FDA, off-label use, and informed consent: Debunking myths and misconceptions

Food and Drug Law Journal

Volumn 53, Issue 1, 1998, Pages 71-104

  Beck, James M ^a   Azari, Elizabeth D ^a  

^a Pepper Hamilton LLP   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FENFLURAMINE; PHENTERMINE;

DEVICE; DRUG APPROVAL; DRUG INDICATION; DRUG LABELING; FOOD AND DRUG ADMINISTRATION; INFORMED CONSENT; MARKETING; PHYSICIAN; REVIEW;

EID: 0031923812     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (267)

1. See, e.g., Laura Johannes & Steve Stecklow, Withdrawal of Redux Spotlights Predicament FDA Faces on Obesity, WALL ST. J., Sept. 16, 1997, at A1 (discussing recall of fenfluramine and dexfenfluramine after reports of incidents of heart valve damage).
2. "Off-label" has more accurately been termed "extra label" use. It means only that a product is used for a condition or in a way not appearing on its FDA-regulated labeling, not that the agency has judged the use adversely. See, e.g., Washington Legal Found, v. Kessler, 880 F. Supp. 26, 28 n.1 (D.D.C. 1995). See infra text accompanying notes 103-107. Off-label can mean many things. "[U]sing an approved drug to treat a disease that is not indicated on its label, but is closely related to an indicated disease, treating unrelated, unindicated diseases, and treating the indicated disease but varying from the indicated dosage, regimen, or patient population may all be considered off-label use." William L. Christopher, Off-Label Drug Prescription: Filling the Regulatory Vacuum, 48 FOOD & DRUG L.J. 247, 248 (1993) (footnotes omitted).
3. Johannes & Stecklow, supra note 1.
4. Health Advisory on Fenfluramine/Phentermine for Obesity, FDA Press Release (July 8, 1997) [hereinafter Health Advisory on Fen/Phen].
5. FDA Announces Withdrawal of Fenfluramine and Dexfenfluramine, FDA Press Release (Sept. 15, 1997) [hereinafter FDA Withdrawal]. FDA also recalled dexfenfluramine, a "purified version of fenfluramine" that was approved for labeling for long-term use. See id. Stephanie Pearson, Combination, Not Appetite Suppressant, is New - And Much More Potent, ARIZ. REP., July 10, 1997, at HL2.
6. FDA Announces Withdrawal of Fenfluramine and Dexfenfluramine, FDA Press Release (Sept. 15, 1997) [hereinafter FDA Withdrawal]. FDA also recalled dexfenfluramine, a "purified version of fenfluramine" that was approved for labeling for long-term use. See id. Stephanie Pearson, Combination, Not Appetite Suppressant, is New - And Much More Potent, ARIZ. REP., July 10, 1997, at HL2.
7. Examples of off-label uses that have serious medical risks abound. See, e.g., 62 Fed. Reg. 64,080-81 (Dec. 3, 1997).
8. Pub. L. No. 105-115, 111 Stat. 2296 (1997).
9. Pub. L. No. 94-295, 90 Stat. 539 (1976).
10. Pub. L. No. 75-717, 52 Stat. 1040 (1938) (codified as amended 21 U.S.C. §§ 301 et seq. (1994)).
11. 21 U.S.C. §§ 360(k) (section 510(k) of the MDA), 360c(f),(i) (detailing 510(k) criteria); 21 C.F.R. §§ 807.81-807.100 (1997).
12. See Medtronic, Inc. v. Lohr, 518 U.S. 470, _, 116 S. Ct. 2240, 2247 (1996).
13. Id. 13 Pub. L. No. 101-629, 104 Stat. 4511 (1990).
14. See 21 C.F.R. §§ 807.87(e)-(h), 807.92(a)(4)-(6).
15. Indications for use include 1) the medical conditions for which use is indicated; 2) the target population; 3) whether the intended use is curative, palliative, or diagnostic; and 4) special instructions for long-term use. In the indications, FDA may require specific disclaimers of effectiveness for particular medical conditions. See Device Labeling Guidance, FDA Guidance Doc. No. G-91, pt III (May 8, 1991).
16. Safety and effectiveness information includes 1) the population of device users, 2) each medical condition that either the labeling or advertising suggests as a use for the device, 3) relative benefits and risks, and 4) reliability. Id.
17. Contraindications involve all situations in which the risk of a device outweighs any possible benefit. Id. pt. IV.
18. Warnings include all serious adverse reactions, potential safety hazards, and limitations on use, as well as the steps to be taken if such a risk occurs. A warning about an off-label use also may be "appropriate" if FDA considers the use both unproven and associated with a serious risk. Id. pt. V.
19. Precautions mean 1) protective clothing, 2) special laboratory tests, or 3) any other particular procedures needed for the safe and effective use of the device. Id. pt. VI.
20. Adverse reactions include any undesirable effects associated with use of the device, as well as the steps to be taken if such an effect occurs. Id. pt. VIII.
21. The manufacturer must advise of concerns unique to users such as 1) pregnant women, 2) children, or 3) patients with anatomic or physiological limitations. Id. pt VII.
22. For example, prescription device labeling must state its prescription-only status and include "information for use including indications, effects, routes, methods, frequency and duration of administration, and any relevant hazards, contraindications, side effects and precautions" for "all purposes for which it is advertised or represented." Id. pt IX. See 21 C.F.R. §§ 801.109(c), (d), 801.15.
23. 21 U.S.C. § 360e; 21 C.F.R. §§ 814.1-814.84. The premarket approval process often takes much longer than the 510(k) process. See Tim Friend, Divided Over Devices, FDA Rules Force Medical Tests Overseas, USA TODAY, May 10, 1995, at A1 (PMA approval to market shoulder implant already marketed in Europe may take seven years).
24. 21 U.S.C. § 360e(c); 21 C.F.R. § 814.20(b)(3)(i). If the manufacturer has data from only one clinical investigation, the manufacturer must show that one investigation is sufficient to demonstrate the safety and effectiveness of the device. 21 C.F.R. § 814.20(b)(7).
25. 21 C.F.R. § 814.20(b)(3)(iv).
26. Id. § 814.20(b)(4)(v).
27. See supra note 23.
28. 21 U.S.C. § 360j(g); 21 C.F.R. pt. 50; 21 C.F.R. §§ 812.1-812.150.
29. 21 C.F.R. § 812.3(g).
30. Id. § 50.3(c).
31. On the other hand, a device can both be marketed generally pursuant to a pre-existing 510(k) or PMA, while also being the subject of an IDE clinical trial for an additional intended use. Femrite v. Abbott Northwestern Hosp., 568 N.W.2d 535, 541 (Minn. Ct. App. 1997). In this circumstance theuse being investigated by the IDE may be (and often is) simultaneously a popular off-label use. See infra text accompanying notes 69-85.
32. 21 C.F.R. § 50.3(g).
33. Id. § 50.3(d).
34. Id. §§ 50.3(e), 812.110, 812.150.
35. Id. § 50.3(i).
36. Id. § 812; id. pts. 50 ("this part applies to all clinical investigations regulated by the [FDA]"), 56.
37. Id. §§ 812.2(b)(1)(iii), 812.150(b)(8).
38. Id. §§ 50.27, 56.109 (b), (c).
39. Id. §§ 50.25, 812.150(a)(5).
40. An investigator must give a prospective subject "sufficient opportunity to consider whether or not to participate" under circumstances that "minimize the possibility of coercion or undue influence." Id. § 50.20. The information must be in "language understandable to the subject." Id. The informed consent form cannot contain any "exculpatory language" that would "waive any of the subject's legal rights." Id. There is an "emergency" exception that permits the investigator to forego informed consent under dire, life-threatening circumstances. Id. §§ 50.23, 50.24. There also is a limited military exception, id. §§ 50.23, 50.24, that was exercised during the Persian Gulf War. See Nelson Borelli et al., The Nuremberg Code, Informed Consent and Involuntary Treatment, 277 JAMA 712 (1997) (military use without informed consent of investigational drug pyrisdostigmine).
41. 21 C.F.R. § 50.25(a).
42. Id. § 50.25(b).
43. Similar to the 510(k) clearance process, there is an abbreviated application process available for drugs that are identical to certain drugs already marketed. See id. § 314.92. Both medical devices and drugs have compassionate use exemptions for life-threatening illnesses with no other treatments. Id. §§ 312.34, 312.80-312.88, 812.36.
44. Id. §§ 312.1-312.70, 312.110-312.145.
45. Id. §§ 312.53(c)(d) (sponsor's informed consent responsibilities pursuant to part 50), 312.60 (investigator's responsibility to obtain informed consent pursuant to part 50), 312.66 (IRB to act pursuant to part 56). See also id. § 312.88 ("All of the safeguards incorporated within parts 50, 56,312, 314 and 600 . . . apply to drugs covered by this section. This includes the requirements for informed consent . . . and institutional review boards.").
46. See supra note 45.
47. For an analysis of safety to effectiveness ratios, see BARUCH A. BRODY, ETHICAL ISSUES IN DRUG TESTING, APPROVAL, AND PRICING 161-62 (1995).
48. 21 C.F.R. §§ 314.1-314.560.
49. Id. § 314.50(c)(5)(vi)(b)(viii).
50. Id. § 314.50.
51. Id. §§ 201.1-201.320.
52. See David A. Kessler, The Regulation of Investigational Drugs, 420 NEW ENG. J. MED. 281-88 (1989); BRODY, supra note 47, at 161. There are exceptions to the NDA process allowing for expedited approval of investigational drugs for compassionate use. Id. at 174-77.
53. See Health Advisory on Fen/Phen, supra note 4 ("the agency is notifying manufacturers to meet with FDA to discuss possible labeling changes"); FDA Withdrawal, supra note 5 (FDA "has asked the manufacturers to voluntarily withdraw" fenfluramine and dexfenfluramine. "The FDA is not requesting the withdrawal of phentermine.").
54. See Health Advisory on Fen/Phen, supra note 4 ("the agency is notifying manufacturers to meet with FDA to discuss possible labeling changes"); FDA Withdrawal, supra note 5 (FDA "has asked the manufacturers to voluntarily withdraw" fenfluramine and dexfenfluramine. "The FDA is not requesting the withdrawal of phentermine.").
