The Informed-Consent Policy of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: Knowledge Is the Best Medicine

Cornell International Law Journal

Volumn 30, Issue 1, 1997, Pages 203-242

  Miller, Michelle D ^a,b,c  

^a MIT Sloan School of Management   (United States)

^b YALE UNIVERSITY   (United States)

^c PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG;

ARTICLE; BIOMEDICAL AND BEHAVIORAL RESEARCH; CONSENSUS; CONSUMER; CULTURAL ANTHROPOLOGY; DECISION MAKING; DRUG INDUSTRY; EUROPE; EUROPEAN UNION; FOOD AND DRUG ADMINISTRATION; FREEDOM; GOVERNMENT; GOVERNMENT REGULATION; HISTORY; HUMAN; HUMAN EXPERIMENT; INFORMED CONSENT; INJURY; INTERNATIONAL CONFERENCE ON HARMONIZATION; INTERNATIONAL COOPERATION; INTERPERSONAL COMMUNICATION; JAPAN; LEGAL APPROACH; PATERNALISM; PERSONAL AUTONOMY; PRACTICE GUIDELINE; RESEARCH; RESEARCH SUBJECT; RISK; RISK ASSESSMENT; SCIENTIFIC MISCONDUCT; SOCIAL CONTROL; SOCIAL PSYCHOLOGY; STANDARD; UNITED STATES;

BIOMEDICAL AND BEHAVIORAL RESEARCH; INTERNATIONAL CONFERENCE ON HARMONIZATION; LEGAL APPROACH;

CONSENSUS; CONSUMER PARTICIPATION; CULTURAL DIVERSITY; DECISION MAKING; DISCLOSURE; DRUG INDUSTRY; EUROPE; EUROPEAN UNION; FEDERAL GOVERNMENT; FREEDOM; GOVERNMENT; GOVERNMENT REGULATION; GUIDELINES; HISTORY; HISTORY, 20TH CENTURY; HUMAN EXPERIMENTATION; HUMANS; INFORMED CONSENT; INTERNATIONAL COOPERATION; INTERNATIONALITY; JAPAN; NEGOTIATING; NONTHERAPEUTIC HUMAN EXPERIMENTATION; PATERNALISM; PERSONAL AUTONOMY; PHARMACEUTICAL PREPARATIONS; REFERENCE STANDARDS; RESEARCH; RESEARCH SUBJECTS; RISK; RISK ASSESSMENT; SCIENTIFIC MISCONDUCT; SOCIAL CONTROL, FORMAL; SOCIAL VALUES; THERAPEUTIC HUMAN EXPERIMENTATION; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION; WOUNDS AND INJURIES;

EID: 0031291981     PISSN: 00108812     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (331)

1. Robert D. Mulford, Note, Experimentation on Human Beings, 20 STAN. L. REV. 99, 99 (1967). This became known as the Jewish Chronic Disease Hospital experiment. Id.
2. ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS, FINAL REPORT 3 (1995). The Atomic Energy Commission funded this research on prison inmates in Washington and Oregon to gain information to be used in government programs. Id.
3. Id. at 2. University scientists in Berkeley, California, Chicago, Illinois, and Rochester, New York, conducted the experiments at the direction of the federal government. The government expected the data to provide information on how to limit the dangers faced by workers building the atomic bomb. Id.
4. JAMES H. JONES, BAD BLOOD 1-2, 5 (1993). The United States Public Health Service (PHS) started the study in 1932 in Macon County, Alabama, to learn more about the natural course of syphilis. The subjects, all black men, were never told that they had syphilis. The doctors only said that they were being treated for "bad blood." In reality, these men were never treated for syphilis. They were given inducements, such as a free physical exam, free treatment for minor ailments, and a burial stipend for their survivors, to continue to allow the PHS doctors to draw their blood periodically. As of 1969, at least 28, and as many as 100, of these men had died as a direct result of syphilis, a disease treatable with antibiotics since the 1940s. Id. at 1-6.
5. See generally THE NAZI DOCTORS AND THE NUREMBERG CODE (George J. Annas & Michael A. Grodin eds., 1992) [hereinafter THE NAZI DOCTORS].
6. George J. Annas & Michael A. Grodin, Introduction, in THE NAZI DOCTORS, supra note 5, at 3, 4. Although the War Crimes Tribunal was multinational, the United States was responsible for the Doctors' Triai. I TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL LAW NO. 10, at 8 (1950) (Military Tribunal Case 1, United States v. Karl Brandt et al.). The judges sitting at the Doctors' Trial were appointed by President Truman. They were: Walter B. Beals (presiding), Justice of the Supreme Court of Washington; Harold L. Sebring, Justice of the Supreme Court of Florida; Johnson T. Crawford, former Justice of the Oklahoma District Court; and Victor C. Swearingen (alternate member), former assistant attorney general of Michigan. THE NAZI DOCTORS, supra note 5, at 113 (photo caption).
7. George J. Annas & Michael A. Grodin, Introduction, in THE NAZI DOCTORS, supra note 5, at 3, 4. Although the War Crimes Tribunal was multinational, the United States was responsible for the Doctors' Triai. I TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL LAW NO. 10, at 8 (1950) (Military Tribunal Case 1, United States v. Karl Brandt et al.). The judges sitting at the Doctors' Trial were appointed by President Truman. They were: Walter B. Beals (presiding), Justice of the Supreme Court of Washington; Harold L. Sebring, Justice of the Supreme Court of Florida; Johnson T. Crawford, former Justice of the Oklahoma District Court; and Victor C. Swearingen (alternate member), former assistant attorney general of Michigan. THE NAZI DOCTORS, supra note 5, at 113 (photo caption).
8. Anthony Szczygiel, Beyond Informed Consent, 21 OHIO N.U. L. REV. 171, 194 (1994) (stating that the "Code set the 'absolutely essential' prerequisite of a voluntary, competent, informed, and comprehending consent for human experiment subjects"). In his opening statements for the prosecution, Gen. Telford Taylor detailed examples of experimentation on concentration camp inmates. Examples include: sterilization via irradiation, submersion for hours in ice cold water, injection with malaria or typhus, exposure to mustard gas, and the collection of skulls for racial comparisons. Telford Taylor, Opening Statement of the Prosecution, December 9, 1946, in THE NAZI DOCTORS, supra note 5, at 67, 71-86. See infra notes 27-29 and accompanying text.
9. Anthony Szczygiel, Beyond Informed Consent, 21 OHIO N.U. L. REV. 171, 194 (1994) (stating that the "Code set the 'absolutely essential' prerequisite of a voluntary, competent, informed, and comprehending consent for human experiment subjects"). In his opening statements for the prosecution, Gen. Telford Taylor detailed examples of experimentation on concentration camp inmates. Examples include: sterilization via irradiation, submersion for hours in ice cold water, injection with malaria or typhus, exposure to mustard gas, and the collection of skulls for racial comparisons. Telford Taylor, Opening Statement of the Prosecution, December 9, 1946, in THE NAZI DOCTORS, supra note 5, at 67, 71-86. See infra notes 27-29 and accompanying text.
10. The U.S. Department of Health and Human Services requires an investigator to obtain "the legally effective informed consent of the subject or the subject's legally authorized representative . . . under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of concern or undue influence." 45 C.F.R. § 46.116 (1996). See infra note 50 for the specific required elements of informed consent.
11. THE NAZI DOCTORS, supra note 5, at 102.
12. Jay Katz, Informed Consent - Must It Remain a Fairy Tale?, 10 J. CONTEMP. HEALTH L. & POL'Y 69, 73-74 (1994). It is only within the last 35 years that physicians have become legally obligated to share decision-making with their patients. Id. at 72.
13. See infra note 313.
14. S. REP. No. 87-448, at 8 (1961).
15. Louis Lasagna, Congress, the FDA, and New Drug Development: Before and After 1962, 32 PERSP. BIOLOGY & MED. 322, 337 (1989). See infra note 263 and accompanying text.
16. Jerome A. Halperin, From Investigation to Marketplace: Moving Drugs Through the System, 36 FOOD DRUG COSM. L.J. 166, 169 (1981).
17. Mark A. Kassel, Note, Getting There First with the Best: The Need to Shorten the Prescription Drug Approval Process, 27 VAL. U. L. REV. 95, 123 (1992). Redundant replication of foreign data is wasteful. However, replicating a foreign study in such a way as to discover new information, such as the drug's effect at different dose levels or on new populations, would be extremely useful. Louis Lasagna, On Reducing Waste in Foreign Clinical Trials and Postregulation Experience, 40 CLINICAL PHARMACOLOGY & THERAPEUTICS 369, 369 (1986).
18. Mark A. Kassel, Note, Getting There First with the Best: The Need to Shorten the Prescription Drug Approval Process, 27 VAL. U. L. REV. 95, 123 (1992). Redundant replication of foreign data is wasteful. However, replicating a foreign study in such a way as to discover new information, such as the drug's effect at different dose levels or on new populations, would be extremely useful. Louis Lasagna, On Reducing Waste in Foreign Clinical Trials and Postregulation Experience, 40 CLINICAL PHARMACOLOGY & THERAPEUTICS 369, 369 (1986).
19. See, e.g., Barrett Scoville, Shifting the Burden: Restructuring the Drug Review Process, 49 CLINICAL PHARMACOLOGY & THERAPEUTICS 229 (1991); GEN. ACCOUNTING OFFICE, FDA DRUG APPROVAL - A LENGTHY PROCESS THAT DELAYS THE AVAILABILITY OF IMPORTANT NEW DRUGS, GAO REP. NO. HRD-80-64 (1980); WILLIAM M. WARDELL & LOUIS LASAGNA, REGULATION AND DRUG DEVELOPMENT 45-47 (1975).
