information is understood, on the latter model, in terms of the managements of patients ("due care") generally. That is, the physician's primary obligadon is to handle information so as to maximize the patient's medical benefits. Here, the principle of beneficence is used to provide clinical-specific meanings for the benefits and harms to be balanced by the physician.
247. RUTH R. FADEN & TOM L. BEAUCHAMP, A HISTORY AND THEORY OF INFORMED CONSENT 59 (1986) (footnotes omitted) (citations omitted). As these authors point out, the progression to the autonomy-based model leaves behind a more paternalistic template for physician-patient interactions in which the pendulum of decisionmaking power still heavily favored the doctor, whose role was to look out for what was best for the patient. The latter, more recent development, allowed for a more equalized form of power sharing; indeed, it placed the responsibility for making decisions about what was in the best interests of the patient in the correct location: with the patient herself. This is the ideal, which is what we aim for both in regulation (or legislation) and practice, certainly when it comes to informed consent for research. But, we also see a similar practice in clinical medicine, especially in the rules governing consent for procedures, surgery and the like.
248. See DOBBS, supra note 62, at 652-53. Only in cases where the patient is incompetent can proxy decisionmaking by physicians and others take place.
249. See supra notes 73-82 and accompanying text (discussing this case law).
250. See DOBBS, supra note 62, at 652-53;
251. supra notes 112-13 and accompanying text (setting out this doctrine).
252. See Beck & Azari, supra note 11, at 72.
253. Even before the advent of the Internet and the wide accessibility to electronic databases for easily available sources of information about FDA-approved uses and indications for drugs-for example
254. see About DailyMed, DAILYMED, http://dailymed. nlm.nih.gov/about.cfm (last visited Feb. 11, 2011), a website maintained by the National Institutes of Health-physicians were able manually to look things up in the ubiquitous PDR, available in hospitals, libraries, and most doctors' offices (often a "gift" from drug detail men). Today, one can quickly research the quality of data for a particular drug using any one of a number of different sources.
255. An even more exacting form of regulation would be to restrict the dispensing of drugs to those for which a valid indication exists, even for those patients who are willing and able to pay for them. However, such a move might require amending the FDA's OLU regulations accordingly.
256. This can be published or unpublished. Indeed, some authors have even lauded the importance of anecdotal "evidence" and lamented its decreasing significance.
257. See Jeffrey K. Aronson, Editorial, Anecdotes as Evidence, 326 BRIT. MED. J. 1346, 1346 (2003); (Pubitemid 36751028)
258. Jeffrey K. Aronson & Manfred Hauben, Anecdotes that Provide Definitive Evidence, 333 BRIT. MED. J. 1267, 1268-69 (2006);
259. John F. Butterworth, Editorial, Case Reports: Unstylish but Still Useful Sources of Clinical Information, 34 REGIONAL ANESTHESIA & PAIN MED. 187, 187-88 (2009);
260. Anne-Michelle Ruha, Editorial, The Case Report: A Tool for the Toxicologist, 5 J. MED. TOXICOLOGY 1, 1-2 (2009);
261. Bill Winett, Letter to the Editor, There Is Value in Anecdotal Reports of Relief from Migraine with Botulinum Toxin, 15 J. MANAGED CARE PHARMACY 78, 78 (2009).
262. See supra note 44 and accompanying text (explaining the basis for this refrain);
263. infra note 132 and accompanying text (noting the limited contexts in which the federal government has affirmatively regulated medical practice).
264. See supra notes 42-44 and accompanying text (summarizing the FDA's jurisdiction).
265. But see Kessler, supra note 7, at 698 (arguing otherwise).
266. See Christopher, supra note 5, at 247.
267. See, e.g., Am. Soc'y of Clinical Oncology, Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications, 24 J. CLINICAL ONCOLOGY 3206, 3206-07 (2006);
268. Joshua Cohen et al., Off-Label Use Reimbursement, 64 FOOD & DRUG L. J. 391, 391-403 (2009);
269. Darren A. DeWalt et al., Significance of Medicare and Medicaid Programs for the Practice of Medicine, 27 HEALTH CARE FINANCING REV. 79, 79-90 (2005);
270. Su-Ying Liang et al., Letter to the Editor, Medicare Formulary Coverage for Top-Selling Biologics, 27 NATURE BIOTECHNOLOGY 1082, 1082-84 (2009).
271. Physicians' prescribing practices are already federally regulated when the drugs at issue fall within the Drug Enforcement Agency's jurisdiction.
272. See Controlled Substances Act, 21 U. S. C. §§ 801-904 (2006). Registration is required for a physician to prescribe controlled substances, and that registration is contingent on following DEA regulatory provisions.
273. See id. § 823 (f).
274. See supra notes 6, 34-36, 43-45 and accompanying text (discussing the FDA's related jurisdiction).
275. See, e.g., N. C. GEN. STAT. § 90-5.1 (2009) (empowering and requiring the board to, for example, "[d]evelop and implement methods to identify... physicians who fail to meet acceptable standards of care" and to "[d]evelop and implement methods to ensure the ongoing competence of" licensed physicians).
276. See supra Part I. B. I,.3 (discussing the current role and limitations of the states' medical licensing boards).
277. See supra Part I. B.2 (describing this case law).
278. See, e.g., Am. Soc'y of Clinical Oncology, supra note 131, at 3206-07;
279. Joëlle Y. Friedman et al., The Medicare Modernization Act and Reimbursement for Outpatient Chemotherapy, 110 CANCER 2304, 2310-12 (2007) (noting concern of commentators that Medicare patients' access to care would suffer as a result of the Medicare Modernization Act, but finding no empirical support that the Act negatively affected patients);
280. Tillman et al., supra note 96, at 348-50.
281. See supra note 8 and accompanying text.
282. See supra notes 9-10 and accompanying text.