Clinical drug trials : studying the safety and efficacy of new pharmaceuticals

(1)

Book

Reference

Clinical drug trials : studying the safety and efficacy of new pharmaceuticals

JUNOD, Valérie

JUNOD, Valérie. Clinical drug trials : studying the safety and efficacy of new pharmaceuticals . Genève : Schulthess, 2005, 545 p.

Available at:

http://archive-ouverte.unige.ch/unige:43019

Disclaimer: layout of this document may differ from the published version.

(2)

Valérie Junod

Clinical drug trials

Studying the safety and efficacy of new pharmaceuticals

Faculté de droit de Genève

C G

Collection

Genevoise

(3)

Clinical drug trials

(4)

C G

Collection Genevoise

Faculté de droit de Genève

(5)

Valérie Junod

Clinical drug trials

Studying the safety and efficacy of new pharmaceuticals

5 5 55 5 5 55555 98555

BRUYLANT 2005

B R U X E L L E S

2 0 0 5

(6)

Information bibliographique: ‹Die Deutsche Bibliothek›.

Die Deutsche Bibliothek a répertorié cette publication dans la Deutsche Nationalbibliografie;

les données bibliographiques détaillées peuvent être consultées sur Internet à l’adresse

‹http://dnb.ddb.de›.

Tous droits réservés. Toute traduction, reproduction, représentation ou adaptation intégrale ou partielle de cette publication, par quelque procédé que ce soit (graphique, électronique ou méca- nique, y compris photocopie et microfilm), et toutes formes d’enregistrement sont strictement interdites sans l’autorisation expresse et écrite de l’éditeur.

Schulthess Médias Juridiques SA, Genève · Zurich · Bâle ISBN 2 8027 2163 1 Bruylant, Bruxelles

www.schulthess.com

La Faculté de droit autorise l’impression de la présente dissertation sans entendre émettre par là une opinion sur les propositions qui s’y trouvent énoncées.

5

(7)

(8)

(9)

George Bernard Shaw, The Doctor’s Dilemma

(10)

(11)

The following persons very kindly provided me with precious information, documents and/or advice on a variety of themes related to pharmaceuticals. Michel Balea (UCSF Medical Center), Henri Bounameaux (ethics committee president at the Geneva’s Uni- versity hospitals); Stefano Dozio (Swiss Competition Commission) ; Pascale Erbeia (lawyer in Geneva and ethics committee member); Jeremy Lack (legal counsel in Ge- neva); Cathy Lawi (Medabiotech); Benoît Merkt (lawyer in Geneva); Laurent Miéville (Unitec at the University of Geneva); Alexandre Mauron (bioethicist at the University of Geneva); Thomas Schuler (OFSP); Pierre Studer (OFSP); Thierry Tanquerel (Professor at the University of Geneva Law School).

Many others are not mentioned here, but their assistance has been nonetheless greatly appreciated. I would also like to extend special thanks to the many people at Swissmedic who patiently and expertly answered my numerous questions; I am par- ticularly grateful to Jean-Christophe Méroz (legal department) and to the entire GCP department.

Obviously, the opinions contained in this thesis may not reflect the views of the persons mentioned above. Moreover, all errors – and, alas, some will certainly remain – are my responsibility only.

My deep gratitude goes to:

– Professor Christian Bovet, the best thesis director I could dream of.

– Professors Dominique Manaï, Philippe Ducor (Law School of the University of Ge- neva), Pierre Dayer (Medical School of the University of Geneva), and Benoît Du- buis (Swiss Federal Institute of Technology, Lausanne). Their insightful observa- tions and advice during the oral defense of this thesis were invaluable.

– The law firm of ‘Junod, Guyet, Muhlstein & Lévy’, particularly Dr. Alain B. Lévy and the secretaries, for assisting me in my project in so many ways.

– Ms. Alia Rahal for careful proofreading the final draft.

– The Stanford Law School, for its superb facilities and the guidance given by my two advisors, Professors John Barton and Jonathan Greenberg, during the year I spent there.

– The Swiss National Science Foundation (“SNSF”), for generously funding my re- search and my stay at Stanford.

– Lexis and Google: How is legal research at all possible without these tools?