55. See, e.g., Femrite, 568 N.W.2d at 539 n.4; Klein v. Biscup, 673 N.E.2d 225, 231 (Ohio Ct. App.), appeal denied, 667 N.E.2d 987 (Ohio 1996); Piazza v. Myers, 33 Phila. Co. Rptr. 144, 148 (Pa. C.P. Philadelphia Co. 1997); see also In re Orthopedic Bone Screw Products Liability Litigation, MDL No. 1014, 1996 WL 107556, at *3 (E.D. Pa. Mar. 8, 1996) ("the decision whether or not to use a drug for an off-label purpose is a matter of medical judgment, not of regulatory approval") (citation and quotation marks omitted). The FDCA was "not intended as a medical practices act and [did] not interfere with the practice of the healing art." S. REP. No. 361, 74th Cong., 1st Sess. 3 (1935).
56. See, e.g., Rhone-Poulenc Rorer Pharm., Inc. v. Marion Merrell Dow, Inc., 93 F.3d 511, 514 n.3 (8th Cir. 1996); Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1496 (D.C. Cir. 1996); Ortho Pharm. Corp. v. Cosprophar, Inc., 32 F.3d 690, 692 (2d Cir. 1994); Weaver v. Reagen, 886 F.2d 194, 198 (8th Cir. 1989); United States v. An Article of Device . . . Diapulse, 768 F.2d 826, 832 (7th Cir. 1985); Schlessing v. United States, 239 F.2d 885, 886 (9th Cir. 1956); Washington Legal Found, 880 F.Supp. at 28 n.1; United States v. Evers, 453 F. Supp, 1141, 1149-50 (M.D. Ala. 1978), aff'd, 643 F.2d 1043, 1052-53 (5th Cir. 1981); FTC v. Simeon Management Corp., 391 F. Supp. 697, 706 (N.D. Cal. 1975), aff'd, 532 F.2d 708 (9th Cir. 1976); Upjohn Co. v. MacMurdo, 562 So. 2d 680, 683 (FIa. 1990); Jones v. Petland Orlando Store, 622 So. 2d 1114, 1115 (Fla. Dist. Ct. App. 1993); Haynes v. Baton Rouge Gen. Hosp., 298 So. 2d 149, 153 (La. Ct. App. 1974), writ denied, 302 So. 2d 33 (La. 1974); Peter Hutt, Regulation of the Practice of Medicine Under the Pure Food & Drug Laws, 33 ASS'N FOOD & DRUG OFFICIALS Q. BULL. 7-11 (1969).
57. See, e.g., ALA. CODE §§ 27-1-10.1(a), (c) (Supp. 1997) (Alabama); CAL. INS. CODE § 10123.195(a) (West Supp. 1997) (California); CAL. HEALTH & SAFETY CODE § 1367.21 (a) (West Supp. 1997) (California); CONN. GEN. STAT. §§ 38a-492b(a), 38a-518b(a) (1995) (Connecticut); FLA. STAT. ANN. § 627.4239 (West 1996) (Florida); GA. CODE ANN. § 33-53-2 (Michie 1993 & Supp. 1997) (Georgia); 1992 ILL. LAWS 980 §§ 1-2(1992, uncodified) (available on LEXIS, 1992 Ill. ALS 980) (Illinois); 5 ILL. COMP. STAT. § 375/6.4 (West 1993 & Supp. 1597) (Illinois); 215 ILL. COMP. STAT. §§ 5/370r, 125/4-6.3 (West 1993 & Supp. 1997) Illinois); IND. CODE ANN. § 27-8-20-7 (Burns 1993 & Supp. 1997) (Indiana); LA. REV. STAT. ANN. § 22:215.18 (West) (Louisiana); MD. CODE ANN., INS., § 15-804 (1997) (Maryland); MASS. GEN. LAWS ANN. ch. 175 §§ 47K-L, 47O-P; ch. 176A §§ 8N, 8Q; ch. 176G § 4G (West Supp. 1996) (Massachusetts); MICH. COMP. LAWS ANN. §§ 500.3406e, 500.3616a (West 1996) (Michigan); N.C. GEN. STAT. §§ 58-67-78, 58-51-59 (Supp. 1996) (North Carolina); N.D. CENT. CODE § 26.1-36-06.1 (1997) (North Dakota); OHIO REV. CODE ANN. § 1751.66 (Banks-Baldwin 1997) (Ohio); OKLA. STAT. ANN. tit. 63 §§ 1-2604, 1-2605 (West 1996) (Oklahoma); R.I GEN. LAWS §§ 27-55-2, 27-55-3 (1996) (Rhode Island); S.C. CODE ANN. § 38-71-275 (Law. Co-op. 1996) (South Carolina); TENN. CODE ANN. § 56-7-2352 (1997) (Tennessee); UTAH CODE ANN. § 26-18-105(7) (Supp. 1997) (Utah); VA. CODE ANN. § 38.2-3407.5 (Michie 1997) (Virginia).
58. N.J. STAT. ANN. § 26:1A-36.9(c) (West Supp. 1997) (New Jersey).
59. Id. § 26:1 A-36.9(d), (e). "Off-label" use of FDA-approved drugs provides efficacious drugs at a lower cost. To require that all appropriate uses of a drug undergo approval by the FDA may substantially increase the cost of drugs and delay or even deny patients' ability to obtain medically effective treatment. FDA approval for each use would require substantial expenditure and time to undergo the clinical trials necessary to obtain FDA approval. Id. § 26:1A-36.9(g).
60. 12 FDA Drug Bulletin 4-5 (1982) (cited in 59 Fed. Reg. 59,820, 159,821 (Nov. 18, 1994)).
61. Id. 61 59 Fed. Reg. at 59,821. Accord, e.g., 52 Fed. Reg. 8798, 8803 (Mar. 19, 1987) (reaffirming legality of off-label use); 48 Fed. Reg. 26,720, 26,733 (June 9, 1983) (reaffirming legality of off-label use); 40 Fed. Reg. 15,392, 15,393-94 (Apr. 7, 1975) (reaffirming legality of off-label use); 37 Fed. Reg. 16,503, 16,503-04 (Aug. 15, 1972) ("[o]nce [an approved] new drug is in a local pharmacy . . . the physician may, as part of the practice of medicine, lawfully . . . vary the conditions of use from those approved"); FOOD AND DRUG ADMIN., COMPLIANCE PROGRAM GUIDANCE MANUAL No. 7382.900 pt. I, at 7 (1992) ("physicians may use devices for off-label uses (This is considered within the practice of medicine)").
62. FOOD AND DRUG ADMIN., UPDATE ON PEDICLE SCREWS (1993).
63. Attachment to letter from FDA to Hon. Joseph Barton, Chairman, Subcomm. on Oversight and Investigation, House Comm. on Commerce (Apr. 14, 1995) (citations omitted).
64. Id. (citations omitted). More recently, an FDA Deputy Commissioner testified The history of the FDC Act indicates that Congress did not intend FDA to interfere with the practice of medicine. Thus, once a product is approved for marketing for a specific use, FDA generally does not regulate how, or for what uses, physicians prescribe [it]. A licensed physician may prescribe a drug for other uses, or in treatments, regimens, or patient populations, that are not listed in the FDA-approved labeling. Michael Friedman, Deputy Comm'r for Operations, FDA, Prepared Statement Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996) (available in 1996 WL 10830744, at *4). See also William B. Schultz, Deputy Comm'r for Policy, FDA, Prepared Statement before Senate Comm. on Labor and Human Resources, available in S. HRG. 104-445, at 81 (Feb. 22, 1996). Most recently, the FDA stated in a legal brief that "there is a well-established and long-standing FDA policy to refrain from initiating enforcement action against physicians who precribe medical products for unapproved uses." [FDA] Memorandum of Points and Authorities in Opposition to Plaintiff's Motion for Summary Judgment at 13, Washington Legal Found. v. Kessler, C.A. Nu.94-1306-RCL (filed Dec. 24, 1997).
65. Pub. L. No. 105-115, § 214, 111 Stat. at 2348 (codified at 21 U.S.C. § 396 (FDCA § 906)).
66. See, e.g., John Calfee, Free Speech, FDA Regulation, and Market Effects on the Pharmaceutical Industry, in BAD PRESCRIPTION FOR THE FIRST AMENDMENT: FDA CENSORSHIP OF DRUG ADVERTISING AND PROMOTION 64 (R. Kaplar, ed. 1993) (off-label uses "may come to dominate the original uses for which the drug was approved").
67. GENERAL ACCOUNTING OFFICE, REPORT TO THE CHAIRMAN, COMM. ON LABOR AND HUMAN RESOURCES, U.S. SENATE, OFF-LABEL DRUGS: REIMBURSEMENT POLICIES CONSTRAIN PHYSICIANS IN THEIR CHOICE OF CANCER THERAPIES 11 (1991) [hereinafter GAO REPORT]. See also Christopher, supra note 2, at 261 (FDA "could not review drugs in its lengthy testing process at a pace equal to that at which physicians discover beneficial off-label uses").
68. United States v. Algon Chemical, Inc., 879 F.2d 1154, 1163 (3d Cir. 1989) (quoting Chaney v. Heckler, 718 F.2d 1174, 1180 (D.C. Cir. 1983), rev'd on other grounds, 470 U.S. 821 (1985)).
69. On February 26, 1992, then-FDA Deputy Commissioner for Policy, Michael Taylor, stated in a speech to FDLI that off-label uses are "often essential to good medical practice, and in some areas . . . constitute a significant portion of standard therapy." Richard Kaplar, Conclusion: Valuing the Freedom of Speech, in BAD PRESCRIPTION FOR THE FIRST AMENDMENT, supra note 66, at 111.
70. Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations. Before such advances can be added to the approved labeling, however, data substantiating the effectiveness of a new use or regimen must be submitted by the manufacturer to FDA for evaluation. This may take time and, without the initiative of the drug manufacturer whose product is involved, may never occur. For that reason, accepted medical practice often includes drug use that is not reflected in approved drug labeling. FDA DRUG BULLETIN, supra note 59, at 4, 5.