20. See, e.g., Barrett Scoville, Shifting the Burden: Restructuring the Drug Review Process, 49 CLINICAL PHARMACOLOGY & THERAPEUTICS 229 (1991); GEN. ACCOUNTING OFFICE, FDA DRUG APPROVAL - A LENGTHY PROCESS THAT DELAYS THE AVAILABILITY OF IMPORTANT NEW DRUGS, GAO REP. NO. HRD-80-64 (1980); WILLIAM M. WARDELL & LOUIS LASAGNA, REGULATION AND DRUG DEVELOPMENT 45-47 (1975).
21. See, e.g., Barrett Scoville, Shifting the Burden: Restructuring the Drug Review Process, 49 CLINICAL PHARMACOLOGY & THERAPEUTICS 229 (1991); GEN. ACCOUNTING OFFICE, FDA DRUG APPROVAL - A LENGTHY PROCESS THAT DELAYS THE AVAILABILITY OF IMPORTANT NEW DRUGS, GAO REP. NO. HRD-80-64 (1980); WILLIAM M. WARDELL & LOUIS LASAGNA, REGULATION AND DRUG DEVELOPMENT 45-47 (1975).
22. Joseph G. Contrera, Comment, The Food and Drug Administration and the International Conference on Harmonization: How Harmonious Will International Pharmaceutical Regulations Become?, 8 ADMIN. L.J. AM. U. 927, 939-40 (1995). See infra Part II.
23. Stuart L. Nightingale, The International Harmonization of Drug Standards: The Status of the International Conference on Harmonization Initiative 3 (Aug. 3, 1995) (on file with the FDA) (Dr. Nightingale is the Associate Commissioner for Health Affairs at the U.S. Food and Drug Administration). See infra Part II.A.
24. International Conference on Harmonization: Draft Guidelines on Good Clinical Practice, 60 Fed. Reg. 42,948 (1995) (proposed Aug. 17, 1995) [hereinafter Draft Guidelines]. "Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects." Id. Each party to the ICH possesses its own Good Clinical Practice guidelines. The ICH-GCP represents an attempt to standardize these individual guidelines.
25. This Note focuses primarily on informed consent to medical research rather than to medical treatment. However, since experimental drugs are usually taken as part of a treatment protocol there is often very little practical difference. See infra notes 38-43 and accompanying text.
26. Maria Woltjen, Note, Regulation of Informed Consent to Human Experimentation, 17 LOV. U. CHI. L.J. 507, 509 (1986). The Nuremberg Doctors' Trial depiction of unethical Nazi experimentation on concentration camp inmates initiated the first widespread public debate in the United States on the subject of human-subjects research. Id. at 510-11.
27. George J. Annas, The Nuremberg Code in U.S. Courts: Ethics Versus Expediency, in THE NAZI DOCTORS, supra note 5, at 202 (citing Ownes v. McClearey, 281 S.W. 682, 685 (Mo. 1926)).
28. Former v. Koch, 261 N.W. 762 (Mich. 1935).
29. Id. at 765. The court recognized the importance of experimentation to medical progress, but cautioned that medical experimentation should not vary greatly from accepted medical practice. Id.
30. Stammer v. Board of Regents, 29 N.Y.S.2d 38 (1941), aff'd, 287 N.Y. 359 (1942) (reversing the revocation of a physician's license after he experimented with a new cream for facial cancer and noting that such experimentation is within the scope of a doctor's practice as long as he obtains informed consent from his patient); Bonner v. Moran, 126 F.2d 121 (D.C. Cir. 1941) (holding that a physician must obtain the informed consent of a minor's parents where a 15-year-old boy underwent a skin graft to benefit a cousin).
31. See supra note 7.
32. THE NAZI DOCTORS, supra note 5, at 102.
33. Because it is part of a judgment by an American tribunal in an international setting, the Nuremberg "Code is part of international common law and may be applied, in both civil and criminal cases, by state, federal and municipal courts in the United States." GEORGE J. ANNAS ET AL., INFORMED CONSENT TO HUMAN EXPERIMENTATION: THE SUBJECT'S DILEMMA 21 (1977). The Code is "[t]he most complete and authoritative statement of the law of informed consent to human experimentation . . . ." Id. at 1. The Nuremberg Code is comprised of ten basic principles: 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted when there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probably cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. II TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL LAW NO. 10, at 181-82 (1950) (Military Tribunal Case 1, United States v. Karl Brandt et al.) [hereinafter Nuremberg Code].
34. Because it is part of a judgment by an American tribunal in an international setting, the Nuremberg "Code is part of international common law and may be applied, in both civil and criminal cases, by state, federal and municipal courts in the United States." GEORGE J. ANNAS ET AL., INFORMED CONSENT TO HUMAN EXPERIMENTATION: THE SUBJECT'S DILEMMA 21 (1977). The Code is "[t]he most complete and authoritative statement of the law of informed consent to human experimentation . . . ." Id. at 1. The Nuremberg Code is comprised of ten basic principles: 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted when there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probably cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. II TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL LAW NO. 10, at 181-82 (1950) (Military Tribunal Case 1, United States v. Karl Brandt et al.) [hereinafter Nuremberg Code].
35. Annas, supra note 22, at 204.
36. Id. at 206, 220 n.21 (citing Kaimowitz v. Michigan Dept. Mental Health, Civil No. 73-19434-AW (Mich. Cir. Ct., Wayne Co., July 10, 1973)). The Kaimowitz court used the Nuremberg Code for guidance in its holding that an involuntarily committed mental patient could not legally consent to experimental psycho-surgery because he lacked the requisite mental competence. Id.
37. Annas, supra note 22, at 204.
38. Jay Katz, The Consent Principle of the Nuremberg Code: Its Significance Then and Now, in THE NAZI DOCTORS, supra note 5, at 228. The American belief that the Nazis were not like Americans is partially responsible for the fact that U.S. courts have avoided invoking the Nuremberg Code even when it is directly applicable. Annas, supra note 22, at 218.
39. Katz, supra note 32, at 228. The testimony of two medical experts helped to convince the judges that, although there had been no official statement incorporating these basic principles, the medical community abided by them. In particular, the testimony of Dr. Andrew Ivy asserted that the hippocratic oath served to establish guidelines for the protection of patients. However, there is no mention in the oath about medical research. Id.
40. Id. Currently, the American Medical Association directs physicians to obtain "voluntary written consent" from any person participating in a clinical investigation designed either for treatment purposes or for the accumulation of scientific knowledge. AM. MED. ASS'N, CODE OF MEDICAL ETHICS: ANNOTATED CURRENT OPINIONS § 2.07(3)(B) (1992).
41. Katz, supra note 32, at 227. In 1931, the Reichminister of the Interior promulgated Regulations on New Therapy and Human Experimentation. Id. The American Medical Association patterned its post-war guidelines on the ethics of human experimentation after the earlier German pronouncements. I TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL LAW NO. 10, at 82-86 (1950) (Military Tribunal Case 1, United States v. Karl Brandt et al.) (testimony of prosecution witness Dr. Andrew C. Ivy).
42. Katz, supra note 32, at 228. See supra notes 1-5 and accompanying text.
43. Katz, supra note 32, at 228.
44. Annas, supra note 22, at 217-18.
45. Id. at 217. As medical experimentation became more scientifically valid, it moved into the medical mainstream and out of the realm of quackery. Id.
46. Id. at 218. Non-therapeutic medical experimentation came to be considered the only real medical experimentation. Therefore, the Nuremberg Code applied only to it. This distinction enables the medical and legal communities to ignore the necessity of a strong informed-consent standard for all medical experimentation. For example, U.S. soldiers have often been used unwittingly as research subjects to test the effects of such substances as LSD and radiation. Id. One author points out that while we were horrified to hear that a Nazi physician told a young colleague not to experiment on herself because "[w]e have concentration camps for that," we seem to see no contradiction when our military says, "[w]e have soldiers for that." Id.
47. See, e.g., United States v. Stanley, 483 U.S. 669 (1987) (holding that active-duty U.S. Army servicemen could not sue the federal government for money damages for injuries resulting from LSD administered experimentally by the Army without the soldier's consent). The majority voiced a reluctance to interfere with military "discipline and decision-making." Id. at 683. The dissent, noting the existence of the Nuremberg Code, asserted that the decision amounted to giving military officials unqualified immunity for intentional infliction of injury on service personnel. Id. at 708. This is the only case in which the U.S. Supreme Court has referred to the Nuremberg Code.
48. See Szczygiel, supra note 7, at 194.
49. Cf. Katz, supra note 10, at 86 (arguing that individual self-determination should always trump medical progress when the two goals are incompatible). Placing individual autonomy in the ascendant position insures that doctors always respect their patients as people. Id. at 85. Until recently, the idea that individual patients must be respected as autonomous moral decision makers was foreign to the medical profession. Id. at 73.
50. John A. Robertson, The Law of Institutional Review Boards, 26 UCLA L. REV. 484, 486-87 (1979).
51. Henry K. Beecher, Ethics & Clinical Research, 274 NEW ENG. J. MED. 1354 (1966). For example, placebos were given to 109 military servicemen suffering from streptococcal respiratory infections as a control group, while another group with the disease were treated with Penicillin G. Id. at 1356. In another case, effective treatment for typhoid fever, by administering Chloramphenicol, was withheld from 157 hospital charity patients to determine the relapse rate without such treatment. Id. A third instance of medical experimentation involved institutionalized mentally retarded children who were purposely infected with infectious hepatitis to determine the infectivity of the virus. Id. at 1358.