Last, but certainly not least, I want to thank my incredible family. My parents and Tony Reynard read several drafts and came back with amazingly sharp comments. It is to my father that I owe my taste for law. My mother encouraged me to start writing, and above all, to finish this thesis: Without her, I would still be collecting notes today.

Finally, I am indebted to Tony who supported me unwaveringly during this delightful ordeal.

June 30, 2004

(12)

(13)

Acronyms

XIII

List of Principal Laws and Regulations cited

XVII

1. Introduction 1

Part I 9

2. Historical overview of clinical trial regulations 9

3. Definition of clinical trials 36

4. The economic dimension of clinical trials 76

Part II

127

5. The professional participants in a clinical trial 127

6. The types and characteristics of drug clinical trials 174

Part III

257

7. Approval of clinical trials 257

8. Research subjects 318

9. Supervision of clinical trials 468

10. End of clinical trials 502

11. Conclusion 521

Glossary 523

List of court cases cited 527

Short Bibliography 531

Index 533

Table of contents 535

(14)

(15)

ADR: Adverse Drug Reaction.

AE: Adverse Event.

AMA: American Medical Association.

ANDA: Abbreviated New Drug Application.

ARR: Absolute Risk Reduction.

ATF: (Swiss) from the French: recueil officiel des arrêts du Tribunal fédéral.

BMJ: British Medical Journals.

C.F.R.: (U.S.) Code of Federal Regulations.

CAFC: (U.S.) Court of Appeals for the Federal Circuit.

CAM: Complementary and Alternative Medicines.

CBER: (U.S) Center for Biologics Evaluation and Review.

CCNE: (France): from the French: Comité consultatif national d’éthique.

CDER: (U.S) Center for Drug Evaluation and Review.

C.F.R.: (U.S.) Code of Federal Regulations.

CIOMS: Council for International Organizations of Medical Sciences.

CPMP: (E.U.) Committee for Proprietary Medicinal Products (presently Committeee for Medicinal Products for Human Use, CHMP)

CRADA: Cooperative Research and Development Agreement.

CRF: Case Report Form.

CRO: Contract Research Organization.

DoD: (U.S.) Department of Defense.

DSMB: Data and Safety Monitoring Board.

EBM: Evidence-Based Medicine.

EGE: (E.U.) European Group on Ethics in Science and New Technologies.

EMEA: European Medicines Agency (previously European Agency for the Evaluation of Medicinal Products).

EPAR: European Public Assessment Report.

ESC: Embryonic Stem Cells.

FDA: (U.S.) Food and Drug Administration.

FDCA: (U.S.) Food, Drug, and Cosmetic Act.

Fed.Reg.: (U.S.) Federal Register.

FF: (Switzerland) from the French: Feuille Fédérale.

FOIA: (U.S.) Freedom of Information Act.

FOPH: (Swiss) Federal Office for Public Health.

GAO: (U.S.) General Accounting Office.

GCP: Good Clinical Practices.

GLP: Good Laboratory Practices.

GMP: Good Manufacturing Practices.

HHS: (U.S.) Department of Health and Human Services.

HUG: (Switzerland) from the French: Hôpitaux Universitaires de Genève; translation. (Geneva University Hospitals).

(16)

IBD: International Birth Date (of a drug).

ICCPR: International Covenant on Civil and Political Rights.

ICF: Informed Consent Form.

ICH: International Conference on Harmonisation.

IFPMA: International Federation of Pharmaceutical Manufacturers Associations.

IND: (U.S.) Investigational New Drug.

IOCM: Intercantonal Office for the Control of Medicaments.

IRB: (U.S.) Institutional Review Board (an institutional ethics committee).

JAAC: (Switzerland) from the French: Jurisprudence des autorités administratives de la Confédération.

JAMA: Journal of the American Medical Association.

JdT: (Switzerland) from the French: Journal des Tribunaux.

MAH: Marketing Authorization Holder.

NBAC: (U.S.) National Bioethics Advisory Commission.

NCE: New Chemical Entity.

NCI: (U.S.) National Cancer Institute.

NDA: (U.S.) New Drug Application.

NIH: (U.S.) National Institutes of Health.

NLS: Nonclinical Laboratory Study.