71. See, e.g., Ian Gilron, The Introduction of New Drugs Into Anaesthetic Practice: A Perspective in Pharmaceutical Development and Regulation, 42 CAN. J. ANAESTHESIA 516, 519 (1995) ("[U]napproved drug uses often become the mainstay of clinical practice without being legally approved.") (discussing five major off-label uses in anaesthesia); Kathleen Kerr, New Heart Cases Spur Fen-Phen Label Move, NEWSDAY, Aug. 28, 1997, at A52 ("it is legal and quite common for doctors to prescribe an 'off-label' use of drugs for other than FDA-approved purposes").
72. See, e.g., Ian Gilron, The Introduction of New Drugs Into Anaesthetic Practice: A Perspective in Pharmaceutical Development and Regulation, 42 CAN. J. ANAESTHESIA 516, 519 (1995) ("[U]napproved drug uses often become the mainstay of clinical practice without being legally approved.") (discussing five major off-label uses in anaesthesia); Kathleen Kerr, New Heart Cases Spur Fen-Phen Label Move, NEWSDAY, Aug. 28, 1997, at A52 ("it is legal and quite common for doctors to prescribe an 'off-label' use of drugs for other than FDA-approved purposes").
73. Promotion of Drugs and Medical Devices for Unapproved Uses: Hearing Before the Human Resources and Intergovernmental Relations Subcomm. of the House Comm. on Gov't Operations, 102d Cong., 1st Sess. 103 (1991) (statement of George Lundberg, M.D.).
74. Lars A. Noah, Constraints on Off-Label Uses, 16(2) J. PROD. & TOXICS LIAB. 139, 139 (1994) (footnotes omitted). See Fran Kritz, FDA Seeks to Add Drugs' Uses to Labels, WASH. POST, Mar. 29, 1997, at 11 (citing American Medical Association estimate of 40% to 60%).
75. Lars A. Noah, Constraints on Off-Label Uses, 16(2) J. PROD. & TOXICS LIAB. 139, 139 (1994) (footnotes omitted). See Fran Kritz, FDA Seeks to Add Drugs' Uses to Labels, WASH. POST, Mar. 29, 1997, at 11 (citing American Medical Association estimate of 40% to 60%).
76. "Off-label drug use is common, and even predominant, in the treatment of cancer patients." GAO REPORT, supra note 67, at 40 (conclusions); id. at 13-14 (65% of all anticancer drug use is off-label). Off-label cancer treatments total about $100,000,000 annually. Firms Tread Path to Favorable Off-Label Use Reimbursement, FOOD & DRUG LETTER, June 4, 1993.
77. Gregory Mundy et al., Current Medical Practice & The Food & Drug Administration, 229 JAMA 1744, 1746 (1974) (describing prevalence of off-label use in treating angina and hypertension). The off-label use of beta-blockers following heart attacks has "proved of immense value." FDA Seeking Prioritized List of Off-Label Uses Deemed Most Important by 10 Professional Societies, 5 HEALTH NEWS DAILY 4 (May 6, 1993) (quoting letter from FDA).
78. Gregory Mundy et al., Current Medical Practice & The Food & Drug Administration, 229 JAMA 1744, 1746 (1974) (describing prevalence of off-label use in treating angina and hypertension). The off-label use of beta-blockers following heart attacks has "proved of immense value." FDA Seeking Prioritized List of Off-Label Uses Deemed Most Important by 10 Professional Societies, 5 HEALTH NEWS DAILY 4 (May 6, 1993) (quoting letter from FDA).
79. More than 80% of AIDS patients are treated with at least one drug being prescribed off-label, and more than 40% of all drugs prescribed for AIDS treatment are prescribed off-label, Carol Brosgart et al., Off-Label Use in Human Immunodeficiency Virus Disease, 12 J. ACQUIRED IMMUNE DEFICIENCY SYNDROMES & HUMAN RETROVIROLOGY 56, 57-58 (1996).
80. Some 70% of kidney dialysis patients use their dialysis equipment in an off-label manner. FDA and Dialyzer Makers Spar Over Device Reuse, FOOD & DRUG LETTER, Apr. 8, 1994.
81. F-D-C REP. ("The Pink Sheet"), Dec. 20, 1993, at T&G-4 (describing treatments for osteoporosis as the most commonly mentioned off-label use reported by manufacturers to FDA); Doctor's Page: Antiresorptive Therapy for Men, OSTEOPOROSIS ONLINE FROM SOUTHEAST TEXAS (visited Oct. 1, 1997) ("No drugs are currently approved by the FDA for treatment of men with osteoporosis. However currently available [drugs] are reasonable to consider as off-label therapeutic interventions.").
82. Off-label use of bone screws occurs "in a large portion of the 30,000 to 70,000 spinal stabilization procedures performed annually." Pedicle Screws, 21 FDA MED. BULL. 10 (1994), See, e.g., AMERICAN ACADEMY OF ORTHOPEDIC SURGEONS, POSITION PAPER (Oct 27, 1993) ("surgery utilizing pedicle screws represents the best available treatment for patients").
83. Off-label use of bone screws occurs "in a large portion of the 30,000 to 70,000 spinal stabilization procedures performed annually." Pedicle Screws, 21 FDA MED. BULL. 10 (1994), See, e.g., AMERICAN ACADEMY OF ORTHOPEDIC SURGEONS, POSITION PAPER (Oct 27, 1993) ("surgery utilizing pedicle screws represents the best available treatment for patients").
84. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
85. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
86. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
87. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
88. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
89. Most diseases afflicting fewer than 200,000 Americans are "totally without" FDA-labeled treatment. Some "90 percent of [patients] must rely on 'off-label' uses" to have any treatment at all. Abbey S. Meyers, Pres., National Org. for Rare Diseases, Inc., Prepared Testimony Before Subcomm. on Human Resources and Intergovernmental Relations of the House Comm. on Gov't Reform and Oversight (Sept. 12, 1996). For a general discussion of other off-label uses, see Katie Rodgers, Dealing with Incontinence, 140 DRUG TOPICS 114 (1996) (six of seven treatments for urinary incontinence in guidelines of Agency for Health Care Policy & Research are off-label uses); Doug Podolsky, Doing Double Duty, U.S. NEWS & WORLD REP., June 26, 1995, at 62-63 (listing six common off-label uses of drugs); Richard Palmer & Shanthi Gaur, Off-Label Use of Prescription Drugs & Devices, RX FOR DEF., Spring 1995, at 4, 5 (listing five common off-label uses of drugs and three common off-label uses of medical devices); Ricahrd Samp & Alan Slobodin, FDA Censorship Threatens Patient Medical Care, 77 CONSUMER'S RES. MAG. 16 (1994) (listing "medically accepted" off-label uses for 28 common drugs); Some Drugs' Unapproved Uses Bring Results, CHARLESTON GAZETTE, Oct 31, 1994, at 3B (listing 10 "double-duty drugs" with common off-label uses); S. Carrell, Unapproved Uses for Drugs Decrease with Time on Market, 137 DRUG TOPICS 44 (1993) (looking at the 22 most-prescribed drugs in 1989, off-label prescriptions totaled more than 50% for 6 drugs and more than 20% for 11 drugs); Cosprophar, 32 F.3d at 692 (45% of sales of Retin-A, a drug approved for acne, are for off-label treatment of aged skin).
90. "[O]ver 80% of all drugs prescribed for children carry . . . orphaning clauses in their package labels," ROBERT LEVINE, ETHICS AND REGULATION OF CLINICAL RESEARCH 241 (2d ed. 1986). "Orphaning clauses" are disclaimers with respect to pediatric use that FDA requires because of the paucity of clinical studies involving children. Id. at 239.
91. Kritz, supra note 73 (quoting American Medical Association vice-president).
92. Ronald Munson, Intervention and Reflection: Basic Issues in Medical Ethics, in MEDICAL EXPERIMENTATION & INFORMED CONSENT 324 (4th ed. 1992). The two concepts were defined and contrasted in Robert Levine's work. The term "research" refers to a class of activities designed to develop or contribute to generalizable knowledge. Generalizable knowledge consists of theories, principles or relationships (or the accumulation of data on which they may be based) that can be corroborated by accepted scientific observation and inference, The "practice" of medicine . . . refers to a class of activities designed solely to enhance the well-being of an individual patient or client. The purpose of medical . . . practice is to provide diagnosis, preventive treatment, or therapy. The customary standard for routine and accepted practice is a reasonable expectation of success. The absence of validation or precision on which to base such an expectation, however, does not in and of itself define the activity in question as research. Uncertainty is inherent in therapeutic practice because of the variability of the physiological and behavioral responses of humans. This kind of uncertainty is, itself, routine and accepted. LEVINE, supra note 81, at 3. See also George J. Annas, Questing for Holy Grails: Duplicity, Betrayal and Self-Deception in Postmodern Medical Research, 12 J. CONTEMP. HEALTH L. & POL'Y 297, 323 (1996) ("Research is research, designed to test a hypothesis and performed based on the rules of the protocol; treatment is something else, designed to benefit a patient, and subject to change whenever change is seen in the patient's best interest"); TOM BEAUCHAMP & JAMES CHILDRESS, PRINCIPLES OF BIOMEDICAL ETHICS 441 (4th ed. 1994); William F. Rayburn, A Physician's Prerogative to Prescribe Drugs for Off-Label Uses During Pregnancy, 81 J. OBSTETRICS & GYNECOLOGY 1054 (1993) ("[d]eparture from formally approved prescribing standards occurs commonly, and does not, in and of itself, constitute research").
