Nevertheless, until the last quarter of the 20 th century, the majority of drugs on the market had not been tested for safety 52 and efficacy, as there was no requirement to do

so.

. When – exceptionally – drugs had been tested, it was often on unaware human

“guinea pigs.”

Protection of research participants enrolled in clinical studies

(i.e.,

49 See, e.g., PAUL DE KRUIF, MICROBE HUNTERS (Harvest Book 1926) (an amusing book describing the early achievements of scientific pioneers such as Koch, Pasteur, Roux and Behring).

50 The most famous exception is a controlled experiment on scurvy carried out by physician James Lind in 1747. See Colin Currie, Clinical arithmetic, An Enlightenment legacy still needs defending – against more subtle adversaries, 327 BMJ 1418-19 (Dec. 20-27, 2003), at

http://bmj.bmjjournals.com/cgi/reprint/327/7429/1418.pdf. See also THESHAPIROS,supra note 4, at 125.

51 As the Shapiros argue convincingly, before the era of controlled clinical trials, most existing remedies were little more than placebos – the main exceptions being quinine against malaria starting in the 17^th century, aspirin in the 19^th century, Paul Ehrlich’s salvarsan against syphilis in the early 1900s, insulin replacement therapy in 1921, vitamin treatment for scurvy, sulfonamides in the 1930s, penicillin and streptomycin in the 1950s, digitalis for heart failure in the 1970s. See THESHAPIROS,supra note 4, at 20, 32, 75-76. This led to the oft-repeated saying that, until quite recently, at best “the history of medicine was largely the history of the placebo effect.” Id. at 2. At worse, “the history of medicine is mostly a history of ineffective and often dangerous treatments.” Richard Smith, Do patients need to read research?, 326 BMJ 1307 (2003), at http://bmj.bmjjournals.com/cgi/content/full/326/7402/1307 [hereinafter Smith (Read Research)]. See also John P. Swann, The Pharmaceutical Sciences in America, 1902-1952, 41 JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION 829, at 830 (Nov./Dec. 2001).

52 In the United States, safety testing was introduced in 1938 as the upshot of the deaths of several patients, mostly children, who had taken poisonous elixir sulfanilamide. For a review of the 1938 Act, see David F.

Cavers,The Food, Drug, and Cosmetic Act of 1938: Its Legislative History and its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2-42 (1939). For more background on the 1938 Act, see FDA, FDA Oral History Pro-gram, Interview with William W. Goodrich, Office of the General Counsel, 1939-1971, (1986), Part I, at http://www.fda.gov/oc/history/oralhistories/goodrich/default.htm [hereinafter FDA (Interview Goodrich I)].

See also subsection 4.1.1.1.1. below.

53 This legal requirement was first introduced in 1962 in the United States. See subsection 4.1.1.2.1. below.

54 See generally SUSAN E. LEDERER, SUBJECTED TO SCIENCE (John Hopkins University Press 1995).

55 Here, the words “clinical study,” “clinical trial,” and “clinical research” are used as synonyms, although litera-ture usually considers clinical trials to be a subset of clinical research. The United States thus distinguishes between three main categories of clinical research: i) patient-oriented research, ii) epidemiologic and be-havioral studies, and iii) outcomes and health service research. See, e.g., NIH Director’s Panel on Clinical Re-search Report (Dec. 1997), Executive Summary, at section 2, at

http://www.nih.gov/news/crp/97report/execsum.htm [hereinafter NIH 1997 Report]. See also NIH, Office of Extramural Research, NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, at section IV.A. (Oct. 2001), at

http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm [hereinafter NIH (Women Inclusion)].

“subjects”) emerged progressively as the consequence of abuses and scandals

2.3.

.

Between 1875 and the First World War, people worried about becoming the un-willing object of experimentation.

Hospitals were feared, not only because they tended to spread infectious diseases, but also because they were suspected of experi-menting with new treatments.

The two World Wars shifted the public focus from the protection of vulnerable elements of society exploited in research (e.g., children) to the need for sacrifices for the greater good. At about the same time, the first truly effective treatments (e.g., penicillin) became available.