NNT: Number Needed to Treat.

OHRP: (U.S.) Office of Human Research Protections.

OIG: (U.S.) Office of Inspector General.

OTA: (U.S.) Office of Technology Assessment.

OTC: Over-the-counter (medicines).

PhRMA: Pharmaceutical Researchers and Manufacturers of America.

PHS: (U.S.) Public Health Service.

PI: Principal Investigator.

PIL: (E.U.) Patient Information Leaflet.

PSURs: Periodic safety update reports.

QoL: Quality of Life.

R&D: Research and Development.

RCT: Randomized Clinical Trial.

REC: Research Ethics Committee.

RRR: Relative Risk Reduction.

RS: (Swiss) from the French: Recueil systématique du droit fédéral.

Rx: Prescription (drugs).

SAE: Serious Adverse Event.

SAMS: Swiss Academy of Medical Sciences.

SSCI: Swiss Society of Chemical Industries.

SEC: (U.S.) Securities and Exchange Commission.

SECO: (Swiss) State Secretariat for Economic Affairs.

SJ: (Swiss) Semaine Judiciaire.

SMO: Site Management Organization.

SNSF: Swiss National Science Foundation.

(17)

SOP: Standard Operating Procedures.

SPC: (E.U.) Summary of Product Characteristics.

SSCI: Swiss Society of Chemical Industries.

U.S.C.: (U.S.) United States Code.

WMA: World Medical Association.

(18)

(19)

Swiss Legal Texts

CC: In French: “Code civil suisse”; December 10, 1907; RS 210.

CO: In French: “Code des obligations suisse”; March 30, 1911; RS 220.

CP: In French: “Code pénal suisse”; December 21, 1937; RS 311.

Cst: Swiss Constitution; April 18, 1999; entered into force on January 1, 2002;

RS 101.

(LATh) (In French: “Loi sur les agents thérapeutiques”; former name of the LPTh when initially proposed by the Federal Council)

LRFP: In French: “Loi fédérale sur la responsibilité du fait des produits”; my transla- tion: Federal Law on product liability; June 18, 1993; entered into force on January 1, 1994; RS 221.112.944.

LPD: In French: “Loi fédérale sur la protection des données”; my translation: Fed- eral Law on data protection; June 19, 1992; entered into force on July 1, 1993; RS 235.1.

LPMA: In French: “Loi fédérale sur la procréation médicament assistée”; my transla- tion: Federal Law on medically assisted procreation; December 18, 1998;

entered into force on January 1, 2001; RS 814.90.

LPTh: In French: “Loi fédérale sur les produits thérapeutiques”; my translation:

Federal Law on therapeutic products; December 15, 2000; entered into force on January 1, 2002; RS 812.21.

LRCS: In French: “Loi fédérale relative à la recherche sur les cellules souches embry- onnaires”; my translation: Federal Law on embryonic stem cell research;

December 19, 2003; entered into force on March 1, 2005; RS 810.31.

OAMéd: In French: “Ordonnance sur les autorisations dans le domaine des médica- ments”; my translation: Federal Council’s Ordinance on authorizations in the sector of pharmaceuticals; October 17, 2001; entered into force on January 1, 2002; RS 812.212.1.

OASMéd: In French: “Ordonnance de l'Institut Suisse des produits thérapeutiques sur l'autorisation simplifiée et l'annonce obligatoire des médicaments”; my trans- lation: Swissmedic’s Ordinance on the simplified authorization and the mandatory notification of pharmaceuticals; November 9, 2001; entered into force on January 1, 2002; RS 812.212.23.

OClin: In French: “Ordonnance sur les essais cliniques”; my translation: Federal Council’s Ordinance on clinical trials; October 17, 2001; entered into force on January 1, 2002; RS 812.214.2.

OEMéd: In French: “Ordonnance de l’Institut Suisse des produits thérapeutiques sur les

exigences relatives à l’autorisation de mise sur le marché des médicaments”; my

(20)

translation: Swissmedic’s Ordinance on the requirements regarding the marketing authorization for pharmaceutical products; November 9, 2001; entered into force on January 1, 2002; RS 812.212.22.