52. Woltjen, supra note 21, at 511.
53. National Research Act of 1974, Pub. L. No. 93-348, 88 Stat. 348 (1974). See also Leonard H. Glantz, The Influence of the Nuremberg Code on U.S. Statutes and Regulations, in THE NAZI DOCTORS, supra note 5, at 183, 187.
54. National Research Act of 1974, Pub. L. No. 93-348, 88 Stat. 348 (1974). See also Leonard H. Glantz, The Influence of the Nuremberg Code on U.S. Statutes and Regulations, in THE NAZI DOCTORS, supra note 5, at 183, 187.
55. National Research Act of 1974, supra note 47, § 202(a)(1)(A).
56. 45 C.F.R. § 46.101(a) (1996).
57. The eight elements are as follows: (1) A statement that the study involves research, an explanation of the purposes of the research and the expanded duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental; (2) A description of any reasonably foreseeable risks or discomforts to the subject; (3) A description of any benefits to the subject or to others which may reasonably be expected from the research; (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; (5) A statement describing the extent, if any, to which the confidentiality of records identifying the subject will be maintained; (6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained; (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and (8) A statement that participation is voluntary, refusal to participate will involve no penalty or no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. 45 C.F.R §§ 46.116(a)(1-8) (1996).
58. 45 C.F.R. § 46.103(b) (1996); 21 C.F.R. § 56.103(a) (1996). See also Glantz, supra note 47, at 188 (discussing Institutional Review Board regulations).
59. Robertson, supra note 44, at 491. The IRBs are mandated to ensure that research subjects receive all information that the members of the IRB judge relevant to the subjects' rights and welfare. 45 C.F.R. § 46.109 (1996).
60. Robertson, supra note 44, at 491.
61. Cf. Kenneth L. Melmon et al., Principles of Therapeutics, in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 40, 43 (Alfred Goodman Gilman et al. eds., 1980) (explaining the desirability for clinical trials in drug efficacy research).
62. Richard C. Litman & Donald S. Litman, Protection of the American Consumer: The Muckrakers and the Enactment of the First Federal Food and Drug Law in the United States, 36 FOOD DRUG COSM. L.J. 647, 647 (1981). Government regulation of pharmaceuticals dates to the colonial period. For example, in 1630, Nicholas Knopf was convicted of selling "a water of no worth or value" as a cure for scurvy. He was sentenced to pay a fine or be whipped. Wallace F. Janssen, The U.S. Food and Drug Law: How It Came; How It Works, 35 FOOD DRUG COSM. L.J. 132, 132-33 (1980). Notwithstanding this example of vigilance, legal action preventing the sale of nostrums (quack medicines) was the exception, rather than the rule until the twentieth century. Id.
63. Richard C. Litman & Donald S. Litman, Protection of the American Consumer: The Muckrakers and the Enactment of the First Federal Food and Drug Law in the United States, 36 FOOD DRUG COSM. L.J. 647, 647 (1981). Government regulation of pharmaceuticals dates to the colonial period. For example, in 1630, Nicholas Knopf was convicted of selling "a water of no worth or value" as a cure for scurvy. He was sentenced to pay a fine or be whipped. Wallace F. Janssen, The U.S. Food and Drug Law: How It Came; How It Works, 35 FOOD DRUG COSM. L.J. 132, 132-33 (1980). Notwithstanding this example of vigilance, legal action preventing the sale of nostrums (quack medicines) was the exception, rather than the rule until the twentieth century. Id.
64. Id. at 133.
65. See Litman & Litman, supra note 55, at 652. In fact, because European countries regulated drugs earlier than the United States, this country became a dumping ground for unsafe and contaminated European drugs in the nineteenth century. Wallace F. Janssen, Outline of the History of U.S. Drug Regulation and Labeling, 36 FOOD DRUG COSM. L.J. 420, 422 (1981).
66. Pure Food and Drug Act of 1906, ch. 3915, 34 Stat. 768 (1906) (repealed 1938).
67. Id.
68. Id.
69. See Catharine E. Bednar, A Constitutional Analysis of Federal Drug Marketing Regulations and Food and Drug Administration Implementation, 13 SW. U. L. REV. 531, 543-46 (1983). For example, a newly named non-narcotic preparation, for which a producer chose not to reveal the contents, fell completely outside the scope of the law. Id. at 543 n.72.
70. United States v. Johnson, 221 U.S. 488, 495 (1911) (Holmes, J.) (holding that the defendant could not be prosecuted under the Pure Food and Drug Act of 1906, even though he knew that his "Mild Combination Treatment for Cancer" would not produce the health effects claimed, because he had made no false ingredient claims).
71. Act of Aug. 23, 1912, ch. 352, 37 Stat. 416 (1912) (amending the Pure Food and Drug Act of 1906).
72. Id.
73. Janssen, supra note 57, at 428.
74. Id.
75. Sulfanilamide was used at the time to treat acute rheumatic fever and pneumonia. MILTON SILVERMAN & PHILIP R. LEE, PILLS, PROFITS, & POLITICS 6 (1974).
76. Id. The human body metabolizes di-ethylene glycol into oxalic acid, leading to a lingering, excruciatingly painful death from kidney failure. Many of the casualties were children. Id.
77. Id. at 86.
78. Id. The choice of di-ethylene glycol appears to have been motivated by the drug's poor solubility in normal solvents, such as water and alcohol. The manufacturer added coloring and raspberry flavoring to complete the mixture. Id.
79. Arthur H. Hayes, Food and Drug Regulation After 75 Years, 246 JAMA 1223, 1224 (1981).
80. SILVERMAN & LEE, supra note 67.
81. Federal Food, Drug, and Cosmetic Act, ch. 675, § 1, 52 Stat. 1040 (1938) (codified as amended at 21 U.S.C. §§ 301-394 (1988)).
82. See id. § 505, 52 Stat. at 1052. In addition, the Act provided the FDA with specific authority to inspect pharmaceutical production plants, eliminated proof of fraud as a requirement to enjoin false drug claims and authorized federal courts to restrain violations of the Act via injunction. Id. See also Janssen, supra note 57, at 429.
83. Lasagna, supra note 13, at 323-24.
84. Barry S. Roberts & David Z. Bodenheimer, The Drug Amendments of 1962: The Anatomy of a Regulatory Failure, 1982 ARIZ. ST. L.J. 581, 584 (1982). These hearings covered the pricing practices of the steel, automobile, bread, and drug industries. S. REP. No. 87-448, at 1 (1961). The investigation of the pharmaceutical industry alone spanned 26 months and generated 12,885 pages of testimony. Lasagna, supra note 13, at 324. The hearings focused on economic concerns rather than drug safety. By 1958, the pharmaceutical industry's annual budget was estimated at $140 million. While it appears small when compared to today's expenditure of $6 to $7 billion per year, it was considered large at the time. Lasagna, supra note 13, at 323.
85. SILVERMAN & LEE, supra note 67, at 94. Thalidomide produces a "refreshing sleep" without grogginess. It was widely given to "fretful infants." Physicians and pharmacists thought the drug was free from side effects. Id. 78. Hayes, supra note 71, at 1224.
86. Id. In Europe, it was estimated that by 1962, 3,500 to 5,000 cases of phocomelia would result from pregnant women's ingestion of Thalidomide. S. REP. No. 87-1744, at 40 (1962).
87. SILVERMAN & LEE, supra note 67, at 95.
88. Drug Amendments of 1962, Pub. L. No. 87-781, 76 Stat. 780 (codified as amended at 21 U.S.C.A. §§ 301-394 (West Supp. 1992)).
89. See id. § 103(b) 76 Stat. at 783 (amending Federal Food, Drug, and Cosmetic Act, § 505(i), 52 Stat. at 1040 (codified as amended at 21 U.S.C. § 355(i) (1988)).
90. Glantz, supra note 47, at 186.
91. Id.
92. Id.
93. Protection of Human Subjects, 21 C.F.R. §§ 50.20-50.27 (1996). These regulations are similar to those promulgated by HHS for institutions receiving federal funds for non-drug-related medical experimentation. See supra note 50. There are two important differences between the sets of regulations. First, the FDA regulations require the physician to inform the subject that the FDA may inspect her records. 21 C.F.R. § 50.25(a)(5) (1996). Second, the written informed-consent requirement may be waived when the FDA determines that the research poses no more than a "minimal risk." 21 C.F.R. § 56.105 (1996). Minimal risk is defined as a risk not greater than that ordinarily encountered in daily life, or during routine physical or psychological examinations. 21 C.F.R. § 56.102(i) (1996).
94. 21 C.F.R. § 50.25(a)(1) (1996). Informed consent shall include identification of any procedures which are experimental. Id.
95. 21 C.F.R. § 50.25(a)(2) (1996).
96. 21 C.F.R. § 50.25(a)(3) (1996).
97. 21 C.F.R. § 50.25(a)(5) (1996).
98. 21 C.F.R. § 50.25(a)(4) (1996).
99. 21 C.F.R. § 50.25(a)(6) (1996).
100. 21 C.F.R. § 50.25(a)(7) (1996).
101. 21 C.F.R. § 50.25(a)(8) (1996).