93. Ronald Munson, Intervention and Reflection: Basic Issues in Medical Ethics, in MEDICAL EXPERIMENTATION & INFORMED CONSENT 324 (4th ed. 1992). The two concepts were defined and contrasted in Robert Levine's work. The term "research" refers to a class of activities designed to develop or contribute to generalizable knowledge. Generalizable knowledge consists of theories, principles or relationships (or the accumulation of data on which they may be based) that can be corroborated by accepted scientific observation and inference, The "practice" of medicine . . . refers to a class of activities designed solely to enhance the well-being of an individual patient or client. The purpose of medical . . . practice is to provide diagnosis, preventive treatment, or therapy. The customary standard for routine and accepted practice is a reasonable expectation of success. The absence of validation or precision on which to base such an expectation, however, does not in and of itself define the activity in question as research. Uncertainty is inherent in therapeutic practice because of the variability of the physiological and behavioral responses of humans. This kind of uncertainty is, itself, routine and accepted. LEVINE, supra note 81, at 3. See also George J. Annas, Questing for Holy Grails: Duplicity, Betrayal and Self-Deception in Postmodern Medical Research, 12 J. CONTEMP. HEALTH L. & POL'Y 297, 323 (1996) ("Research is research, designed to test a hypothesis and performed based on the rules of the protocol; treatment is something else, designed to benefit a patient, and subject to change whenever change is seen in the patient's best interest"); TOM BEAUCHAMP & JAMES CHILDRESS, PRINCIPLES OF BIOMEDICAL ETHICS 441 (4th ed. 1994); William F. Rayburn, A Physician's Prerogative to Prescribe Drugs for Off-Label Uses During Pregnancy, 81 J. OBSTETRICS & GYNECOLOGY 1054 (1993) ("[d]eparture from formally approved prescribing standards occurs commonly, and does not, in and of itself, constitute research").
94. Ronald Munson, Intervention and Reflection: Basic Issues in Medical Ethics, in MEDICAL EXPERIMENTATION & INFORMED CONSENT 324 (4th ed. 1992). The two concepts were defined and contrasted in Robert Levine's work. The term "research" refers to a class of activities designed to develop or contribute to generalizable knowledge. Generalizable knowledge consists of theories, principles or relationships (or the accumulation of data on which they may be based) that can be corroborated by accepted scientific observation and inference, The "practice" of medicine . . . refers to a class of activities designed solely to enhance the well-being of an individual patient or client. The purpose of medical . . . practice is to provide diagnosis, preventive treatment, or therapy. The customary standard for routine and accepted practice is a reasonable expectation of success. The absence of validation or precision on which to base such an expectation, however, does not in and of itself define the activity in question as research. Uncertainty is inherent in therapeutic practice because of the variability of the physiological and behavioral responses of humans. This kind of uncertainty is, itself, routine and accepted. LEVINE, supra note 81, at 3. See also George J. Annas, Questing for Holy Grails: Duplicity, Betrayal and Self-Deception in Postmodern Medical Research, 12 J. CONTEMP. HEALTH L. & POL'Y 297, 323 (1996) ("Research is research, designed to test a hypothesis and performed based on the rules of the protocol; treatment is something else, designed to benefit a patient, and subject to change whenever change is seen in the patient's best interest"); TOM BEAUCHAMP & JAMES CHILDRESS, PRINCIPLES OF BIOMEDICAL ETHICS 441 (4th ed. 1994); William F. Rayburn, A Physician's Prerogative to Prescribe Drugs for Off-Label Uses During Pregnancy, 81 J. OBSTETRICS & GYNECOLOGY 1054 (1993) ("[d]eparture from formally approved prescribing standards occurs commonly, and does not, in and of itself, constitute research").
95. Ronald Munson, Intervention and Reflection: Basic Issues in Medical Ethics, in MEDICAL EXPERIMENTATION & INFORMED CONSENT 324 (4th ed. 1992). The two concepts were defined and contrasted in Robert Levine's work. The term "research" refers to a class of activities designed to develop or contribute to generalizable knowledge. Generalizable knowledge consists of theories, principles or relationships (or the accumulation of data on which they may be based) that can be corroborated by accepted scientific observation and inference, The "practice" of medicine . . . refers to a class of activities designed solely to enhance the well-being of an individual patient or client. The purpose of medical . . . practice is to provide diagnosis, preventive treatment, or therapy. The customary standard for routine and accepted practice is a reasonable expectation of success. The absence of validation or precision on which to base such an expectation, however, does not in and of itself define the activity in question as research. Uncertainty is inherent in therapeutic practice because of the variability of the physiological and behavioral responses of humans. This kind of uncertainty is, itself, routine and accepted. LEVINE, supra note 81, at 3. See also George J. Annas, Questing for Holy Grails: Duplicity, Betrayal and Self-Deception in Postmodern Medical Research, 12 J. CONTEMP. HEALTH L. & POL'Y 297, 323 (1996) ("Research is research, designed to test a hypothesis and performed based on the rules of the protocol; treatment is something else, designed to benefit a patient, and subject to change whenever change is seen in the patient's best interest"); TOM BEAUCHAMP & JAMES CHILDRESS, PRINCIPLES OF BIOMEDICAL ETHICS 441 (4th ed. 1994); William F. Rayburn, A Physician's Prerogative to Prescribe Drugs for Off-Label Uses During Pregnancy, 81 J. OBSTETRICS & GYNECOLOGY 1054 (1993) ("[d]eparture from formally approved prescribing standards occurs commonly, and does not, in and of itself, constitute research").
96. AMERICAN COLLEGE OF PHYSICIANS, ETHICS MANUAL 959 (3d ed. 1992) (reprinted from 117 ANNALS INTERNAL MED. 97 (1992)).
97. AMERICAN COLLEGE OF PHYSICIANS, ETHICS MANUAL 959 (3d ed. 1992) (reprinted from 117 ANNALS INTERNAL MED. 97 (1992)).
98. NATIONAL COMM'N FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH, BELMONT REPORT 2-3 (1978). See also Kathryn Tuthill, Human Experimentation: Protecting Patient Autonomy Through Informed Consent, 18 J. LEGAL MED. 221, 222-24 (1997) (applying Belmont Report standard). Federal regulations define "research" as "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." 45 C.F.R. § 46.102(d) (1997). Subpart A of chapter 45 is the "Basic HHS Policy for Protection of Human Research Subjects" and it "applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any federal department or agency. " Id. § 46.101(a).
99. NATIONAL COMM'N FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH, BELMONT REPORT 2-3 (1978). See also Kathryn Tuthill, Human Experimentation: Protecting Patient Autonomy Through Informed Consent, 18 J. LEGAL MED. 221, 222-24 (1997) (applying Belmont Report standard). Federal regulations define "research" as "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." 45 C.F.R. § 46.102(d) (1997). Subpart A of chapter 45 is the "Basic HHS Policy for Protection of Human Research Subjects" and it "applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any federal department or agency. " Id. § 46.101(a).
100. "Experimental" is defined at title 21 of the Code of Federal Regulations section 312.3(b) (discussing clinical investigation) and section 50.3(c) (discussing IND informed consent); the term "investigational" is defined at section 812.3(b) (IDE devices). IDE devices are not necessarily (or even usually) experimental. FDA categorizes IDE devices as either experimental or nonexperimental investigational; the nonexperimental category of IDE devices are those that FDA "believe[s] to be in Class I or Class II, or a device believed to be in Class III for which . . . underlying questions of safety and effectiveness . . . have been resolved." 61 Fed. Reg, 7011, 7011-12 (Feb. 23, 1996). Medical treatment using nonexperimental IDE devices is reimbursed by Medicare. Id.; see 42 C.F.R § 405.205 (1997).
101. Pirozzi v. Blue Cross-Blue Shield, 741 F. Supp. 586, 590 (E.D. Va. 1990) (quotation marks omitted). See also Weaver, 886 F.2d at 198 (experimental treatment is "not generally accepted by the professional medical community as an effective and proven treatment for the condition" or is "rarely used, novel or relatively unknown").
102. LEVINE, supra note 81.
103. Even in the less demanding 510(k) notification process, detailed information is required of the manufacturer and is considered by FDA. See supra text accompanying notes 8-22.
104. FOOD AND DRUG ADMIN., INVESTIGATIONAL USE OF MARKETED PRODUCTS (1989). "[I]t is not the agency's [FDA's] policy, intent, or bias to indicate that off-label uses are wrong, improper or even investigational." GAO REPORT, supra note 67, at 11. Cf. Duvall v. Bristol-Myers-Squibb Co., 103 F.3d 324, 330 (4th Cir. 1996) (IDE regulations applly only to devices actually used in the IDE).
105. FOOD AND DRUG ADMIN., INVESTIGATIONAL USE OF MARKETED PRODUCTS (1989). "[I]t is not the agency's [FDA's] policy, intent, or bias to indicate that off-label uses are wrong, improper or even investigational." GAO REPORT, supra note 67, at 11. Cf. Duvall v. Bristol-Myers-Squibb Co., 103 F.3d 324, 330 (4th Cir. 1996) (IDE regulations applly only to devices actually used in the IDE).
106. 21 C.F.R. § 312.2(d).
107. Ramon v. Farr, 770 P.2d 131, 135 (Utah 1989) (emphasis original) (quoting Salgo v. Leland Stanford, Jr. University Board of Trustees, 317 P.2d 170, 180 (Cal. Ct. App. 1957)), See Weaver, 886 F.2d at 198-99 (rejecting as "overly broad" a claim that all drug use "outside the FDA approved indications is perse 'experimental'"); Doe v. Sullivan, 756 F. Supp. 12, 15-16 (D.D.C.) ("[U]se of unapproved drugs does not involve the type of scientific investigation under controlled circumstances that "research" connotes . . . . The FDA, therefore, does not view every use of unapproved drugs as research.") (citation omitted), aff'd, 938 F.2d 1370 (D.C. Cir. 1991); Simeon Management Corp., 391 F. Supp. at 706; Femrite, 568 N.W.2d at 540-41 (patient treated off-label with same device in same way as in an IDE was not subjected to "experimental research" or "investigational study"); Wyttenhove v. Fairview Hosp. & Healthcare Serv., No. MP 95-14941 (Minn. Dist. Hennepin Co. Sept. 24, 1996) (off-label use held not to be "experimental"), aff'd mem., No. C3-97-51, 1997 WL 585813 (Minn. App. Sept 23, 1997).
108. FDA regulatory status is not a "risk" of surgery. Klein, 673 N.E.2d at 231.
109. See generally 21 C.F.R §§ 312.34 (providing for use of investigational drugs as treatment outside of IND), 314.70-314.71 (procedures for changing approved applications of drugs), pt 860, subpt. C (procedures for reclassification of medical devices).
110. Tracey v. Merrell Dow Pharmaceuticals, 569 N.E.2d 875, 880 (Ohio 1991). The same is true for medical devices. See Orthopedic Bone Screw, 1996 WL 107556, at *3 ("FDA labels given to a medical device do not speak directly to the medical issues surrounding a particular surgery. They are not, therefore, required to be disclosed pursuant to the law of informed consent").
