Successive U.S. regulations of clinical trials

As mentioned above (subsection 1.3.), the United States adopted federal regulations of clinical trials long before Switzerland. Today, U.S. federal regulations are split into two sets of regulations.

The first one was adopted by the FDA; it applies to clinical trials of drugs and medical devices. The Department of Human Health and Services (“HHS”) is the author of the second set of regulations, called the HHS Regulations or “Common Rule.”

The HHS Regulations are followed by federal research agencies, particularly the National Institutes of Health (“NIH”) and by research institutions receiving federal funding.

Clinical trials that are neither submitted to the FDA nor funded or otherwise supported by federal institutions may escape federal regulation;

they are subject to State legislations only.

In this thesis, the emphasis is placed on FDA regulations since they represent a more accurate counterpart to the Swiss OClin.

U.S. efforts to regulate experimentation began in the early 1900s.

Several bills were submitted to Congress, only to be defeated by mixed coalitions of interested par-ties.

For instance, doctors banded with the pharmaceutical industry, newspapers and advertisers to oppose any regulations that would constrain the freedom to prescribe or to do business. In 1906, the short Food and Drugs Act was enacted. It only authorized

241 The FDA and the HHS regulations may be applicable concurrently, for example when a clinical trial receives funding (directly or indirectly) from the NIH and is to be submitted in support of a drug marketing applica-tion. For a list of differences between the two regulations, see FDA, Comparison of FDA and HHS Human Subject Protection Regulations (2000), at http://www.fda.gov/oc/gcp/comparison.html.

242 Because so many U.S. agencies are applying the HHS regulations, these are referred to as the “Common Rule.” The Common Rule provides notably for a system of assurance adopted by each recipient institution (e.g., universities) to guarantee compliance with applicable regulations. See 45 C.F.R. § 46.103.

243 In addition, many research centers choose to apply the Common Rule even to research projects that do not receive federal funding.

244 This is undeniably a worrisome loophole. Critics have repeatedly asked that this problem be addressed by comprehensive regulations. See, e.g., National Bioethics Advisory Commission (“NBAC”), Ethical and Policy Issues in Research Involving Human Participants, Summary, at 6, (Aug. 2001), at

http://www.georgetown.edu/research/nrcbl/nbac/human/oversumm.pdf, [hereinafter NBAC (Issues in Re-search)].

245 Research projects which fall neither within neither the FDA regulations nor the Common Rule jurisdiction are rare. See, e.g., Harold T. Shapiro & Eric M. Meslin, Ethical Issues in the Design and Conduct of Clinical Trials in Developing Countries, 345 NEW. ENG. J. MED. 139 (July 12, 2001), at

http://content.nejm.org/cgi/reprint/345/2/139.pdf.

246 See SUZANNE PARISIAN, FDA INSIDE AND OUT, at 11-13 (Fast Horse Press, 2001).

247 See Russell S. Sobel, Public Health and the Placebo: The Legacy of the 1906 Pure Food and Drugs Act, Independent Institute Working Paper No.28, (Apr. 2001), at 5, at

http://www.independent.org/pdf/working_papers/28_public_health.pdf. The patent medicine lobby and the media industry (journals lived on medical advertisements) were the most vocal opponents to drug regula-tions.

“Senator Gallinger introduced in 1900 a proposal for the regulation of human experimentation in the District of Columbia. Senate Bill 3424 required the prior disclosure of an investigator’s purpose and procedures in any nontherapeutic experiment on human beings, as well as the written consent of the subjects. The bill ex-plicitly outlawed scientific experimentation on persons considered incapable of giving consent, including newborns and children under the age of twenty, pregnant women or women who had given birth in the pre-vious year, the aged, the insane, the feeble-minded, and people with epilepsy.” LEDERER,supra note 54, at 71-72.

the FDA to order products to be withdrawn from the market if they were deemed mis-branded or adulterated.

In 1962, Congress passed the Kefauver-Harris Amendments to the Food and Drug Cosmetic Act (“FDCA”). These Amendments added the requirement of informed consent to clinical investigations of products under the jurisdiction of the FDA.