102. See supra notes 1-5, 45 and accompanying text.
103. Only three states, California, New York, and Virginia, have statutes specifically addressing informed consent in the context of medical experimentation. In all three states researchers must provide the following information in order to obtain legal informed consent from their subjects: an explanation of the procedures, drugs, or devices to be used in the experiment; a disclosure of alternatives; a description of potential risks and benefits; an offer to field any questions the subject may have; and the instruction that the subject may voluntarily withdraw from the experiment at any time. Both New York and Virginia require the creation of an Institutional Review Board for any institution proposing to do research involving human subjects. See CAL. HEALTH & SAFETY CODE § 24172 (West 1984); N.Y. PUB. HEALTH LAW § 2441 (McKinney 1985); VA. CODE ANN. § 32.1-162.16 (Michie 1984); Woltjen, supra note 21, at 518-23.
104. See 45 C.F.R. § 46.101(a) (1996), supra note 49 and accompanying text.
105. The term European Union (EU) superseded European Community (EC) when the Maastricht Treaty took effect in 1992. Treaty on European Union, Feb. 1, 1992, art. a, 31 I.L.M. 247, 255 (1992).
106. Commission Directive 91/507/EEC, 1991 O.J. (L 270) 32, 48 [hereinafter Commission Directive]. This particular directive falls into the category of "[a]cts whose publishing is not obligatory" for the member states. Id.
107. World Medical Association, Declaration of Helsinki IV (1989), reprinted in THE NAZI DOCTORS, supra note 5, at 339 [hereinafter Helsinki IV].
108. Commission Directive, supra note 99, at 48. A clinical trial is "[a] carefully designed and executed investigation of the effects of a drug administered to human subjects." TABER'S CYCLOPEDIC MEDICAL DICTIONARY 341 (15th ed. 1985).
109. Commission Directive, supra note 99, at 48.
110. Sharon Perley et al., The Nuremberg Code: An International Overview, in THE NAZI DOCTORS, supra note 5, at 149, 159. The WMA Committee on Medical Ethics first submitted a resolution for a code of ethics regarding human experimentation to the WMA's 15th General Assembly in September 1961. Id. The World Health Organization, the branch of the United Nations responsible for directing international public health initiatives of member nations, adopted the Helsinki Declaration in 1964. Katz, supra note 32, at 233.
111. Helsinki IV, supra note 100.
112. The principles of the Helsinki Declaration are as follows: 1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature. 2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed. 3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent. 4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. 5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society. 6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject. 7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits. 8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. 9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject's freely-given informed consent, preferably in writing. 10. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship. 11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation. Whenever the minor child is in fact able to give a consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian. 12. The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with. Id.
113. Id.
114. Katz, supra note 32, at 233 (citing Ethical Committee of the World Medical Assc dation, Draft Code of Ethics on Human Experimentation, 2 BRIT. MED. J. 1119 (1962)).
115. Id.
116. Katz, supra note 32, at 233.
117. Commission Directive, supra note 99, at 48.
118. It is beyond the scope of this Note to address the history and tradition of informed consent in every EU member state.
119. See Canterbury v. Spence, 464 F.2d 772, 783 (D.C. Cir. 1972). The majority opinion details the distinction between the professionally oriented standard and the reasonable-patient standard.
120. Id.
121. Id. at 783 n.38.
122. Id.
123. JUDITH AREEN ET AL., LAW, SCIENCE AND MEDICINE 384 (1984).
124. Szczygiel, supra note 7, at 209-10. A subjective-patient standard focuses on what the patient in the particular case believes to be adequate disclosure, rather than what a hypothetical reasonable person would find adequate. Id.
125. 464 F.2d at 787. In this case Dr. Spence performed a laminectomy on a nineteen year old man suffering from back pain. A laminectomy is the excision of the posterior portion of a vertebra. On the first day after the surgery, the man fell from his bed while unattended. Consequently, he experienced difficulty breathing and became paralyzed below the waist. Eventually he regained the use of his legs, but permanently required crutches to walk and had difficulty with bowel and bladder incontinence. The patient sued the doctor for failing to apprise him of the risks involved in the operation. Id. at 776-78.
126. Id. at 787.
127. See Sidaway v. Bethlem Royal Hospital Governors, 1 All E.R. 643 (H.L. 1985) (holding that professional judgment should determine what medical treatment risks are disclosed to patients). The plaintiff suffered spinal cord damage as the result of an operation. The physician had warned her in simple terms of some risks, but failed to mention possible damage to the spinal cord. Id. The following story further illustrates the distinct approaches to the respective responsibilities of patient and physician. In the United States, an older man was admitted to a hospital with cardiac pathology. The diagnosis was explained to the patient, as were the competing alternatives available for treatment. He was then given a video explaining the two procedures and encouraged to watch the tape and discuss it with his family. The decision between by-pass surgery or angioplasty was left to him. In the United Kingdom, a man of similar age, having the same type of cardiac trouble visited a hospital. Leaving the man and his family at one end of the room, a group of doctors proceeded to huddle around his x-rays, occasionally glancing up at him. At the end of their discussion one of the doctors said to his patient, "Sir, here's what we're going to do for you." The doctors never gave the man any information upon which to base a decision. In fact, the man and his family were completely excluded from the decision-making process. Interview with David C. Lodemore, Editor-in-Chief, Cornell Law Review (Jan. 9, 1996) (the men in the account are his father-in-law and father, respectively).
128. Nuremberg Code, supra note 28.
129. See supra discussion accompanying notes 29-37.
130. Szczygiel, supra note 7, at 209-10.
131. See supra notes 86-94 and accompanying text.
132. Nobuyuki Honna, Cultural Insights; Loan Words from English Have Important Roles to Play, DAILY YOMIURI, July 31, 1995, at 8. Informed consent (i.e. explaining medical treatment issues to a patient and seeking her agreement) is not a concept that is easily expressed in Japanese. Direct translation would not convey the correct idea. Id.
133. Gov't to Work Out Manual on Informed Consent, MAINICHI DAILY NEWS, July 16, 1993.
134. Masao Onishi, Physician, Explain Thyself; Doctors Must Get Down from Pedestal, DAILY YOMIURI, Dec. 15, 1992, at 9 (in a typical medical examination in Japan, the white-gowned doctor arrogantly dispenses whatever treatment he deems best to the apprehensive patient).
135. Norio Higuchi, The Patient's Right to Know of a Cancer Diagnosis: A Comparison of Japanese Paternalism and American Self-Determination, 31 WASHBURN L.J. 455 (1992). Historically, Japanese doctors have refused to reveal a cancer diagnosis to a patient because it amounted to a death sentence. Id. Although now cancer is often treatable, many Japanese doctors are still reluctant to inform patients, particularly when the prognosis is poor, since they believe the shock may worsen the patient's condition. Id. at 456.
136. Id. at 455.
137. Joy Onozuka, Check It Out; The Bottom Line on Illness, DAILY YOMIURI, Mar. 9, 1995, at 10.
138. Higuchi, supra note 128, at 456.
139. Id. Many Japanese doctors criticize American doctors for disclosing too much to patients. There is a suspicion that the American practice of full disclosure is motivated more by the desire to avoid legal liability than a respect for the patient's autonomy. Id. at 457. However, some American physicians assert that their Japanese counterparts are too paternalistic. They claim that giving doctors so much discretion fails to recognize a patient's right to self-determination. Id.
140. Id.
141. Id. The heightened awareness of informed-consent issues heralded by Beecher's exposé of unethical medical experimentation may explain this extraordinary change in attitude. See supra note 45 and accompanying text.
142. Higuchi, supra note 128, at 456 (citing Tokyo District Court Judgment,
143. Id. at 456 (citing Nagoya District Court Judgment, May 27, 1983, 507 HANTA 282).
144. Id. The courts rely on the importance of physician discretion in making the "delicate" medical determination of whether particular information may worsen a patient's condition. Id.
145. Id. at 458 (citing Makino v. The Red Cross Hospital, Nagoya District Court Judgment, May 29, 1989, 1325 HANJI 103).
146. Id. at 460-61.
147. Id. at 458.
148. Id. at 459.
149. Id. at 458-59.
150. Id.
151. Id.
152. Id. at 460.
153. Id. The court explained that in Japan a doctor would never be required to disclose a diagnosis of cholecystic cancer to a patient, since it is virtually incurable. Id.
154. Id.
155. Id. Self-determination is limited when the doctor decides that disclosure would have possible adverse effects on therapy. In such a situation the physician may decide to whom, when, and how much information he should divulge. Id.
156. Akihiko Nishiyama, New Rules Will Shake Drug Firms, NIHON KEIZAI SHIMBUN (JAPAN ECONOMIC JOURNAL), Sept. 22, 1990, at 25.
157. Ben Hills, Japan: Prescription for Disaster, SYDNEY MORNING HERALD, July 30, 1994.
158. Id. For example, Enteroviroform, an anti-diarrheal drug, killed many people and may have blinded as many as 3,000 others. In addition, many Western parents in Japan take their children to the United States or Hong Kong for vaccinations because defective Japanese vaccines have killed children. Id.
159. Id.
160. Id.
161. Id.
162. Id.
163. Id. (quoting a former Nippon Shoji executive).
164. Id.
165. Id. Given the pressures on the Ministry, a denial of approval of the drug would have been unlikely. First, the Japanese Committee has only two inspectors to verify the validity of clinical data, as compared with the FDA's 100 inspectors, while Japan ingests twice as many medical drugs per year as the United States. In addition, Nippon Shoji spent $13,000 entertaining each government official involved. Finally, if officials approve drugs, they can expect to be offered lucrative positions on a pharmaceutical company's executive board when they take early retirement in their fifties. Id.