U.S. medical research emerged from the Second World War cast in glory. As a result, the public became thrilled with the poten-tial of scientific and medical progress.

For almost twenty years, the protection of re-search subjects and the regulation of the pharmaceutical industry took the back seat.

2.1. International principles 2.1.1. The Nuremberg Code

Still today, the Nuremberg Code is the text most often referred to – though mostly in gen-eral terms – in the context of clinical trials. It marks the beginning of a radically differ-ent perspective on experimdiffer-entation. Instead of a purely scidiffer-entific-medical view point, the Nuremberg Code introduces a legal and ethical perspective.

Furthermore, it sug-gests that this perspective is to prevail over the traditional medical stance. As a result, this Code became the prototype for a succession of many other bioethical norms.

Rare are the bioethical statements that do not allude to the Nuremberg Code.

Despite the historical importance of the Nuremberg Code, its practical significance was far more limited. For several years following its enactment, it was basically ignored (see

. This paradox deserves an explanation, which is the reason why I have cho-sen to describe in some details the Nuremberg Code and its consequences, although most readers are probably familiar with this document.

56 See L^EDERER,supra note 54.

57 See Jochen Vollmann & Rolf Winau, Informed consent in human experimentation before the Nuremberg code, 313 BMJ 1445-47 (Dec. 7, 1996), at http://bmj.com/cgi/content/full/313/7070/1445.

This same apprehension is still underscored in an advice issued by the French National Ethics Committee in 1984, see CCNE, Avis sur les essais de nouveaux traitements chez l'homme, réflexions et propositions, Avis N°2 [Advice on trials of new treatments on man: thoughts and proposals, Advice N°2], at 6 (Oct. 9, 1984), at http://www.ccne-ethique.fr/francais/pdf/avis002.pdf [hereinafter CCNE N°2].

58 See supra note 51.

59 See Wendy K. Mariner, AIDS Research and the Nuremberg Code, in T^HE NAZI DOCTORS AND THE NUREMBERG CODE286, 288 (Oxford University Press 1992). See also SPRUMONT,supra note 16, at 116.

60 See generally Dominique Manaï, Le contrat de soins entre l’éthique et le droit, in P^ACTE, CONVENTION, CONTRAT, MÉLANGES EN L’HONNEUR DU PROF. SCHMIDLIN 301, 303 (Helbing & Lichtenhahn, 1998) [hereinafter Manaï (l’éthique et le droit)].

61 See, for example, the introduction and note 1 to the (U.S.) Belmont Report on Ethical Principles and Guide-lines for the Protection of Human Subjects of Research that was adopted by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, (Apr. 18, 1979); the text is available at http://ohsr.od.nih.gov/guidelines/belmont.html [hereinafter Belmont report].

With the end of the Second World War, the Nazi’s horrific experiments came to full light. Prisoners in concentration camps had been subjected to experiments that did not even aim at finding or testing possible remedies. While German physicians may have believed that they were engaging in valid scientific projects as part of the war effort,

their experiments were mostly torture and genocide under the guise of research.

This cruelty had been supported by the German chemical and pharmaceutical industry.

The United States’ response was the enactment in 1947 of the Nuremberg Code.

The Code is part of the Nuremberg Tribunal’s decision in the Doctors’ trial (also called the “Medical Case”).

The Tribunal aimed to bring to justice 26 Nazi doctors and scien-tists who had tortured and murdered Jews, Slavs, Russians, Gypsies, homosexuals, po-litical dissidents, and prisoners.

The trial was led by the U.S. government.

The Tri-bunal’s judges and lawyers (for the prosecution) were Americans.

The key witnesses

62 See Jesse A. Goldner, An Overview of Legal Controls on Human Experimentation and the Regulatory Implica-tions of Taking Professor Katz Seriously, 38 ST. LOUISL.J. 63, at 90 (1993).