OLPD: In French: “Ordonnance relative à la loi fédérale sur la protection des données”;

my translation: Federal Council’s Ordinance regarding the LPD; June 14, 1993, entered into force on July 1, 1993; RS 235.11.

OMéd: In French: “Ordonnance sur les médicaments”; my translation: Federal Council’s Ordinance on pharmaceuticals; October 17, 2001; entered into force on January 1, 2002; RS 812.212.21.

ORCS: In French: “Ordonnance relative à la recherche sur les cellules souches embry- onnaires”; my translation: Federal Council’s Ordinance regarding embry- onic stem cell research; February 2, 2005; entered into force on March 1, 2005; RS 810.311.

OUC: In French: “Ordonnance sur l'utilisation des organismes en milieu confiné”;

my translation: Ordinance on the use of organisms in confined settings;

August 25, 1999; entered into force on November 1, 1999; RS 814.912.

Swiss Draft Laws (as of July 2005)

LAGH: In French: “Loi fédérale sur l’analyse génétique humaine”; my translation:

Federal Law on human genetic analysis; October 8, 2004; no RS number yet.

LTrans: In French: “Loi fédérale sur le principe de transparency dans l’administration”;

my translation: Federal Law on transparency in the administration; De- cember 17, 2004, no RS number yet.

LTransplant: In French: “Loi sur la transplantation d’organes, de tissus et de cellules”; my translation: Federal Law on transplantation; October 8, 2004; no RS number yet; my abbreviation.

U.S. Legal Texts

Title 21 (Food and Drugs) of United States Code (U.S.C.), chapter 9 (Federal Food, Drug, and Cosmetic Act), subchapter 5 (drugs and devices), part A (drugs and devices), particularly § 355(a) and § 355(b).

Title 21 (Food and Drugs) of the Code of Federal Regulations (C.F.R.), particularly part 50 (protection of human subjects), part 54 (financial disclosure by clinical investigators), 56 (institutional review boards), part 312 (investigational new drug application).

Title 45 (Public Welfare) of the Code of Federal Regulations (C.F.R.) part 46 (protection

of human subjects) (§ 46.101 to §46.409).

(21)

E.U. Legal Texts

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Mem- ber States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal product for human use, published in the Official Journal (“OJ”) L 121, 1.5.2001, p.34; entered into force on May 5, 2001.

Consolidated Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human use, published in OJ L 311, 28.11.2001, p. 67-128, as modified in particular by Directive 2004/27/EC of 31 March 2004, published in OJ L 136, 30.04.2004, p. 34-57.

Regulation 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medici- nal products for human and veterinary use and establishing a European Medicines Agency, published in OJ L 136, 30.4.2004. p. 1-33.

European Commission, Detailed guidance on the collection, verification and presenta- tion of adverse reaction reports arising from clinical trials on medicinal products for human use, April 23, 2004.

European Commission, Detailed guidance on the European database of Suspected Un- expected Serious Adverse Reactions (Eudravigilance – Clinical Trial Module), April 23, 2004.

European Commission, Detailed guidance on the European clinical trials database (EUDRACT Database), April 23, 2004.

European Commission, Detailed guidance on the application format and documenta- tion to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use, April 23, 2004.

European Commission, Detailed guidance for the request for authorisation of a clinical

trial on a medicinal product for human use to the competent authorities, notification of

substantial amendments and declaration of the end of the trial, April 23, 2004.

(22)

(23)

1.1. Scope of the thesis

The objective of this thesis is to present a thorough review of clinical trial regulations.

The analysis is limited to clinical trials of drugs, more precisely therapeutic drugs.

¹

Trials of diagnostic drugs and vaccines present certain distinct features and are therefore not discussed in any depth.

²

Clinical trials of medical devices (e.g., an artificial hip) and therapeutic procedures (e.g., heart surgery)

³

are also beyond the scope of this thesis as they obey partly different rules.

⁴

Treatments that do not involve a therapeutic product, such as psychological (e.g., psychotherapy), behavioral (e.g., physical exercise

⁵

) or nutri- tional (e.g., low-fat diet

⁶

) studies, are not reviewed.

Programs extending compassionate access to experimental drugs share common characteristics with clinical trials and will be analyzed in subsection 3.4.6.2.