111. This description formerly might violate even FDA regulations. For example, 510(k) medical devices are not "approved" at all, and their manufacturers are forbidden from claiming that they are. 21 C.F.R. § 807.97. This regulation is now questionable, however, because its statutory basis, 21 U.S.C. § 331(1); was repealed by section 421 of the FDAMA. Pub. L. No. 105-115, § 421, 111 Stat. at 2380.
112. "Off-label drug use by oncologists is quite common" but people "mistakenly equate[] the off-label categorization of these uses . . . with lack of evidence of effectiveness." Letter to the Editor, 267 JAMA 2473-74 (1992). A recent notable example of a court falling into precisely this error is Proctor v. Davis, 682 N.E.2d 1203, 1213 (Ill. App. 1997), in which the court repeatedly refers to off-label use as "unauthorized" by FDA, when, as previously discussed, the agency lacks and has disclaimed any power to allow or disallow off-label use.
113. See 21 U.S.C. § 360e(d) (FDA "shall rely on the conditions of use included in the proposed labeling as the basis for determining whether or not there is a reasonable assurance of safety and effectiveness" for purpose of PMAs); 21 C.F.R. §§ 314.50(a)(1) (proposed indications to be stated in IND), 314.54 (amending INDs to add indications), 807.100(b)(1) (FDA action based upon intended use in premarket notification), 807.92(a)(5) (describing required manufacturer statement of intended use).
114. This appears to be the situation in the Proctor case. In Proctor, no application was filed with FDA concerning the off-label use at issue. 682 N.E.2d at 1209-10. Indeed, FDA refused the manufacturer's request to add adverse reactions relating to that precise off-label use to its labeling shortly before the incident at suit. Id. at 1210. For unexplained reasons the manufacturer's request, and FDA's refusal of it, were excluded from evidence in Proctor, id., and the court took the position that the manufacturer was liable for not including in its labeling the information that FDA had refused to allow. Id. at 1214.
115. See Guidance on the Center for Devices and Radiological Health's Premarket Notification Review Program, FDA Guidance Doc. No. K86-3, at 7 (June 30, 1986) ("if a device has a different intended use, there is no reason to proceed further to decide whether the devices are substantially equivalent"). The FDAMA recently gave FDA the right, for a five-year trial period, to consider off-label uses in its 510(k) review process and to require appropriate labeling changes. Pub. L. No. 105-115, § 205(b), 111 Stat. at 2337-38 (codified at 21 U.S.C. § 360c(i)(1)(E)).
116. See S. REP. No. 105-43, 105th Cong., 1st Sess. 27 (1997).
117. See infra text accompanying notes 228-231.
118. The reason for the omission of a use from FDA-regulated labeling could be any of the following: 1) FDA lacked sufficient information to make an affirmative finding of safety or effectiveness; 2) the manufacturer never submitted an application concerning the use to FDA; or 3) in the case of a device, FDA lacked evidence of a substantially equivalent predicate (pre-1976) device.
119. See supra text accompanying notes 89-102.
120. See supra note 2. FDA's webpage includes a description of "off-label" as "use for indication, dosage form, dose regimen, population or other use parameter not mentioned in the approved labeling." Janet "Woodcock, Shift in Regulatory Approach, FDA slide presentation at DIA Montreal 3 (June 23, 1997), available in
121. GAO REPORT, supra note 67, at 11.
122. Senator Frist, a physician, asked Now what does off-label mean? Off-label scares people. Is somebody going in some secret closet and pulling out a medicine and using it? No . . . that is why "extra label" is probably a better term. But right now off-label is something that we in the medical profession understand is used routinely . . . probably 50 percent of all pediatric drugs prescribed are off-label. So it is not a term to be scared of or to fear. 143 CONG. REC. S8165 (daily ed. July 28, 1997).
123. The legal and ethical distinctions between "research" and "therapy" made in the Belmont Report were recognized by FDA when it promulgated title 21 of the Code of Federal Regulations part 50. See 44 Fed. Reg. 47,713 ,47,716 (Aug. 14, 1979) (referencing Belmont Report and other Commission reports).
124. 21 C.F.R. pt 50.
125. See supra text accompanying notes 26-32, 41-42.
126. The "intent" language of section 50.3(c) "is intended solely as a shorthand way of referring to at least 22 separate categories of information that are now, or in the near future will become, subject to requirements for submission to the agency." 44 Fed. Reg. at 47,719.
127. The FDCA contains no provisions that can force physicians or hospitals to participate in an IDE or IND clinical trial against their will. See 21 C.F.R. §§ 56.109(a), 312.66, 812.42 (no investigation may begin unless the investigational plan has been approved by an IRB). Cf. Friter v. Iolab Corp., 607 A.2d 1111, 1115 (Pa. Super. Ct. 1992) (hospital had informed consent liability going beyond common-law duties only when it voluntarily assumed IDE obligations); Kus v. Sherman Hosp., 644 N.E.2d 1214, 1221 (Ill. App. Ct. 1995) (same), appeal denied, 652 N.E.2d 343 (Ill. 1995).
128. See text accompanying notes 39-42, 45-46.
129. 21 C.F.R. §§ 312.53(c), 812.43(c).
130. Physicians who perform a medical procedure within the context of a clinical investigation are required, per FDA clinical investi gation regulations, to inform the patient-participant of the investigational nature of the medical device. They are required to give the patient-participants such information not because state informed consent law mandates it, but rather in return for the benefit of engaging in a research project that has received the FDA's "stamp" of approval. Orthopedic Bone Screw, 1996 WL 107556, at *4.
131. See id.
132. See, e.g., id. (discussing Friter, 607 A.2d at 1111).
133. Pub. L. No..105-115, § 214, 111 Stat. at 2348 (codified at 21 U.S.C § 396 (FDCA § 906)).
134. See infra text accompanying notes 128-130.
135. Id.
136. Arato v. Avedon, 858 P.2d 598, 609 (Cal. 1993).
137. "The fact that a physician has 'fiducial' obligations ... does not mean that he or she is under a duty, the scope of which is undefined, to disclose every contingency that might affect the patient's nonmedical 'rights and interest."' Arato, '858 P.2d at 608-09 (citation and footnote omitted) (emphasis original).
138. 742 P.2d 1126 (Okla. 1987).
139. Id. at 1129.
140. Id.
141. Aceto v. Dougherty, 615 N.E.2d 188, 191 (Mass. 1993), Likewise, although a patient may want to know how his or her physician performed in a particular medical school class, and might consider it material to a decision to pursue treatment, that information is not material to any particular medical risk.
142. Klein, 673 N.E.2d at 231.
143. Reed v. Campagnolo, 630 A.2d 1145, 1146 (Md. 1993). See, e.g., Reidisser v. Kelson, 534 P.2d 1052, 1054 (Ariz. 1975) ("all the reasonable and recognized risks" of treatment, as well as "the nature of the surgical procedure attempted and the probable results") (citation and quotation marks omitted); Canterbury v. Spence, 464 F.2d 772, 787-88 (D.C. Cir.) ("hazards of the proposed treatment," "alternatives," and likely results of nontreatment), cert. denied, 409 U.S. 1064 (1972); Zalazar v. Vercimak, 633 N.E.2d 1223, 1226 (Ill. App. Ct. 1993) ("risks of surgery," "foreseeable results," and "reasonable alternatives"); Palmer v. Biloxi Reg'l Med. Ctr., 564 So. 2d 1346, 1363 (Miss. 1990) ("diagnosis," "nature and purpose of the treatment," "risks and consequences," "probable success," "alternatives," and "prognosis if the treatment is not administered"); Harrell v. Wirt, 755 S.W.2d 296, 299 (Mo. Ct. App. 1988) ("specific risks" and "the existence and feasibility of specific possible alternatives"); Largey v. Rothman, 540 A.2d 504, 506 (N.J. 1988) ("nature of treatment," "substantial risks," and "alternative therapies"); Petriello v. Kalman, 576 A.2d 474, 478 (Conn. 1990) ("nature of the procedure," "risks," "hazards," "alternatives," and "anticipated benefits"); Miller v. Rhode Island Hosp., 625 A.2d 778, 783 (R.I. 1993) ("what [is] to be done, the risk involved and the alternatives to the contemplated treatment") (citation and quotation marks omitted); Hook v. Rothstein, 316 S.E.2d 690, 694-95 (S.C. Ct. App.) ("diagnosis," "general nature of the contemplated procedure," "material risks," "probability of success," prognosis" if untreated, and "existence of any alternatives"), cert. denied, 320 S.E.2d 35 (S.C. 1984); Rizzo v. Schiller, 445 S.E.2d 153, 155 (Va. 1994) ("specific procedures," "foreseeable risks," and "risks of non-treatment").
144. See Nickell v. Gonzalez, 477 N.E.2d 1145, 1148 (Ohio 1985) ("fail[ure] to disclose to the patient and discuss the material risks and dangers inherently and potentially involved with respect to the proposed therapy"). See also Craig v. Borcicky, 557 So. 2d 1253, 1258 (Ala. 1990) ("the significant perils involved in the procedure") (quotation marks omitted); Kerr v. Carlos, 582 N.E.2d 860, 864 (Ind. Ct. App. 1991) ("inherent risks of the proposed treatment"); Kennis v. Mercy Hosp. Med. Ctr., 491 N.W.2d 161, 166 (Iowa 1992) ("material risks"); Cornfeldt v. Tongen, 262 N.W.2d 684, 699-701 (Minn. 1977) (recognizing informed consent as a claim for "negligent nondisclosure" of a "risk").