166. Id. Nippon Shoji's president, Takakazu Hattori, claimed in private that Sorivudine was the most expensive drug on the market. The value of the company's shares soared as a result of the profits generated by the drug. Id.
167. Id. The warning label did not contain a description of the potential for death or severe injury resulting from the combination of Sorivudine and anti-cancer drugs. Id.
168. Id.
169. Sorivudine Should Not Have Been Approved, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Nov. 28, 1994.
170. James Sterngold, Japan's Health Care: Cradle, Grave and No Frills, N.Y. TIMES, Dec. 28, 1992, at A1. Consider the story of 70-year-old Genji Ito as an illustration of a typical visit to the doctor in Japan. Mr. Ito traveled 20 minutes by bicycle to get to the Toho University Hospital. He arrived at 7:30, an hour before the doctors start seeing patients. Because he was so early he was 69th in line. After waiting on a vinyl-covered bench until noon, he saw the doctor briefly for his heart medication. In Japan, crowded clinics and impersonal visits are the order of the day. On the positive side, Mr. Ito pays just 900 yen ($7.25) a month for health care. Id.
171. Hills, supra note 150.
172. Id. Minutes from a meeting at Nippon Shoji headquarters prove that company executives knew of the mounting death toll. The company expected the deaths to remain a "secret within the company." Id.
173. Id. The belated warning saved company employees money. The day of the Health Ministry's warning 175 employees of Nippon Shoji dumped their shares on the market, personally saving millions of dollars. "After the announcement, [the company] shares plummeted from $47 per share to $22" per share. Id.
174. Id.
175. Id.
176. Id.
177. Pharma Japan Statistics; Ethical Drug Market Trends, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Nov. 13, 1995.
178. Kaoruko Aita, Citizens' Groups Seek Bill to Protect Patients' Rights, JAPAN TIMES WKLY. (International Edition), Oct. 19, 1992, at 14. The group wants to create a system to review medical malpractice claims. About 350 new malpractice claims are filed each year. Plaintiffs rarely win these cases in court, even though the citizens' group asserts that 70% to 80% of the medical records used by doctors to defend against malpractice claims are altered. In fact, medical records are considered to be the doctor's property and patients cannot access their own records. The citizens' group seeks to decrease malpractice by requiring doctors to obtain informed consent for all medical procedures. Id.
179. Id.
180. Akiko Fukami, Informed Consent: Doctor Says Patients Have Right to Know, JAPAN TIMES WKLY. (International Edition), Aug. 17, 1992, at 8.
181. Id. The group proposes an informed-consent requirement, as well as a non-jurisdictional check system to investigate malpractice claims. Id.
182. Aita, supra note 171.
183. Kazuo Maeno & Futoshi Kataoka, Medical Congress Discusses 'Humane' Treatment, DAILY YOMIURI, Apr. 17, 1995, at 3.
184. Id.
185. Japan: GCP to Be Implemented in Fall 1990, CHEMICALS BUS. NEWS BASE, Dec. 1, 1989.
186. Id.
187. National Cancer Center Introduces New Clinical Trial Method for Anticancer Agents, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Apr. 24, 1995.
188. Study on Proper Clinical Trial Methods to Start Soon, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Jan. 30, 1995. See supra notes 51-53 and accompanying text.
189. Id.
190. Informed Consent-Integral Part of Clinical Trials on New Drugs, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., July 3, 1995.
191. The 15th General Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Dec. 26, 1994.
192. Id. The questionnaire addressed pharmaceutical approval-process topics, including approval application fees, review procedures, clinical trial methodology, and clinical trial guidelines. Id.
193. Most Cancer Patients Want to Be Fully Informed, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Mar. 6, 1995. See supra note 101 for a definition of clinical trial.
194. Importance of IRB Independence Stressed, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Sept. 25, 1995.
195. Id.
196. Id. (quoting Kazuhiko Mori, deputy director of the Pharmaceuticals and Cosmetics Division of the Pharmaceutical Affairs Bureau).
197. Id.
198. Japan: GCP Inspections Started on Full Scale in Japan, CHEMICALS BUS. NEWS BASE, June 4, 1993. The inspections emphasize clinical-trial contracts, informed consent, preservation of records, and institutional review boards. Id.
199. Japan: PAB to Place Greater Importance on Informed Consent in Clinical Trials, CHEMICALS BUS. NEWS BASE, Oct. 13, 1994.
200. Yomiuri Shimbun, Cancer Center to Implement 'Informed Consent' System, DAILY YOMIURI, July 27, 1995, at 3.
201. Consensus Not Reached on Informed Consent in Clinical Trials, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Sept. 12, 1995 [hereinafter Consensus Not Reached].
202. Role of Chief Investigators in New GCP Not Clear, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Sept. 12, 1995. In particular, the survey response indicated agreement among chief investigators for strengthening GCP inspections and for thorough monitoring. Id.
203. Informed Consent Must Be Obtained in Writing: Mr. Tanaka of the PAB, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Nov. 14, 1994.
204. Id.
205. Id.
206. Id.
207. Consensus Not Reached, supra note 194.
208. Yomiuri Shimbun, Editorial, Protecting Patients' Human Rights, DAILY YOMIURI, Apr. 26, 1995, at 6.
209. Onishi, supra note 127.
210. Id.
211. Id.
212. Id.
213. Medical Practitioners Law (Civil Code), Law No. 201 of 1948 (Supp. 1991) (Japan).
214. Id. art. 22 (Duty to Deliver Prescription).
215. Id.
216. See supra Part I.A.1.
217. See supra Part I.C.
218. See supra Part I.B.
219. Id.
220. P.F. D'Arcy & D.W.G. Harron, Proceedings of the First International Conference on Harmonization Brussels 1991, 1991 INT'L FED'N PHARMACEUTICALS MFRS. ASS'N 8-9 (1991). Located in Geneva, Switzerland, the IFPMA acts as an international consultant to the pharmaceutical industry on all issues relating to the research and manufacture of prescription medications. Id. at xxiii.
221. Id.
222. Nightingale, supra note 18, at 3. The work of the ICH is conducted by 1) Expert Working Groups, 2) the Steering Committee in charge of oversight and policy, composed of two members of the regulatory agency of each country, two industry representatives from each country, and one person from each of three observer groups from Canada, the European Free Trade Area, and the World Health Organization, 3) an ICH coordinator, which rotates depending on which nation is sponsoring the current conference, and 4) a Secretariat to coordinate the ICH process, provided by the IFPMA. Id. at 4.
223. The European Commission is the executive body of the EU. D'Arcy & Harron, supra note 213, at xxi.
224. Draft Guidelines, supra note 19, at 42948.
225. Nightingale, supra note 18, at 3. The countries hold a conference every two years in one of the member countries. Id. at 4. The first conference was located in Brussels, Belgium in 1991. In 1993, Orlando, Florida hosted the conference. Yokohama, Japan was the site of the most recent conference held in November 1995. D'Arcy & Harron, supra note 213, at 2.
226. See supra note 18 and accompanying text.
227. Contrera, supra note 17, at 928.
228. Id.
229. See infra Part II.C.
230. THE FDA TASK FORCE REPORT ON INTERNATIONAL HARMONIZATION, REPORT TO THE COMMISSIONER OF FOOD AND DRUGS OF DECEMBER 1992 (1992).
231. Dr. David A. Kessler, FDA Commissioner, Keynote Address at the Second International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (Oct. 27, 1993) [hereinafter Kessler Address].
232. The ICH Steering Committee met in April 1990 to set the goals and structure of the ICH process. D'Arcy & Harron, supra note 213, at 9.
233. Id. In the first step of the ICH process the Expert Working Groups (EWGs) prioritize the harmonization issues with which they are dealing. The probability of reaching a group consensus is factored into the priority decision. Id. at 9. Each of these issues represents a regulatory difference between two or more of the parties. When confronting a harmonization problem, the group first lists several general considerations that should be followed when promulgating a regulation governing pharmaceutical testing. Id. at 9. Drafting committees composed of representatives from each party's regulatory agency build draft guidelines around these considerations. Contrera, supra note 17, at 940 n.57 (citing INTERNATIONAL CONFERENCE ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, CLOSING REPORT, STATUS OF HARMONIZATION INITIATIVES, Annex 5, 17 (1993)) [hereinafter CLOSING REPORT]. FDA technical experts from both the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research participate in these drafting efforts. Contrera, supra note 17, at 941 n.57 (citing Draft Memorandum from FDA on FDA/ICH Stages of Document Development 1 (Dec. 23, 1993)) [hereinafter FDA Memorandum]. In the United States, the proposed standards are then made available to the public for comment. The FDA Office of the General Counsel and the FDA Office of Policy approve the final FDA draft. Id. at 2. Eventually, the EWG adopts party consensus draft guidelines which are forwarded to the ICH Steering Committee. Id. Step two of the ICH process involves the Steering Committee's approval of the EWG's recommendations. The Steering Committee first sends a copy of the consensus draft guidelines to each of the regulatory agencies for consultation pursuant to its internal consultation process. Each regulatory body reviews the guidelines for policy considera-tions and approves the draft. CLOSING REPORT, supra, at 17. At the FDA, the draft then goes back to the Office of General Counsel for final clearance before being published for public comment. The content of the draft guidelines and a request for public comment are published in the Federal Register. Contrera, supra note 17, at 940 n.57 (citing INTERNATIONAL CONFERENCE ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, REPORT OF THE STEERING COMMITTEE MEETING, March 9-10, 1993, Brussels 9 (1993) (ICH document Ref: ICH 2/14)) [hereinafter REPORT OF THE STEERING COMMITTEE]. Step three involves review of the comments and draft guidelines. In the United States, the FDA responds to public comments following publication of the draft guidelines in the Federal Register. The Office of General Counsel and the Office of Policy examine the revised guidelines after this round of notice and comment. After approval by these two offices, the FDA transmits the results to the appropriate EWG for its approval. The EWG then sends the tripartite guidelines to the Steering Committee for further approval. FDA Memorandum, supra, at 2. Step four involves the ICH acceptance of the final tripartite guidelines. After receiving the final iteration of the draft guidelines, the Steering Committee either approves the draft or recommends changes. If approved the Steering Committee submits the harmonized tripartite guidelines to the regulatory agencies of each party for adoption according to the party's internal procedures. CLOSING REPORT, supra, at 17. In the United States, the FDA Steering Committee approves the document before the General Counsel and the Office of Policy see it once again. The FDA then publishes a notice of final rule in the Federal Register. FDA Memorandum, supra, at 3. The fifth step of the ICH process concerns the incorporation of the guidelines into each party's pharmaceutical production regulations. CLOSING REPORT, supra, at 17. In the United States, the FDA makes the requisite changes in the Code of Federal Regulations. If it becomes necessary to amend the regulation, the FDA reviews any further comments. FDA Memorandum, supra, at 3.