63 Nonetheless, Americans and British scientists tried to retrieve the results of Nazi experiments. See Paul Weindling, Human guinea pigs and the ethics of experimentation: the BMJ’s correspondent at the Nurem-berg medical trial, 313 BMJ 1467-70 (Dec. 7, 1996), at http://bmj.com/cgi/content/full/313/7070/1467.

The dubious position of the United States was further revealed during the Japanese War Crimes trials:

“The United States had evidence that Japanese physicians had engaged in extensive lethal human ex-perimentation on American prisoners of war in China at Unit 731. These experiments involved freezing, plague, gas gangrene, and other experiments of biological warfare not distinguishable in kind from those performed on concentration camp prisoners by the Nazi doctors. Nonetheless, the United States in-formed the Japanese physicians of Unit 731 that they would not be prosecuted if they agreed to turn over their records and findings to the United States. At least part of the explanation for this decision seems to be that the United States did not want to reveal the results of the Japanese biological warfare studies to the Russians.”

George J. Annas & Michael A. Grodin, Where Do We Go From Here?, in T^HENAZIDOCTORS AND THE NUREMBERGCODE307, 310 (Oxford University Press 1992). See also PAUL M. MCNEIL, THEETHICS AND POLITICS OFHUMANEXPERIMENTATION 23-26 (Cambridge Univ. Press, 1993).

64 For instance, IG Farben, which was later dismantled into Hoechst, BASF and Bayer, wrote to Nazi officers at Auschwitz:

“In contemplation of experiments with the new soporific drug, we would appreciate your procuring for us a number of women … We received your answer but consider the price of 200 marks a woman ex-cessive. We propose to pay no more than 170 marks a head. If agreeable, we will take possession of the women. We need approximately 150… Received the order of 150 women. Despite their emaciated con-dition, they were found satisfactory. We shall keep you posted on developments concerning this experi-ment…. The tests were made. All subjects died. We shall contact you shortly on the subject of a new load.”

JOHNBRAITHWAITE, CORPORATE CRIME IN THE PHARMACEUTICAL INDUSTRY 5 (Routledge & Kegan Paul 1984), (cit-ing to JONATHAN GLOVER, CAUSING DEATH AND SAVING LIVES58 (Penguin 1977)).

65 The text of the Code is available for example from http://bmj.com/cgi/content/full/313/7070/1448.

66 See, e.g., George J. Annas & Michael A. Grodin, Introduction, in THENAZIDOCTORS AND THE NUREMBERGCODE 3, 4 (Oxford University Press 1992); Michael A. Grodin, Historical Origins of the Nuremberg Code, in THE NAZIDOCTORS AND THE NUREMBERGCODE121, at 121 (Oxford University Press 1992) [hereinafter Grodin (His-torical Origins)].

67 On the relationship between the charges of genocide and unethical medical experimentation, see Arthur L.

Caplan, The Doctors’ Trial and Analogies to the Holocaust in Contemporary Bioethical Debates, in THENAZI DOCTORS AND THE NUREMBERGCODE258, 265 and also 259 (Oxford University Press 1992).

68 The Medical Case was different from the other Nuremberg trials of war criminals, in that these other trials represented a common initiative sponsored by Britain, France, Russia and the United States. See Paul Weindling, supra note 63. See also Jennifer Leaning, War crimes and medical science, Editorial, 313 BMJ 1413-1415 (Dec. 7, 1996), at http://bmj.com/cgi/content/full/313/7070/1413; Robert F. Drinan, The Nurem-berg Principles in International Law, in THENAZIDOCTORS AND THE NUREMBERG CODE174, 176 (Oxford Univer-sity Press 1992); George J. Annas, The Nuremberg Code in U.S. Courts: Ethics versus Expediency, in THE NAZIDOCTORS AND THE NUREMBERGCODE201 and 204 (Oxford University Press 1992) [hereinafter Annas (Ex-pediency)].

69 See, e.g., In Re Cincinnati Radiation Litigation, 874 F. Supp. 796, at 820 (S.D. Ohio 1995).

for the accusation were American scientists. The Tribunal applied American proce-dures.

Although the Nuremberg Tribunal purported to codify preexisting ethical