145. See ALASKA STAT. § 9.55.556 (Michie 1996) ("common risks and reasonable alternatives to the proposed treatment or procedure"); ARK. CODE ANN. § 16-114-206(b) (Michie 1987) ("risks or hazards inherent in such treatment"); DEL. CODE ANN. tit. 18, § 6852 (1997) ("risks of the treatment, procedure or surgery"); FLA. STAT. ANN. § 766.103(3)(a) (West Supp. 1996) ("the medically acceptable alternative procedures or treatments, and the substantial risks and hazards inherent in the proposed treatments or procedures"); GA. CODE ANN. § 31-9-6(d) (1991) ("in general terms [of] the treatment or course of treatment"); HAW. REV. STAT. § 671-3(b) (1985) ("[t]he condition being treated," "[t]he nature and character of the proposed treatment," "anticipated results," "recognized possible alternative forms of treatment," and "recognized serious possible risks, complications, and anticipated benefits involved in the treatment or surgical procedure, and in the recognized possible alternative[s]"); IDAHO CODE § 39-4304 (1993) ("the need for, the nature of and the significant risks ordinarily attendant"); 20 ILL. COMP. STAT. ANN. 301/30-5(p) (West 1997) ("complete and current information concerning the nature of care, procedures, and treatment"); IND. CODE § 27-12-3 (1996) ("general nature of ... condition," "proposed treatment," "expected outcome," "material risks," and "reasonable alternatives"); IOWA CODE ANN. § 147.137(1) (West 1989) ("in general terms the nature and purpose of the procedure or procedures, together with the known risks ..., with the probability of each such risk if reasonably determinate"); KY. REV. STAT. ANN. § 304.40-320(2) (Michie 1988) ("a general understanding of the procedure," "acceptable alternative procedures," "substantial risks and hazards"); LA. REV. STAT. ANN. § 40:1299.40 (A), (C) (West 1992) ("in general terms the nature and purpose of the procedure or procedures," together with the existence of enumerated "known" risks); ME. REV. STAT. ANN. tit. 24 § 2905(1)(B) (West 1990) ("a general understanding of the procedure[]," "usual and most frequent risks"); MINN. STAT. ANN. § 144.651 (West 1996) ("information concerning ... diagnosis, treatment, alternatives, risks and prognosis"); NEB. REV. STAT. § 44-2816 (1996) ("information ordinarily provided. .. [about] operation, treatment or procedure"); NEV. REV. STAT. § 41A.110 (1995) ("in general terms ... the procedure," "methods of treatment," and the "general nature and extent of risks without enumerating [them]"); N.H. REV. STAT. ANN. §§ 507-E:2(II)(b), 507C.2 (1995) ("risks or hazards inherent in such treatment); N.J. STAT. ANN. § 26:2H-12.8(d) (West 1996) ("the specific procedure or treatment, the medically significant risks involved, and the possible duration of incapacitation," and "any medically significant alternatives"); N.C. GEN. STAT. § 90-21.13(a)(2) (1993) ("a general understanding of the procedure[]," "usual and most frequent risks"); OR. REV. STAT. § 677.097(1) (1994) ("the procedure ... to the undertaken," "alternative procedures," and "risks"); TEX. REV. CIV. STAT. ANN. art. 4590i (Vernon 1995) (such "risks and hazards" as determined by the "Texas Medical Disclosure Panel"); VT. STAT. ANN. tit. 12 § 1909(a)(1) (Supp. 1994) ("alternatives" and "reasonably foreseeable risks and benefits"); WASH. REV. CODE ANN. § 7.70.050(3) (West 1992) (" nature and character of the treatment," anticipated results," "recognized possible alternative[s]" "recognized serious possible risks ... and anticipated benefits"); WIS. STAT. ANN. § 448.30 (West 1988) ("alternate, viable . .. treatment," and "benefits and risks"). Cf. CAL. HEALTH & SAFETY CODE § 24173 (West 1992) (applicable to medical experiments only; does not require disclosure of FDA regulatory status).
146. N.Y. PUB. HEALTH LAW § 2805-d(1) (McKinney 1993). Section 2805-d(1) was held to be "clear and unambiguous" in Tenuto v. Lederle Laboratories, 616 N.Y.S.2d 391, 392 (App. Div. 1994), appeal dismissed, 662 N.E.2d 1073 (N.Y. 1995). The contrary suggestion in Retkwa v. Orentreich, 584 N.Y.S.2d 710, 712 (N.Y. Sup. Ct. 1992), that the statute has "ambiguities" permitting its extension to FDA regulatory status, is thus not well taken.
147. 40 PA. STAT. ANN. § 1301.811-A (Purdon Supp. 1997). Notably, the Pennsylvania statute lists "using an approved medication or device in an experimental manner," as a type of procedure for which informed consent must be obtained, but does not require that any mention be made of regulatory status. Id. 133 As the Pennsylvania statute shows, even the reasonable patient approach limits material information to that concerning medical risks and benefits. See also Canterbury, 464 F.2d at 786-87 ("whether a particular peril must be divulged is its materiality to the patient's decision: all risks potentially affecting the decision must be unmasked").
148. See supra note 130.
149. The recent fenfluramine/dexfenfluramine recall demonstrates that an after-discovered safety issue may be determined later to outweigh the benefit of a particular labeled use. See supra text accompanying notes 1-5.
150. Pub. L. No. 105-115, § 205(a), 111 Stat at 2337 (codified at 21 U.S.C. § 360c(i)(1)(E)(i)). This section applies to 510(k) clearance, and is therefore limited to off-label uses known at the time of initial introduction. It is to be in force for a five-year trial period only. Id. (codified at 21 U.S.C § 360c(i)(1)(E)(iv)). There is no comparable provision for drugs.
151. LEVINE, supra note 81, at 100, See also Shadrick v. Coker, 1997 WL 62615, at *5 (Tenn. Feb. 17, 1998) ("patient must also be informed ... if applicable, that the proposed treatment or procedure is experimental"); Estrada v. Jaques, 321 S.E.2d 240, 253-54 (N.C. Ct. App. 1984) (informed consent required disclosure of experimental nature of procedure when only "one article and one [previous] operation" involved the procedure); Gaston v. Hunter, 588 P.2d 326, 350-51 (Ariz. Ct. App. 1978) (while the novelty of drug therapy must be explained to patient, FDA regulatory status was properly exclude.
152. See supra text accompanying notes 71-81 (discussing conditions for which the standard treatments are actually off-label uses).
153. 588 P.2d at 335. In Retkwa v. Orentreich, 584 N.Y.S.2d at 710, a New York county court ostensibly relied on Gaston, but allowed what Gaston had expressly prohibited - evidence of FDA regulatory status in an informed consent case. Id at 712-13. Retkwa found no other precedent for its admittedly "novel" ruling. Id. The medical use in Retkwa apparently was truly unproven, because FDA never had allowed the liquid silicone involved to be marketed for any purpose whatsoever. Id. at 710 n.1.
154. 682 N.E.2d 1203 (Ill. App. Ct. 1997).
155. Id. at 1213.
156. Id. at 1207-09.
157. See id. at 1207 n.1 (noting treating physician's testimony that "the technique of periocular injection was widely used ... an estimated one million times each year"). The dissent discussed at length the literature addressing the relevant risks that had appeared prior to the incident at suit Id. at 1219.
158. The Proctor case has a remarkable procedural history, and the result was dependent on a change in the composition of the panel See Proctor v. Davis, 656 N.E.2d 23 (Ill. App. Ct. 1995) (authors of majority and dissenting opinions), invalidated by 677 N.E.2d 918 (Ill. 1997). The tenor of the most recent Proctor opinions suggests to the authors that, over the course of this long appellate history, the court may have lost its ordinary sense of judicial detachment.
159. Cobbs v. Grant, 502 P.2d I, 11 (Cal. 1972).
160. Hondroulis v. Schuhmacher, 553 So. 2d 398, 418-19 (La. 1988). A "detailed technical medical explanation" is not necessary. McGeshick v. Choucair, 9 F.3d 1229, 1233 (7th Cir. 1993), cert. denied, 116 S. Ct. 1834 (1996) (citation and quotation marks omitted). Thus, "[t]his doctrine has not emerged to educate the patient generally on medical matters." Turner v. Children's Hosp., Inc., 602 N.E.2d 423, 431 (Ohio Ct. App. 1991), motion overruled, 590 N.E.2d 1268 (Ohio 1992). "A mini-course in medical science is not required; the patient is concerned with the risk of death or bodily harm, and problems of recuperation." Cobbs, 502 P.2d at 11.
161. Ritz v. Florida Patient's Compensation Fund, 436 So. 2d 987, 992 (Fla. Dist Ct. App. 1983) (citation and quotation marks omitted), appeal denied, 450 So. 2d 488 (Fla. 1984).
162. Christopher, supra note 2, at 255.
163. See, e.g., Sinclair v. Block, 633 A.2d 1137, 1140 (Pa. 1993) (citation and quotation marks omitted) (emphasis in original); Gouse v. Cassel, 615 A.2d 331, 334 (Pa. 1992).
164. 40 PA. STAT. ANN. § 1301.811-A.
165. Festa v. Greenberg, 511 A.2d 1371, 1373 (Pa. Super. Ct. 1986), appeal denied, 527 A.2d 541 (Pa. 1987) See also Gray v. Grunnagle, 223 A.2d 663, 674 (Pa. 1966) ("informed" consent includes "the nature of the operation to be performed, the seriousness of it, the organs of the body involved, the disease or incapacity sought to be cured, [or] the possible results" of surgery) (citation and quotation marks omitted); Neal v. Lu, 530 A.2d 103, 111 (Pa. Super. Ct. 1987) (physicians must disclose "any risk in the recommended treatment, or the existence of any alternative method of treatment, that a reasonable person would deem material in deciding whether to undergo[] treatment") (citation omitted).
166. Gouse, 615 A.2d at 334.
167. 194 A.2d 167 (Pa. 1963).
168. Id. at 175 (quoting trial court).
169. Id. See Gouse, 615 A.2d at 334 (quoting and following Smith v. Yohe formulation of informed consent doctrine); Moure v. Raeuchle, 604 A.2d 1003, 1008 (Pa. 1992) (same).
170. 423 F.2d 940, 946 (3d Cir. 1970).
171. Id. at 946.
172. 612 A.2d 493 (Pa. Super Ct. 1992), appeal denied, 629 A.2d 1380 (Pa. 1993).
173. Id. at 496 (affirming summary judgment). Dible thus contrasts with Stover v. Association of Thoracic & Cardiovascular Surgeons, 635 A.2d 1047 (Pa. Super. Ct. 1993). In Stover, the court held that a surgeon discussing heart valve replacement surgery was obligated legally to inform the patient about the "risks of alternative prostheses." Id. at 1051. While this conclusion is arguably inconsistent with the Smith v. Yohe's holding that particular medical devices need not be discussed at all, 194 A.2d at 175, Stover remained explicitly tied to surgical risks - specifically the risks of alternative surgical procedures.