234. Id. In the first step of the ICH process the Expert Working Groups (EWGs) prioritize the harmonization issues with which they are dealing. The probability of reaching a group consensus is factored into the priority decision. Id. at 9. Each of these issues represents a regulatory difference between two or more of the parties. When confronting a harmonization problem, the group first lists several general considerations that should be followed when promulgating a regulation governing pharmaceutical testing. Id. at 9. Drafting committees composed of representatives from each party's regulatory agency build draft guidelines around these considerations. Contrera, supra note 17, at 940 n.57 (citing INTERNATIONAL CONFERENCE ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, CLOSING REPORT, STATUS OF HARMONIZATION INITIATIVES, Annex 5, 17 (1993)) [hereinafter CLOSING REPORT]. FDA technical experts from both the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research participate in these drafting efforts. Contrera, supra note 17, at 941 n.57 (citing Draft Memorandum from FDA on FDA/ICH Stages of Document Development 1 (Dec. 23, 1993)) [hereinafter FDA Memorandum]. In the United States, the proposed standards are then made available to the public for comment. The FDA Office of the General Counsel and the FDA Office of Policy approve the final FDA draft. Id. at 2. Eventually, the EWG adopts party consensus draft guidelines which are forwarded to the ICH Steering Committee. Id. Step two of the ICH process involves the Steering Committee's approval of the EWG's recommendations. The Steering Committee first sends a copy of the consensus draft guidelines to each of the regulatory agencies for consultation pursuant to its internal consultation process. Each regulatory body reviews the guidelines for policy considera-tions and approves the draft. CLOSING REPORT, supra, at 17. At the FDA, the draft then goes back to the Office of General Counsel for final clearance before being published for public comment. The content of the draft guidelines and a request for public comment are published in the Federal Register. Contrera, supra note 17, at 940 n.57 (citing INTERNATIONAL CONFERENCE ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, REPORT OF THE STEERING COMMITTEE MEETING, March 9-10, 1993, Brussels 9 (1993) (ICH document Ref: ICH 2/14)) [hereinafter REPORT OF THE STEERING COMMITTEE]. Step three involves review of the comments and draft guidelines. In the United States, the FDA responds to public comments following publication of the draft guidelines in the Federal Register. The Office of General Counsel and the Office of Policy examine the revised guidelines after this round of notice and comment. After approval by these two offices, the FDA transmits the results to the appropriate EWG for its approval. The EWG then sends the tripartite guidelines to the Steering Committee for further approval. FDA Memorandum, supra, at 2. Step four involves the ICH acceptance of the final tripartite guidelines. After receiving the final iteration of the draft guidelines, the Steering Committee either approves the draft or recommends changes. If approved the Steering Committee submits the harmonized tripartite guidelines to the regulatory agencies of each party for adoption according to the party's internal procedures. CLOSING REPORT, supra, at 17. In the United States, the FDA Steering Committee approves the document before the General Counsel and the Office of Policy see it once again. The FDA then publishes a notice of final rule in the Federal Register. FDA Memorandum, supra, at 3. The fifth step of the ICH process concerns the incorporation of the guidelines into each party's pharmaceutical production regulations. CLOSING REPORT, supra, at 17. In the United States, the FDA makes the requisite changes in the Code of Federal Regulations. If it becomes necessary to amend the regulation, the FDA reviews any further comments. FDA Memorandum, supra, at 3.
235. The Steering Committee oversees both the preparation for each ICH meeting and the development of the harmonization initiatives via the ICH process. REPORT OF THE STEERING COMMITTEE, supra note 226, at 9.
236. Id.
237. Id.
238. CLOSING REPORT, supra note 226, at 15.
239. Id.
240. Id.
241. D'Arcy & Harron, supra note 213, at 351. The Safety EWG concentrates on the toxicological aspect of pharmaceuticals. CLOSING REPORT, supra note 226, at 4-5. Toxicology is the study of a drug's harmful properties. GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 2 (Alfred Goodman Gilman et al. eds., 1980). The Quality EWG deals with stability testing, specifications for drug classification and dosage form, and standardization of pharmacopoeias. D'Arcy & Harron, supra note 213, at 39. Because this Note focuses on informed consent, only the Efficacy EWG will be discussed at length.
242. D'Arcy & Harron, supra note 213, at 351. Another example of draft guidelines produced by this EWG is Studies in Support of Special Populations (Geriatrics; Draft Guideline Availability), 58 Fed. Reg. 21,082 (1993). In addition, the Steering Committee has issued consensus draft texts from the Efficacy EWG to the larger group for consultation. These include: "Dose Response Information to Support Drug Registration," "Guidance on Clinical Safety Data Management-Definitions and Standards for Expedited Reporting," and "The Extent of Population Exposure Required to Assess Clinical Safety for Drugs Intended for Long-Term Treatment." CLOSING REPORT, supra note 226, at 10-11.
243. Draft Guidelines, supra note 19.
244. Id. at 42,948.
245. Id.
246. Id.
247. Id. at 42,948-57.
248. Contrera, supra note 17, at 937.
249. PETER L. STRAUSS ET AL., ADMINISTRATIVE LAW 400-02 (1995). See generally Philip J. Harter, Negotiating Regulations: A Cure for Malaise, 71 GEO. L.J. 1, 42-52 (1982) (discussing requisite factors for the success of regulatory negotiation). Generally, a regulatory agency may create rules on the basis of its own knowledge and information. STRAUSS, supra, at 293. The proposed rule then enters the "notice-and-comment" process during which interested parties may suggest modifications. Id. at 292 (citing Administrative Procedure Act, 5 U.S.C. § 553(c) (1946)). Eventually, the agency adopts a final rule, taking into consideration the comments it received. Id. at 293. In contrast, regulatory negotiation requires the agency to negotiate the content of a proposed rule before it enters the notice-and-comment period. Id. at 400. Therefore, "Negotiated Rulemaking . . . permits affected interests to have greater control over the content of agency rules while ensuring fairness and balanced participation." Henry H. Perritt, Jr., Negotiated Rulemaking Before Federal Agencies: Evaluation of Recommendations by the Administrative Conference of the United States, 74 GEO. L.J. 1625, 1627 (1986). Its history reveals that regulatory negotiation is arguably successful. For example, none of the rules developed as a result of negotiated rulemaking and issued as final rules by the Environmental Protection Agency through 1987 has been litigated. Lee M. Thomas, The Successful Use of Negotiated Rulemaking by EPA, 13 ADMIN. L. NEWS 1, 3 (1987). But see Susan Rose-Ackerman, Consensus Versus Incentives: A Skeptical Look at Regulatory Negotiation, 43 DUKE L.J. 1206, 1206 (1994) (arguing that regulatory negotiation has been "oversold" as a reform).
250. PETER L. STRAUSS ET AL., ADMINISTRATIVE LAW 400-02 (1995). See generally Philip J. Harter, Negotiating Regulations: A Cure for Malaise, 71 GEO. L.J. 1, 42-52 (1982) (discussing requisite factors for the success of regulatory negotiation). Generally, a regulatory agency may create rules on the basis of its own knowledge and information. STRAUSS, supra, at 293. The proposed rule then enters the "notice-and-comment" process during which interested parties may suggest modifications. Id. at 292 (citing Administrative Procedure Act, 5 U.S.C. § 553(c) (1946)). Eventually, the agency adopts a final rule, taking into consideration the comments it received. Id. at 293. In contrast, regulatory negotiation requires the agency to negotiate the content of a proposed rule before it enters the notice-and-comment period. Id. at 400. Therefore, "Negotiated Rulemaking . . . permits affected interests to have greater control over the content of agency rules while ensuring fairness and balanced participation." Henry H. Perritt, Jr., Negotiated Rulemaking Before Federal Agencies: Evaluation of Recommendations by the Administrative Conference of the United States, 74 GEO. L.J. 1625, 1627 (1986). Its history reveals that regulatory negotiation is arguably successful. For example, none of the rules developed as a result of negotiated rulemaking and issued as final rules by the Environmental Protection Agency through 1987 has been litigated. Lee M. Thomas, The Successful Use of Negotiated Rulemaking by EPA, 13 ADMIN. L. NEWS 1, 3 (1987). But see Susan Rose-Ackerman, Consensus Versus Incentives: A Skeptical Look at Regulatory Negotiation, 43 DUKE L.J. 1206, 1206 (1994) (arguing that regulatory negotiation has been "oversold" as a reform).