1 The words “drug” and “pharmaceutical” are used interchangeably in this thesis. The term “drug” is the one commonly used in the United States. It is also the expression most frequently encountered in the medical literature. I refer – of course – to licit drugs, not illegal substances

2 Pharmaceuticals include drugs administered not only to prevent and treat diseases, but also to diagnose them. See also NCI (U.S. National Cancer Institute), Data and Safety Monitoring Guidelines, at

http://www.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines/page2 (explaining when use of a diagnostic test involves a clinical trial). Many diagnostic products can be approved without extensive testing directly on humans (i.e., administration of the investigational product to human research subjects). Instead, tests may be performed on biological material.

3 On clinical trials of surgical procedures, see for instance Karen Antman et al., Designing and Funding Clinical Trials of Novel Therapies, 344 NEW. ENG. J. MED. 762-763 (Mar. 8, 2001), at

http://content.nejm.org/cgi/reprint/344/10/762.pdf; Nicholas J. Petrelli, Clinical Trials Are Mandatory for Im- proving Surgical Cancer Care, Editorial, 287 JAMA 377-78 (2002), at

http://jama.ama-assn.org/cgi/reprint/287/3/377.pdf; Peter McCulloch et al., Randomised trials in surgery:

problems and possible solutions, 323 BMJ 1448-51 (June 15, 2002), at

http://bmj.bmjjournals.com/cgi/reprint/324/7351/1448.pdf; Henry K. Beecher, Ethics and Experimental Therapy, 186 JAMA 858-59 (Nov. 30, 1963) (stressing the need to distinguish between the placebo effect and the true results of surgery).

4 See Lars Noah, Informed Consent and the Elusive Dichotomy Between Standard and Experimental Therapy, 28 AM. J. L. AND MED. 361, at 392 (2002). Noah highlights the paradox in that studies of surgical techniques and other non-drug therapy are relatively unregulated. See also ARTHUR AND ELAINE SHAPIRO, THEPOWERFUL PLACEBO, FROMANCIENTPRIEST TO MODERNPHYSICIAN 83 (John Hopkins University Press 1997) [hereinafter THE SHAPIROS].

5 See, e.g., Matti Viljanen et al., Effectiveness of dynamic muscle training, relaxation training, or ordinary activity for chronic neck pain: randomised controlled trial, 327 BMJ 475 (Aug. 30, 2003)

http://bmj.com/cgi/reprint/327/7413/475.pdf; John M. Jakicic et al., Effect of Exercise Duration and Intensity on Weight Loss in Overweight, Sedentary Women, A Randomized Trial,290 JAMA 1323-1330 (2003), at http://jama.ama-assn.org/cgi/reprint/290/10/1323.pdf.

6 A nutritional study can also be combined with a drug clinical trial. See, e.g., David J. A. Jenkins et al., Effects of a Dietary Portfolio of Cholesterol-Lowering Foods vs Lovastatin on Serum Lipids and C-Reactive Protein, 290 JAMA 502-510 (2003), at http://jama.ama-assn.org/cgi/reprint/290/4/502.pdf.

(24)

1.2. Focus of the thesis

This thesis strives to approach the topic from a multidisciplinary perspective. To fully understand clinical trials, I believe that it is crucial to expand the focus beyond statutes, regulations and case law; it is essential to further consider guidelines as well as medical and economic literature.

1.2.1. A broad regulatory outlook

The Swiss Law on therapeutic products (“LPTh”)

⁷

and the Swiss Ordinance on clinical trials (“OClin”)

⁸

constitute the main subject matter of this thesis.

⁹

I aim to highlight their weaknesses, inconsistencies, and gaps. I am therefore chiefly interested in administrative law, while civil law only plays a peripheral role here.