174. 589 A.2d 213 (Pa. Super. Ct), appeal denied, 600 A.2d 954 (Pa. 1991).
175. Id. at 214.
176. Id. at 216-17.
177. Id. at 217. See also Semeraro v. Connolly, C.A. No. 92-4636, 1992 WL 392621, at *2 (E.D. Pa. Dec. 14, 1992) (no claim for lack of informed consent for surgeon's alleged failure to inform patient of "[surgeon's] deteriorating sight, coordination and mental faculties"); cf. Grabowski v. Quigley, 684 A.2d 610, 617 (Pa. Super. Ct. 1996) ("ghost surgery" violates informed consent; nature of surgery changed by substitution of surgeon unknown to patient), appeal granted, 698 A.2d 594 (Pa. 1997).
178. 869 F. Supp. 1202 (E.D. Pa. 1994).
179. Id. at 1207.
180. Orthopedic Bone Screw, 1996 WL 107556, at *3 (citation omitted).
181. TENN. CODE ANN. § 29-26-101 et seq. (Supp. 1997).
182. Id. § 29-26-11.8.
183. Cardwell v. Bechtol, 724 S.W.2d 739,750 (Tenn. 1987).
184. Id. (quoting German v. Nichopoulos, 577 S.W.2d 197, 204 (Tenn. Ct. App. 1978), appeal denied (Tenn. 1979)). "[F]ailure to inform a patient of a risk that does not ripen into a condition as a result of the surgery is immaterial as to whether informed consent was given," See Bryant v. Bauguss, C.A. No. 03A01-9603-CV-00105, 1996 WL 465539, at *6 (Tenn. Ct. App. Aug. 16, 1996). A legal status, of course, cannot cause or be a risk, and cannot "ripen into a condition."
185. Longmire v. Hoey, 512 S.W.2d 307, 310 (Tenn. Ct. App. 1974), appeal denied (Tenn. L974).
186. Cary v. Arrowsmith, 777 S.W.2d 8, 21 (Tenn. Ct. App. 1989) (rejecting requirement that informed consent requires separate informed consent for specific drugs used in connection with surgery).
187. Cole v. Cobb, C.A. No. 91-5557; 1992 WL 92788, at *6 (6th Cir. May 4, 1992). Cole is listed in a table at 961 F.2d 1576.
188. Id. at *6.
189. Id.
190. Id. (citation omitted).
191. 1998 WL 62615 (Tenn. Feb. 17, 1998).
192. Id. at *3.
193. Id. at *3, *8.
194. Id. at *7.
195. Id. at n.5 (listing 23 items); see id. at *2-*3, *7. 182 In other cases involving the same products, courts determined that off-label use was involved, and addressed informed consent and FDA regulatory status on the merits. Femrite, 568 N.W.2d at 540; Klein, 673 N.E.2d at 231; Orthopedic Bonecrew, 1996 WL 107556, at *4.
196. The court characterized the device as "not approved" by FDA, the description contained in the plaintiff' affidavit. 1998 WL 62615, at *2-*3. That imprecise description could mean off-label use or use of products (such as injectable silicone, see supra note 138) without any FDA pedigree.
197. TEX. REV. CIV. STAT. ANN. art. 4590i, § 6.02 (Vernon 1997). See Peterson v. Shields, 652 S.W.2d 929, 930-31 (Tex. 1983); Price v. Hurt, 711 S.W.2d 84, 88 (Tex. Ct. App. 1986).
198. TEX. REV. CIV. STAT. ANN. art. 4590i, § 6.04(a).
199. See 25 TEX. ADMIN. CODE § 601.1 (West 1995).
200. TEX. REV. CIV. STAT. ANN. art. 4590i, § 6.05. (aphysician "shall be considered to have complied" with informed consent requirements if the "disclosure is made as provided" on List A). See Blakesley v. Wolford, 789 F.2d 236, 239-40 (3d Cir. 1986) (describing Texas informed consent procedures).
201. TEX. REV. CIV. STAT. ANN. art. 4590i, § 6.05.
202. Id. art. 4590i, § 6.06.
203. Id.
204. Id. art. 4590i, § 6.07(b).
205. Id. art. 4590i, § 6.02.
206. Barclay v. Campbell, 704 S.W.2d 8, 10 (Tex. 1986).
207. Jordan v. Geigy Pharm., 848 S.W.2d 176, 179 (Tex. Ct. App. 1992); Gibson v. Methodist Hosp., 822 S.W.2d 95, 101 (Tex. Ct. App. 1991), writ denied (Tex. 1992).
208. In Texas, the statutory duty of informed consent has not even been extended to disclosure of alternative procedures. Duff v. Yelin, 721 S.W.2d 365, 372 (Tex. Ct. App. 1986), aff'd, 751 S.W.2d 175 (Tex. 1988).
209. Aiken v. Clary, 396 S.W.2d 668, 674 (Mo. 1965). Accord Hoffman v. Rotskoff, 715 S.W.2d 538, 543 (Mo. Ct. App. 1986); Douthitt v. United States, 491 F. Supp. 891, 894 (E.D. Mo. 1980).
210. Cruzan v. Harmon, 760 S.W.2d 408, 417 (Mo. 1988), aff'd, 497 U.S. 261 (1990).
211. Aiken, 396 S.W.2d at 674; Eichelberger v. Barnes Hosp., 655 S.W.2d 699, 705 (Mo. Ct. App. 1983).
212. Wilkerson v. Mid-America Cardiology, 908 S.W.2d 691, 698 (Mo. Ct. App. 1995).
213. 886 F.2d 194 (8th Cir. 1989).
214. Id. at 198.
215. Id. at 199 (quotation marks omitted).
216. Id. at 198.
217. Freiman v. Ashcroft, 584 F.2d 247, 251 (8th Cir. 1978) (citation omitted), aff'd, 440 U.S. 941 (1979).
218. 502 P.2d 1, 10 (Cal. 1972).
219. Id. 207 Id. at 11.
220. Id.
221. Id.
222. Id.
223. Id.
224. 611 P.2d 902 (Cal. 1980).
225. Id. at 906 (emphasis in original).
226. 793 P.2d 479 (Cal. 1990).
227. Id. at 483.
228. Id. at 484.
229. Id. Without the patient's knowledge, the physician in Moore utilized the patient's tissue in private research that allegedly had a potential market value of several billion dollars. Id. at 482.
230. 858 P.2d 598 (Cal. 1993).
231. Id. at 607.
232. Id.
233. Id. at 608.
234. Id. at 609 (citation and footnote omitted) (emphasis in original). A physician "is not the patient's financial advisor." Id. (citation and quotation marks omitted). Nor is a physician required to give legal advice. See Moore, 793 P.2d at 522 (physicians not "competent to explain esoteric questions of law") (Mosk, J. dissenting).
235. 61 Cal. Rptr. 2d 260 (Cal. Ct. App. 1997).
236. Id. at 271, 273.
237. See supra notes 40, 45, 112.
238. Other opinions of the California Court of Appeals likewise have limited informed consent liability. See Spann v. Irwin Mem'l Blood Ctrs., 40 Cal. Rptr. 2d 360, 368 (Cal. Ct. App. 1995) (no duty to disclose the theoretical possibility of a blood donor reduction program that the physician "had no professional duty to maintain"); Munro v. Regents of the Univ. of Ca., 263 Cal. Rptr. 878, 885 (Cal. Ct. App. 1989) (no liability for failing to disclose the heightened incidence of Tay-Sachs disease in certain population groups, when the physician had no information suggesting that the plaintiffs belonged to any of those groups); Scalere v. Stenson, 260 Cal. Rptr. 152, 159-60 (Cal. Ct. App. 1989) (no duty to disclose risks and benefits of further treatment when the physician did not recommend any further treatment); McKinney v. Nash, 174 Cal. Rptr. 642, 648 (Cal. Ct. App. 1981) (informed consent required warnings against current risks of medical treatment, but not against a surgical risk that had been eliminated or against extremely rare idiosyncratic reactions).
239. A single course of treatment frequently involves many FDA-regulated drugs or devices.
240. See supra text accompanying notes 93-107.
241. See Id.
242. Weaver, 886 F.2d at 198.
243. Simeon Management Corp., 391 F. Supp. at 705.
244. Longmire, 512 S.W.2d at 310; see infra text accompanying note 234.
245. 43 Fed. Reg. 1101, 1104 (Jan. 6, 1978).
246. "There is no rational reason . . . that justifies forcing physicians to give [patients] information that the physician considers injurious to the [patient's] health or simply untrue." Planned Parenthood Ass'n v. Ashcroft, 655 F.2d 848, 868 (8th Cir. 1981) (citation omitted), aff'd in part and rev'd in part on other grounds, 462 U.S. 476 (1983).
247. 59 Fed. Reg. at 59,822. "Manufacturers cannot proactively discuss off-label uses, nor may they distribute written materials (promotional pieces, reprints of articles, etc.) that mention off-label uses." Woodcock, supra note 105, at 4; Rayburn, supra note 83, at 1053 ("[I]n the absence of formal approval, education and targeted marketing efforts [are] either hampered or discouraged").
248. See 62 Fed Reg. 14,912, 14,917 (Mar. 28, 1997); 61 Fed. Reg. 48,707, 48,708-09 (Sept. 16, 1996); Marc J. Scheineson, Legal Overview of Likely FDA Regulation of Internet Promotion, 51 FOOD & DRUG L.J. 697, 709 (1996) (parsing manufacturer web pages between labeling and promotion).
249. FDA'S obstruction of medically-related communication has led some to question the validity of the agency's position on promotion of off-label uses under the First Amendment See, e.g., Washington Legal Found., 880 F. Supp. at 34-36; BAD PRESCRIPTION, supra note 66, at 43-58; Edmund Polubinski III, Note, Closing the Channels of Communication: A First Amendment Analysis of the FDA's Policy on Manufacturer Promotion of "Off-Label" Use, 83 VA. L. REV. 991, 1010-34 (1997); Richard M. Cooper, Unapproved Uses of Drugs: An Analysis and Some Proposals, 49 FOOD & DRUG L.J, 533, 537 (1994). For an FDA response, see 62 Fed. Reg. 64,074, 64,076-82 (Dec. 3, 1997).