251. PETER L. STRAUSS ET AL., ADMINISTRATIVE LAW 400-02 (1995). See generally Philip J. Harter, Negotiating Regulations: A Cure for Malaise, 71 GEO. L.J. 1, 42-52 (1982) (discussing requisite factors for the success of regulatory negotiation). Generally, a regulatory agency may create rules on the basis of its own knowledge and information. STRAUSS, supra, at 293. The proposed rule then enters the "notice-and-comment" process during which interested parties may suggest modifications. Id. at 292 (citing Administrative Procedure Act, 5 U.S.C. § 553(c) (1946)). Eventually, the agency adopts a final rule, taking into consideration the comments it received. Id. at 293. In contrast, regulatory negotiation requires the agency to negotiate the content of a proposed rule before it enters the notice-and-comment period. Id. at 400. Therefore, "Negotiated Rulemaking . . . permits affected interests to have greater control over the content of agency rules while ensuring fairness and balanced participation." Henry H. Perritt, Jr., Negotiated Rulemaking Before Federal Agencies: Evaluation of Recommendations by the Administrative Conference of the United States, 74 GEO. L.J. 1625, 1627 (1986). Its history reveals that regulatory negotiation is arguably successful. For example, none of the rules developed as a result of negotiated rulemaking and issued as final rules by the Environmental Protection Agency through 1987 has been litigated. Lee M. Thomas, The Successful Use of Negotiated Rulemaking by EPA, 13 ADMIN. L. NEWS 1, 3 (1987). But see Susan Rose-Ackerman, Consensus Versus Incentives: A Skeptical Look at Regulatory Negotiation, 43 DUKE L.J. 1206, 1206 (1994) (arguing that regulatory negotiation has been "oversold" as a reform).
252. PETER L. STRAUSS ET AL., ADMINISTRATIVE LAW 400-02 (1995). See generally Philip J. Harter, Negotiating Regulations: A Cure for Malaise, 71 GEO. L.J. 1, 42-52 (1982) (discussing requisite factors for the success of regulatory negotiation). Generally, a regulatory agency may create rules on the basis of its own knowledge and information. STRAUSS, supra, at 293. The proposed rule then enters the "notice-and-comment" process during which interested parties may suggest modifications. Id. at 292 (citing Administrative Procedure Act, 5 U.S.C. § 553(c) (1946)). Eventually, the agency adopts a final rule, taking into consideration the comments it received. Id. at 293. In contrast, regulatory negotiation requires the agency to negotiate the content of a proposed rule before it enters the notice-and-comment period. Id. at 400. Therefore, "Negotiated Rulemaking . . . permits affected interests to have greater control over the content of agency rules while ensuring fairness and balanced participation." Henry H. Perritt, Jr., Negotiated Rulemaking Before Federal Agencies: Evaluation of Recommendations by the Administrative Conference of the United States, 74 GEO. L.J. 1625, 1627 (1986). Its history reveals that regulatory negotiation is arguably successful. For example, none of the rules developed as a result of negotiated rulemaking and issued as final rules by the Environmental Protection Agency through 1987 has been litigated. Lee M. Thomas, The Successful Use of Negotiated Rulemaking by EPA, 13 ADMIN. L. NEWS 1, 3 (1987). But see Susan Rose-Ackerman, Consensus Versus Incentives: A Skeptical Look at Regulatory Negotiation, 43 DUKE L.J. 1206, 1206 (1994) (arguing that regulatory negotiation has been "oversold" as a reform).
253. PETER L. STRAUSS ET AL., ADMINISTRATIVE LAW 400-02 (1995). See generally Philip J. Harter, Negotiating Regulations: A Cure for Malaise, 71 GEO. L.J. 1, 42-52 (1982) (discussing requisite factors for the success of regulatory negotiation). Generally, a regulatory agency may create rules on the basis of its own knowledge and information. STRAUSS, supra, at 293. The proposed rule then enters the "notice-and-comment" process during which interested parties may suggest modifications. Id. at 292 (citing Administrative Procedure Act, 5 U.S.C. § 553(c) (1946)). Eventually, the agency adopts a final rule, taking into consideration the comments it received. Id. at 293. In contrast, regulatory negotiation requires the agency to negotiate the content of a proposed rule before it enters the notice-and-comment period. Id. at 400. Therefore, "Negotiated Rulemaking . . . permits affected interests to have greater control over the content of agency rules while ensuring fairness and balanced participation." Henry H. Perritt, Jr., Negotiated Rulemaking Before Federal Agencies: Evaluation of Recommendations by the Administrative Conference of the United States, 74 GEO. L.J. 1625, 1627 (1986). Its history reveals that regulatory negotiation is arguably successful. For example, none of the rules developed as a result of negotiated rulemaking and issued as final rules by the Environmental Protection Agency through 1987 has been litigated. Lee M. Thomas, The Successful Use of Negotiated Rulemaking by EPA, 13 ADMIN. L. NEWS 1, 3 (1987). But see Susan Rose-Ackerman, Consensus Versus Incentives: A Skeptical Look at Regulatory Negotiation, 43 DUKE L.J. 1206, 1206 (1994) (arguing that regulatory negotiation has been "oversold" as a reform).
254. Neil Eisner, Regulatory Negotiation: A Real World Experience, 31 FED. B. NEWS & J. 349, 371-73 (1984).
255. Id.
256. Negotiated Rulemaking Act of 1990, 5 U.S.C. § 563 (1990). Although this is an American statute, the ICH process is designed to work in a similar fashion. Contrera, supra note 17, at 938.
257. The general guidelines of an administrative agency serve to alert the regulated community of the agency's position on a given matter and are non-binding. In contrast, rules bind both the agency and the regulated industry to a substantive norm. See Community Nutrition Institute v. Young, 818 F.2d 943 (D.C. Cir. 1987).
258. Contrera, supra note 17, at 937.
259. Id. at 938.
260. Id.
261. See infra text accompanying notes 255-60.
262. See infra notes 281-89 and accompanying text.
263. Kassel, supra note 15, at 95 n.9.
264. Kessler Address, supra note 224.
265. See supra Part I.A.2.
266. Kassel, supra note 15, at 104.
267. Id. at 95.
268. Ann Gibbons, Can David Kessler Revive the FDA?, 252 SCI. 200, 201 (1991). The FDA is slower than the comparable agencies of other nations at every stage of the process. For example, in 1988, the average review interval for a newly developed drug was 15 months in the country of first approval. The FDA required an average of 29.7 months to review the same products. John C. Petricciani, Disease, Drugs, and Delay: Suggested Changes for the FDA, 38 CLINICAL RES. 701, 701 (1990).
269. Ann Gibbons, Can David Kessler Revive the FDA?, 252 SCI. 200, 201 (1991). The FDA is slower than the comparable agencies of other nations at every stage of the process. For example, in 1988, the average review interval for a newly developed drug was 15 months in the country of first approval. The FDA required an average of 29.7 months to review the same products. John C. Petricciani, Disease, Drugs, and Delay: Suggested Changes for the FDA, 38 CLINICAL RES. 701, 701 (1990).
270. David Hanson, Pharmaceutical Industry Optimistic About Improvements at FDA, 70 CHEMICAL & ENGINEERING NEWS 28, 28 (1992).
271. Kassel, supra note 15, at 97. The time delays not only reduce early access for consumers, but also increase the cost of research and development. A one-and-a-half-year decrease in approval time can cut five years off the time needed to recoup research costs. Barry S. Roberts & Sara M. Biggers, Regulatory Update: The FDA Speeds Up Hope for the Desperately Ill and Dying, 27 AM. BUS. L.J. 403, 405-06 n.13 (1989).
272. William Wardell, The Drug Lag Revisited: Comparison by Therapeutic Area of Patterns of Drugs Marketed in the United States and Great Britain from 1972 Through 1976, 24 CLINICAL PHARMACOLOGY & THERAPEUTICS 499, 521 (1978).
273. Roberts & Bodenheimer, supra note 76, at 597. Former FDA Commissioner Hayes estimated that timolol would prevent approximately 17,000 deaths annually from secondary myocardial infarctions (i.e. heart attacks secondary to another disease or trauma). Anthony Hayes, Current FDA Directives for Promoting Public Health, 39 AM. J. HOSP. PHARMACY 427, 428 (1982).
274. Recommendations to Speed Drug Approvals Issued, [1990-91 Transfer Binder] Food Drug Cosm. L. Rep. (CCH) ¶ 42,603, at 43,617 (Nov. 18, 1991) [hereinafter Recommendations]. The recommendations were as follows: (1) use of external review, (2) expanded use of advisory committees, (3) an expanded role for Institutional Review Boards, (4) flexible interpretation of the efficacy standard, (5) accelerated approval, (6) expanded use of foreign data and recognition of foreign approvals in the United States, (7) enhanced computerization, (8) establishment of a classification system for application priorities, (9) use of internal systems of accountability, (10) reduction of excessive liability costs, and (11) direction of staff and financial resources toward new drug review. Id. at 43,619-26.
275. New FDA Approval Guidelines Set, FACTS ON FILE, May 14, 1992, at 353. This recommendation would have required the FDA, in conjunction with foreign countries, to develop common standards for clinical studies, a common format for submission of drug approval applications, common sets of requirements for animal testing, criteria for plant inspections and good manufacturing practices, a reciprocity for approvals, and a process for the mutual acceptance of data. Recommendations, supra note 261, at 43,623-24.