¹⁰

The thesis looks into both binding and non-binding regulatory prescriptions. Refer- ences to guidelines are indispensable because laws and ordinances contain only few general provisions. Statutory material chiefly contains procedural rules (e.g., a 30 day deadline to issue an opinion), while substantive rules are mostly explained by guide- lines (e.g., how an ethics committee should reach its decisions). Furthermore, non- binding guidelines have long been at the basis of Western countries’ legislations con- cerning clinical trials. These were not devised by parliaments, but by medical associa-

7 See Federal Law on therapeutic products of December 15, 2000; RS 812.21; entered into force on January 1, 2002; in French: “Loi fédérale sur les médicaments et les dispositifs médicaux (loi sur les produits thérapeu- tiques)”; abbreviated (from the French): LPTh; text in English (unofficial translation) at

http://www.swissmedic.ch/files/pdf/HMG_English_New_version.pdf; in French at http://www.admin.ch/ch/f/rs/8/812.21.fr.pdf; in German at

http://www.admin.ch/ch/d/sr/8/812.21.de.pdf; in Italian at http://www.admin.ch/ch/i/rs/8/812.21.it.pdf.

The LPTh was the subject of debate before the Swiss Parliament from March to December 1999. The tran- scripts of these discussions are available from

http://www.parlament.ch/ab/frameset/d/n/4602/8187/d_n_4602_8187_8363.htm. The Federal Council issued its Message on March 1, 1999; FF 1999 3151; text (in French) at

http://www.bag.admin.ch/heilmitt/gesetz/f/botschaft%20hmg_f.pdf. Previously, a draft law (then called law on therapeutic agents or “LAth”) had been circulated among interested parties for comments. See Depart- ment of Home Affairs (“DHA”), Rapport sur les résultats de la procédure de consultation concernant l’avant- projet de loi sur les agents thérapeutiques [Report on the results of the consultation procedure regarding the draft law on therapeutic agents], (Dec. 8, 1997) [hereinafter DHA 1997 Consultation Report]; DHA, Rapport explicatif sur l’avant-projet de loi sur les agents thérapeutiques [Explicative Report on the draft law on therapeutic agents], (Feb. 19, 1997) [hereinafter DHA 1997 Explicative Report]. See also Paul Richli, Instrumente des Gesundheits- und Lebensschutzes im neuen Heilmittelgesetz vor dem Hintergrund der Grundrecht, 3/2002 PRATIQUE JURIDIQUE ACTUELLE(PJA) 340-44 (2002).

8 See Federal Council’s Ordinance on clinical trials of therapeutic products of October 17, 2001; RS 812.124.2;

entered into force on January 1, 2002; in French: “Ordonnance sur les essais cliniques de produits théra- peutiques”; abbreviated (from the French): OClin; text in French at

http://www.admin.ch/ch/f/rs/8/812.214.2.fr.pdf; in German at http://www.admin.ch/ch/d/sr/8/812.214.2.de.pdf; in Italian, at http://www.admin.ch/ch/i/rs/8/812.214.2.it.pdf.

The OClin is loosely based on a proposed text prepared by the Federal Office for Public Health (“FOPH”) in December 2000; this draft is cited hereinafter as the “2000 draft OClin.”

9 When referring to the LPTh and the OClin jointly, I speak of the “2002 Federal Regulation.”

10 Issues regarding contract law (e.g., qualification of the legal relationship between the investigator and the subject) and tort law (e.g., liability of the investigator toward the subject) are only briefly addressed (see respectively subsection 8.2. and 8.6.5.).

(25)

tions, international organizations, commissions and courts. The consequence is that statutes tend to lag behind the guidelines that these groups regularly produce. For ex- ample, the Swiss legislation on clinical trials

¹¹

is a much abridged version of key inter- national guidelines.

¹²

One difficulty is that all guidelines are not equally observed. While the pharmaceu- tical industry consistently abides by guidelines of the International Conference on Harmonization (“ICH”), they pay less attention to others, such as those of the Council for International Organizations of Medical Sciences (“CIOMS”). To indicate that a pre- scription is not necessarily strictly followed, I use the modal verb “should,” instead of

“must.”

¹³

For example, the principle according to which pharmaceutical companies are to offer the investigational product to former research subjects who responded posi- tively to the drug is not strictly compulsory;

¹⁴

I would therefore write that the company should – and not, must – offer follow-up supplies of the investigational product.

1.2.2. Medical literature

Pharmaceutical regulations have not been the preserve of jurists and lawyers. Regula- tory departments of pharmaceutical companies are not staffed by jurists, but by people with medical, biological, or chemical backgrounds. For a long time, the regulatory norms that these people had to master were not found in laws or ordinances, but in technical guidances. There was very little case law because law suits deriving from clinical trials were fairly rare.