However, the Amendments had excessively broad exceptions for situations where informed consent was found “not feasible” or “contrary to the best interests” of the subjects.

In 1974, the short National Research Act was passed.

This Act set up the U.S.

National Commission for the Protection of Human Subjects of Biomedical and Behav-ioral Research.

In 1979, the Commission published its report, commonly referred to as the “Belmont Report.”

This Report holds significant importance in the United States,

where its role is at least comparable to that of the Helsinki Declaration (on the Helsinki Declaration, see subsection 2.1.2. above).

248 See PARISIAN,supra note 246, at 14. The passage of the 1906 Act was helped by the novel “The Jungle” by Upton Sinclair, which generated public furor at the lack of regulations in the food industry.

249 See JONES(TUSKEGEE),supra note 78, at 189. See Julie A. Grow, The Legislative History of the 1962 Drug Amendments: A Failure to Forget or A Lesson to Learn From? Harvard Law School, at 109 at n.536 (May 1, 1997), at http://leda.law.harvard.edu/leda/data/189/jgrow.pdf.

Previously, the American Medical Association started to require that subjects consent to research in 1946.

However, its recommendation was not widely followed. See L^EDERER,supra note 54, at 140.

In 1966, the Surgeon-General also issued its own recommendations. See also Glantz, supra note 83, at 186-87; JONES(TUSKEGEE),supra note 78, at 189; Goldner, supra note 62, a 95. See also SPRUMONT,supra note 16, at 117.

250 According to the Amendments (at § 103), experts testing the safety and efficacy of new drugs had “to cer-tify to [the] manufacturer or sponsor that they will inform any human beings to whom such drugs, or any controls used in connection therewith, are being administered, or their representatives, that such drugs are being used for investigational purposes and will obtain the consent of such human beings or their represen-tatives, except where they deem it not feasible or, in their professional judgment, contrary to the best inter-ests of such human beings.” (emphasis added). As a result, the protection that the Act extended to research subjects was quite limited in practice. See Goldner, supra note 62, at 94. See also SPRUMONT,supra note 16, at 113-14.

251 See National Research Act, Public Law 93-348, (July 12, 1974) available at

http://www.kent.edu/rags/Compliance/IRB-National-Research-Act.cfm. See also LEDERER,supra note 54, at 142; Palmer, supra note 212, at 616-17.

252 See further SPRUMONT,supra note 16, at 120.

253 Belmont report, supra note 61. See also A^RNO& FEIDEN,supra note 125, at 27.

Baram has criticized the Belmont report as being overly permissive. Michael Baram, Making Clinical Trials Safer for Human Subjects, 27 AM. J. L. AND MED. 253, at 258 (2001).

254 See Burns, supra note 81, at 133; Richard A. Rettig, Military Use of Drugs Not Yet Approved by the FDA for CW/BW Defense, Rand Report, (Apr. 1999), at chapter 3, access to full text of all chapters from http://www.gulflink.osd.mil/library/randrep/index.html [hereinafter Rand Report]; NBAC (Issues in Re-search), supra note 244, at 2; NBAC, Ethical and Policy Issues in International Research: Clinical Trials in De-veloping Countries, Volume I, Report and Recommendations, at 5, (Apr. 2001), at

http://www.georgetown.edu/research/nrcbl/nbac/clinical/Vol1.pdf [hereinafter NBAC (Developing)];

SPRUMONT,supra note 16, at 54 and 120.

However, in a 2002 decision, the U.S. Supreme Court of Connecticut agreed with a lower court that the use of the Belmont report as evidence could unduly sway the jury. According to the Court, the Belmont report would invite “the jury to engage in a highly abstract and philosophical level of inquiry into such subjects as respect for the autonomy of persons, the notion of self-determination, the concept of beneficence, and the various theories of justice. It invited the jury to think about using children and criminal prisoners as subjects of medical research. It invited the jury to think about the meaning of the physician’s Hippocratic oath, which was neither given in full nor explained in any detail. It invited the jury to compare the hospital’s conduct to the infamous Tuskegee study. … We cannot fault the trial court … for determining that submitting this mate-rial to the jury would unduly arouse its emotions of prejudice, hostility or sympathy, and would tend to con-fuse the issues and mislead the jury.” Ancheff v. Hartford Hospital, 799 A.2d at 1079 (Conn. 2002).