250. FDA'S obstruction of medically-related communication has led some to question the validity of the agency's position on promotion of off-label uses under the First Amendment See, e.g., Washington Legal Found., 880 F. Supp. at 34-36; BAD PRESCRIPTION, supra note 66, at 43-58; Edmund Polubinski III, Note, Closing the Channels of Communication: A First Amendment Analysis of the FDA's Policy on Manufacturer Promotion of "Off-Label" Use, 83 VA. L. REV. 991, 1010-34 (1997); Richard M. Cooper, Unapproved Uses of Drugs: An Analysis and Some Proposals, 49 FOOD & DRUG L.J, 533, 537 (1994). For an FDA response, see 62 Fed. Reg. 64,074, 64,076-82 (Dec. 3, 1997).
251. See, e.g., ADVISORY COMM. ON CONSUMER PROTECTION AND QUALITY IN THE HEALTH CARE INDUS., REPORT TO THE PRESIDENT: CONSUMER BILL OF RIGHTS AND RESPONSIBILITIES (1997) [hereinafter CONSUMER BILL OF RIGHTS] (especially chapters 1, 4, and 8, discussing the need for informed patient decisionmaking, the need for risk/ benefit information concerning medical options, and patients' responsibility to be aware of limits of medicine and to comply with treatment programs); Greg Borzo, "PCASSO" with a Mouse, 24 AM. MED. NEWS, Oct 13, 1997, at 24 (discussing the Internet's effect on health care delivery systems and its utility in "(bring[ing] patients into the loop ... to tak[e] responsibility for themselves").
252. See, e.g., ADVISORY COMM. ON CONSUMER PROTECTION AND QUALITY IN THE HEALTH CARE INDUS., REPORT TO THE PRESIDENT: CONSUMER BILL OF RIGHTS AND RESPONSIBILITIES (1997) [hereinafter CONSUMER BILL OF RIGHTS] (especially chapters 1, 4, and 8, discussing the need for informed patient decisionmaking, the need for risk/ benefit information concerning medical options, and patients' responsibility to be aware of limits of medicine and to comply with treatment programs); Greg Borzo, "PCASSO" with a Mouse, 24 AM. MED. NEWS, Oct 13, 1997, at 24 (discussing the Internet's effect on health care delivery systems and its utility in "(bring[ing] patients into the loop ... to tak[e] responsibility for themselves").
253. Medical information abounds on the Internet, demonstrating the futility of FDA's attempt to restrict discussion of off-label use by manufacturers. See, e.g., Mark Perkiss, Patients Seek Their Cure on the Net, TRENTON TIMES, Dec. 22, 1997, at C1; Amy Lavalley, Medical Group Sets up Shingle on Web, NEWS LEADER, July 17, 1996, at A6; David Hayes, Medical Facts Plentiful on Internet, KAN. CITY STAR, June 9, 1996, at F9; Aggi Raeder, Finding Medical Information (on the Internet), 4 SEARCHER 40 (1996) (listing Internet medical sources).
254. Medical information abounds on the Internet, demonstrating the futility of FDA's attempt to restrict discussion of off-label use by manufacturers. See, e.g., Mark Perkiss, Patients Seek Their Cure on the Net, TRENTON TIMES, Dec. 22, 1997, at C1; Amy Lavalley, Medical Group Sets up Shingle on Web, NEWS LEADER, July 17, 1996, at A6; David Hayes, Medical Facts Plentiful on Internet, KAN. CITY STAR, June 9, 1996, at F9; Aggi Raeder, Finding Medical Information (on the Internet), 4 SEARCHER 40 (1996) (listing Internet medical sources).
255. Medical information abounds on the Internet, demonstrating the futility of FDA's attempt to restrict discussion of off-label use by manufacturers. See, e.g., Mark Perkiss, Patients Seek Their Cure on the Net, TRENTON TIMES, Dec. 22, 1997, at C1; Amy Lavalley, Medical Group Sets up Shingle on Web, NEWS LEADER, July 17, 1996, at A6; David Hayes, Medical Facts Plentiful on Internet, KAN. CITY STAR, June 9, 1996, at F9; Aggi Raeder, Finding Medical Information (on the Internet), 4 SEARCHER 40 (1996) (listing Internet medical sources).
256. Medical information abounds on the Internet, demonstrating the futility of FDA's attempt to restrict discussion of off-label use by manufacturers. See, e.g., Mark Perkiss, Patients Seek Their Cure on the Net, TRENTON TIMES, Dec. 22, 1997, at C1; Amy Lavalley, Medical Group Sets up Shingle on Web, NEWS LEADER, July 17, 1996, at A6; David Hayes, Medical Facts Plentiful on Internet, KAN. CITY STAR, June 9, 1996, at F9; Aggi Raeder, Finding Medical Information (on the Internet), 4 SEARCHER 40 (1996) (listing Internet medical sources).
257. CONSUMER BILL OF RIGHTS, supra note 238, at 23 (citations and quotation marks omitted).
258. See, e.g., DHHS Accepts Private Sector Patient Education Plan; USP Commits Support, STANDARD, Jan. 1997, (U.S. Pharmacopeial Convention supports access to off-label use information); John Merline, Firms Contend with Worst 10 Washington Regulations, INVESTOR'S BUSINESS DAILY, Aug. 20, 1996, at A4, available at ("By Forbidding manufacturers from spreading the word [about off-label uses], needless illnesses and deaths are occurring"); Sam Kazman, Cardiac and Cancer Specialists on the Need for FDA Reform, in COMPITITIVE ENTER. INST., DEATH BY REGULATION (1996), available at (polls of surgeons and oncologists demonstrate "overwhelming opposition to FDA's policy of restricting information about off-label use, and strong support for making unapproved therapies available to physicians").
259. See, e.g., DHHS Accepts Private Sector Patient Education Plan; USP Commits Support, STANDARD, Jan. 1997, (U.S. Pharmacopeial Convention supports access to off-label use information); John Merline, Firms Contend with Worst 10 Washington Regulations, INVESTOR'S BUSINESS DAILY, Aug. 20, 1996, at A4, available at ("By Forbidding manufacturers from spreading the word [about off-label uses], needless illnesses and deaths are occurring"); Sam Kazman, Cardiac and Cancer Specialists on the Need for FDA Reform, in COMPITITIVE ENTER. INST., DEATH BY REGULATION (1996), available at (polls of surgeons and oncologists demonstrate "overwhelming opposition to FDA's policy of restricting information about off-label use, and strong support for making unapproved therapies available to physicians").
260. See, e.g., DHHS Accepts Private Sector Patient Education Plan; USP Commits Support, STANDARD, Jan. 1997, (U.S. Pharmacopeial Convention supports access to off-label use information); John Merline, Firms Contend with Worst 10 Washington Regulations, INVESTOR'S BUSINESS DAILY, Aug. 20, 1996, at A4, available at ("By Forbidding manufacturers from spreading the word [about off-label uses], needless illnesses and deaths are occurring"); Sam Kazman, Cardiac and Cancer Specialists on the Need for FDA Reform, in COMPITITIVE ENTER. INST., DEATH BY REGULATION (1996), available at (polls of surgeons and oncologists demonstrate "overwhelming opposition to FDA's policy of restricting information about off-label use, and strong support for making unapproved therapies available to physicians").
261. AMA Supports Greater Physician Access to Unlabeled Use Information? STANDARD, July 1997, available at .
262. Id. 244 Under section 551 (a) of the FDCA, the following audiences may receive information from manufacturers about off-label uses: "(1) a health care practitioner; (2) a pharmacy benefit manager; (3) a health insurance issuer; (4) a group health plan; or (5) a Federal or State governmental agency." Pub. L. No. 105-115, § 401, 111 Stat. at 2356-57 (codified at 21 U.S.C, § 360aaa).
263. Section 552 of the FDCA allows manufacturers to disseminate written information about off-label uses, provided that information is "unabridged" and is in the form of published, peer-reviewed articles or generally available "reference publication[s]." Id. at 2358 (codified at 21 U.S.C. § 360aaa-1). The manufacturer also must include[] along with the information .... (A) a prominently displayed statement that discloses - (i) that the information concerns a use of a drug or device that has not been approved or cleared by the [FDA]; (ii) if applicable, that the information is being disseminated at the expense of the manufacturer; (iii) if applicable, the name of any authors of the information who are employees of, or consultants to, or have received compensation from, the manufacturer or who have a significant financial interest in the manufacturer; (iv) the official labeling for the drug or device and all updates with respect to the labeling; if applicable, a statement that there are products or treatments that have been approved or cleared for the use that is the subject of the information ...; and (vi) the identification of any person who has provided funding for the conduct of a study relating to the new use of [the] drug or device ...; and (B) a bibliography of other articles from a scientific reference publication or scientific or medical journal that have been previously published about the use of the drug or device covered by the information disseminated. Id. at 2357 (codified at 21 U.S.C. § 360aaa(b)(6) (FDCA § 551(b)(6))).
264. Section 551 (c) of the FDCA provides for FDA review. If FDA concludes that the information "fails to provide data, analyses, or other written material that is objective and balanced," it may require the manufacturer to include 1) additional objective and scientifically sound information that pertains to the safety or effectiveness of the use andis necessary to provide objectivity and balance ...; and 2) an objective statement of the Secretary, based on data or other scientifically sound information ..., that bears on the safety or effectiveness of the new use of the drug or device. Id. at 2358 (codified at 21 U.S.C. § 360aaa(c)).
265. Section 554 (a), (c) of the FDCA requires manufacturers who wish to disseminate information about off-label uses either to have a supplemental application on file with FDA, or to file such an application within a fixed period of time if the necessary studies are incomplete. Id. at 23 59-60 (codified at 21 U.S.C. § 360aaa-3(a)-(c)).
266. Id. at 2360-61 (codified at 21 U.S.C. § 360aaa-3(d) (FDCA § 554(d))).
267. A recent survey of physicians indicates that "85% of the doctors said FDA labels have 'little influence' or 'practically no influence at all' in their treatment of patients." Marlene Cimons, FDA's Approval Process Faces Challenge in New Senate Bill, A. TIMES, July 22, 1997, at A5.