276. Halperin, supra note 14, at 168. The agency is concerned with the following safety barriers implicated in accepting foreign data: the FDA's lack of familiarity with foreign languages, Europe's shorter historical commitment to high-quality clinical trials, discomfort with validating foreign data, poor design of foreign experiments, and a large number of statistical problems. Lasagna, supra note 13, at 370.
277. Halperin, supra note 14, at 169.
278. Lasagna, supra note 13, at 369.
279. Id. at 370.
280. Draft Guidelines, supra note 19, at 42,948.
281. See supra text accompanying notes 85-94.
282. 21 C.F.R. § 50.25(a)(1-8) (1985).
283. Draft Guidelines, supra note 19, at 42,949.
284. Id.
285. Negotiated Rulemaking Act of 1990, supra note 244, § 563.
286. Id. § 563(a)(3)(A). Of course, the ICH process is not subject to the requirements of the U.S. Negotiated Rulemaking Act since it is an international effort. However, as a form of regulatory negotiation, the ICH process implicates identical considerations to those addressed by the U.S. Act.
287. William Funk, When Smoke Gets In Your Eyes: Regulatory Negotiation and the Public Interest-EPA's Woodstove Standards, 18 ENVTL. L. 55 (1987).
288. Id. at 57. See also Hudson Preservation Conference v. Fed. Power Comm'n, 354 F.2d 608, 620 (2d Cir. 1965), cert. denied, 384 U.S. 941 (1966) (asserting that "the rights of the public must receive active and affirmative protection at the hands of the [agency]"). By deeming the agency merely another party to the agreement, regulatory negotiation limits the agency's responsibility for achieving consensus. As a result, the mandate of the statute may be subordinated to achieving consensus. This reliance on consensus for legitimacy is not problematic when all interests are represented. The fact that unrepresented interests do not participate in the notice-and-comment period or challenge the final rule in court does not indicate approval of the rule. Funk, supra note 274, at 57.
289. See supra part II.A.
290. Nightingale, supra note 18, at 4. See supra text accompanying note 213.
291. Draft Guidelines, supra note 19, at 42,948.
292. Nightingale, supra note 18, at 5 (describing public meetings held by the FDA to explain the ICH process).
293. For instance, because interests represented by consumer groups are likely to be well organized, they are able to make their voices heard. Yet, consumer groups' interests may be more aligned with the pharmaceutical companies than with research subjects because they demand that the FDA approve new drugs faster. See Kassel, supra note 15, at 95 n.9.
294. STRAUSS ET AL., supra note 241, at 1121.
295. Sierra Club v. Morton, 405 U.S. 727 (1972). In this case, the U.S. Forest Service accepted a bid by Walt Disney Enterprises, Inc. to build a ski resort in the Sequoia National Forest. Sierra Club sued the agency, seeking a declaratory judgment that the planned development contravened federal national park preservation law. The court held that although non-economic harm, such as loss of recreation in a national park, can constitute the "injury in fact" required for standing, the Sierra Club did not have standing because it had not made a showing that any of its members had sustained the alleged injury. Id.
296. STRAUSS ET AL., supra note 241, at 1121.
297. Id. at 1257. The cases are Block v. Community Nutrition Institute, 467 U.S. 340, 351 (1984) (holding that a consumer suit against the Secretary of Agriculture was precluded because congressional intent to exclude such suits was "fairly discernible in the statutory scheme"), Lujan v. Defenders of Wildlife, 504 U.S. 555 (1992) (holding that plaintiff conservation groups lacked standing to sue the Secretaries of Commerce and the Interior for promulgating regulations that misinterpreted the Endangered Species Act), and Reno v. Catholic Social Services, 509 U.S. 43 (1993) (O'Connor, J., concurring in the judgment) (acknowledging Lujan's stricter standards for beneficiary standing).
298. 504 U.S. at 555. The Court held that the "desire to use or observe an animal species, even for purely esthetic purposes" is a cognizable interest to support standing. Id. at 562. However, the plaintiffs had not shown that they had any plans to travel to Egypt or Sri Lanka, where the animal species endangered by the projects partially funded by the Secretaries of Commerce and the Interior, were located. Therefore, the plaintiffs had demonstrated no "injury on fact." Id. In addition, the Court argued that the citizen-suit provision of the Endangered Species Act violated the president's power under Article II of the United States Constitution to execute federal law. Id. at 576.
299. Id.
300. Id.
301. Id. at 562.
302. Id.
303. Lasagna, supra note 13, at 322.
304. The interaction between the ICH process and standing doctrine is important because an agency is less likely to ignore a party's interests during the rulemaking process if that party is capable of hauling the agency into court to challenge the regulations at the end of the process. STRAUSS ET AL., supra note 241, at 1121. Because standing doctrine precludes potential research subjects from suing the FDA over relaxed informed-consent standards, the agency lacks this incentive to include their interests in the ICH negotiations.
305. See supra part I.B.
306. See supra note 99 and accompanying text.
307. Revised Japanese GCP Should Include IND Application System, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Nov. 7, 1995 (IND is an abbreviation for "Investigational New Drug"). See supra notes 178-83 and accompanying text.
308. ICH-GCP Draft Clarifies Responsibility of Sponsors, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., July 31, 1995.
309. D'Arcy & Harron, supra note 213, at 473.
310. See supra note 125 and accompanying text.
311. Hills, supra note 150. The Japanese spend more on pharmaceuticals than on their defense budget, and they spend almost twice as much on medicines as they do on rice, their main food staple. Id.
312. Id. The Japanese lead the world in pharmaceutical consumption. Japanese Health Care; Keeping Well in Their Own Way, ECONOMIST, July 7, 1990, at 38 [hereinafter Japanese Health Care]. See also Sterngold, supra note 163.
313. Id. The Japanese lead the world in pharmaceutical consumption. Japanese Health Care; Keeping Well in Their Own Way, ECONOMIST, July 7, 1990, at 38 [hereinafter Japanese Health Care]. See also Sterngold, supra note 163.
314. Hills, supra note 150.
315. Id. Japanese doctors are paid poorly under the national health care system. One doctor estimated that he would need to see 150 patients per day in order to make a living. The incentives for taking kickbacks from the pharmaceuticals companies is, therefore, strong. The kickbacks come in the form of secret discounts on the approved prices. Id. The MHW has attempted to end this practice, but the physicians comprise a powerful lobby in Japan. Japanese Health Care, supra note 299, at 38.
316. Hills, supra note 150. Doctors often remove labels from prescription drugs before giving them to a patient. Sterngold, supra note 163, at A1.
317. Hills, supra note 150.
318. See Onishi, supra note 127; Sterngold, supra note 163; Japanese Health Care, supra note 299.
319. Japanese Society of Clinical Pharmacology and Therapeutics: Me-Too Drug Trials Pose Dilemma for Physicians, COMLINE DAILY NEWS BIOTECH. AND MED. TECH., Nov. 27, 1995.
320. Hills, supra note 150.
321. Id.
322. Editorial, Orient Clinical Tests to Patients, DAILY YOMIURI, Dec. 3, 1995, at 5.
323. Id. Japanese clinical trial data is poorly rated by foreign countries because the research is known to lack thoroughness. Id. 310. See supra notes 152-68 and accompanying text.
324. Hills, supra note 150.
325. Petricciani, supra note 256, at 701.
326. See Schloendorff v. Society of New York Hosp., 105 N.E. 92, 92-93 (N.Y. 1914) (Cardozo, J.) ("[e]very human being of adult years and sound mind has a right to deter-mine what shall be done with his own body."). Ironically, the plaintiff, who complained that her doctors had performed an operation to remove a fibroid tumor without her consent, lost the case. Judge Cardozo asserted that the hospital could not be held accountable for the actions of the private physicians who admitted patients. That is, there was no master-servant relationship between the hospital and doctors upon which to base hospital liability. Id. However, other informed-consent cases have cited the concept of self-determination represented by the case with approval. See e.g. Canterbury v. Spence, 464 F.2d 772, 786 (D.C. Cir. 1972), cert. denied, 409 U.S. 1064 (1972). As a necessary incident of self-determination, informed consent in the medical context is now widely accepted in the United States. See Problems in Securing Informed Consent of Subjects in Experimental Trials of Unapproved Drugs and Devices: Hearing Before the Subcommittee on Regulation, Business Opportunities, and Technology of the Committee on Small Business, 103d Cong. 1 (1994) (opening statement of Chairman Wyden).
327. See supra notes 171-75 and accompanying text (discussing the growing patients' rights movement in Japan).
328. See supra Part II.C.
329. In contrast to the political process in which all interests are represented by definition, regulatory negotiation is not democratically legitimate unless all interests are explicitly represented. Rose-Ackerman, supra note 241, at 1211.
330. Motor Vehicles Mfrs. Assoc. of the U.S., Inc. v. State Farm Mutual Auto. Ins. Co., 463 U.S. 2958 (1983) (Rehnquist, J., dissenting)(explaining that the agency's modification of regulations seemed to be in response to the election of a new president from a different political party).
331. See Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837, 843 (1984) (holding that the Environmental Protection Agency's interpretation of ambiguous statutory language is entitled to deference). The Court further held that an agency's construction of an unclear statute may rely upon the incumbent administration's policy views; however, an agency must give effect to the unambiguously stated intent of Congress. Id. at 843.