Even before these statutes entered into force, the NIH and the FDA had adopted their own guidelines. The NIH adopted its first rules in the early 1950s.

The FDA en-acted its regulations in 1963,

which it then revised several times.

Starting in 1971, the FDA required clinical studies of investigational

products to get approval from ethics committees.

In 1981, the FDA enacted formal guidelines on clinical trials.

In 1996, the Agency authorized and regulated emergency clinical research through yet an-other guideline

.

255 The first NIH guideline for intra-muros research dates back to 1953. See SPRUMONT,supra note 16, at 115.

See also In Re Cincinnati, 874 F. Supp. at 821.

256 See 28 Fed. Reg. 179 (Jan. 8, 1963). See also SPRUMONT,supra note 16, at 113.

257 See FDA, Statement on Policy Concerning Consent for Use of Investigational New Drugs on Humans, 31 Fed.

Reg. 11,415 (Aug. 1966); 32 Fed. Reg. 8,753 (June 20, 1967).

Even prior to 1966, informed consent was considered as a general obligation, even though the precise shape of the obligation was unclear. See Burton v. Brooklyn Doctors Hospital, 452 N.Y.S.2d 875 (N.Y.App. 1982) (“While the law in New York at that time [1953] did not require the detailed imparting of information such as has been statutorily mandated since 1975, either with respect to treatment or the conduct of research, doc-tors were never free to expose their patients to unwarranted risks without first obtaining their consent.” Id.

at 881). See also In Re Cincinnati, 874 F. Supp. at 821 and 826 (mentioning a 1953 Directive by the U.S.

Department of Defense). See also Glantz, supra note 83, at 186. See also FDA, FDA Oral History Program, Interview with William W. Goodrich, Office of the General Counsel, 1939-1971, Part III, (1986), at http://www.fda.gov/oc/history/oralhistories/goodrich/part3.html (describing the controversy about the early FDA regulations on clinical investigations).

258 The words “investigational” and “experimental” are often used as synonyms. However, they have a slightly different meaning. The word “investigational” reflects the fact that the drug lacks marketing approval for its considered therapeutic indication. The word “experimental” suggests that little is known about the drug and its indication. A drug that has been used for a long time for its therapeutic indication would no longer be considered experimental, whereas it still remains investigational. However, in this thesis, I sometimes use the two terms synonymously.

259 In the United States, these ethics committees are called Institutional Review Boards (“IRBs”), a term which conveys correctly the fact that their main task is to review research conducted in their institutions. For a definition, see for example 21 Code of Federal Regulations (“C.F.R.”) § 50.3(i) or § 56.102(g) (chapter 21, part 50 of the Code of Federal Regulations is available at

http://www.fda.gov/oc/ohrt/irbs/appendixb.html; part 56 at

http://www.fda.gov/oc/ohrt/irbs/appendixc.html); also 45 C.F.R. § 46.102(g) (at

http://www.hhs.gov/ohrp/Humansubjects/guidance/45cfr46.htm#46.102. See also FDA, FDA Operations, In-formation Sheet, Guidance for Institutional Review Boards and Clinical Investigators, (1998 update), at http://www.fda.gov/oc/ohrt/irbs/operations.html [hereinafter FDA (Operations)].

260 See FDA, HHS, Final Rule, Protection of Human Subjects, Informed Consent, 46 Fed. Reg. 8942 (Jan. 27, 1981) [hereinafter FDA (1981)]

261 See FDA, Exception from Informed Consent, Requirements for Emergency Research, Guidance for Institu-tional Review Boards, Clinical Investigators and Sponsors, Draft Guidance, at 4, (Mar. 30, 2000), at http://www.fda.gov/ora/compliance_ref/bimo/emrfinal.pdf [hereinafter FDA (Emergency Guidance)].