One consequence of this situation is that comments on these guidances were mostly published in medical journals. This is still partly true today. For example, over the last fifty years, the most comprehensive discussions of issues related to informed consent of research subjects has taken place in medical, and not legal journals. Moreo- ver, medical articles exhibit a practical perspective that legal journals sometimes lack.

¹⁵

Lastly, I think basic knowledge of medical concepts is important to understand how clinical trials are conducted and regulated. However, I would like to draw the readers’ attention to the fact that I have neither medical expertise nor a scientific back- ground. This should make this thesis all the more comprehensible to nonscientists.

11 I refer here to the Law on therapeutic products (LPTh) together with the Ordinance on clinical trials (OClin).

12 The OClin takes was inspired by the ICH E6 Guideline. See International Conference on Harmonization’s Harmonized Tripartite E6 Guideline for Good Clinical Practice, (Step 4 of ICH Process), (May 1, 1996), from http://www.ich.org/cache/compo/475-272-1.html#E6 [hereinafter ICH E6].

13 As the FDA says in its own guidelines, “[t]he use of the word should … means that something is suggested or recommended, but not required.” See, e.g., FDA, Fast Track Drug Development Programs – Designation, Development, and Application Review, Guidance for Industry, at 1 (July 2004), at

http://www.fda.gov/cber/gdlns/fsttrk.pdf.

14 This principle is continuing to gain in importance; providing post-trial access may become a strictly compulsory component of trial organization in the future. See subsection 8.6.2.3. below

15 For example, medical articles are often based on surveys designed to find out how the informed consent process is understood by clinical researchers and human research subjects.

(26)

1.2.3. Economic literature

I find numbers and statistics fascinating. I acknowledge that they can be misleading, but I have nonetheless chosen to use them extensively. Figures shed an instructive light on the topics under review; they flesh out the subject matter. Although one might argue that the issue of, say, clinical trial costs is beyond the scope of a legal thesis, I consider it indispensable to grasp the impact of clinical trials.

1.2.4. Ethics

When hearing the expression “clinical trial,” “ethics” immediately comes to mind.

However, I have deliberately left general ethical issues (e.g., the Dignity of Human Be- ings) aside. What is ethics or bioethics? How do they differ from religious morality or professional deontology? How can they be delineated in concrete cases? These are all thorny (and possibly unanswerable) questions that I will not discuss here.

¹⁶

I will only comment on ethical doctrines to the extent that they are incorporated into guidelines. In any event, existing guidelines are so excruciatingly detailed that, in my view, they ob- viate the need to apply general ethical principles.

1.3. Laws under analysis

Regulation of clinical trials is analyzed chiefly under Swiss law. However, to under- stand Swiss regulations, it is helpful to refer to those of other countries, in particular the United States.

¹⁷

Several reasons justify this broader orientation.

First, the Swiss regulatory system is not as elaborate as the American.

¹⁸

To illustrate this, the U.S. Food and Drug Administration (“FDA”)

¹⁹

regulations on clinical trials span some 40 pages,

²⁰

whereas the Swiss equivalent Ordinance is only 14 pages long.

²¹

16 For possible approaches, see for example TOML. BEAUCHAMP & JAMES F. CHILDRESS, PRINCIPLES OF BIOMEDICAL ETHICS, mainly at chapters 1, 2, 8 and 9 (Oxford Univ. Press, 5^th ed., 2001). See also DOMINIQUESPRUMONT, LA PROTECTION DES SUJETS DE RECHERCHE NOTAMMENT DANS LE DOMAINE BIOMÉDICAL, at 53-62 (Ed. Staempfli, Berne, 1993) [hereinafter SPRUMONT]; Dominique Sprumont, Regard critique sur les rapports entre éthique et droit médical, 40(3/4) CMS 255-68 (1996); DOMINIQUE MANAÏ, LES DROITS DU PATIENT FACE À LA MÉDECINE CONTEMPORAINE at 29-30 and at 44-45 (Helbing & Lichtenhahn, 1999) [hereinafter MANAÏ(CONTEMPORAINE)].

See also the excellent comments regarding the flaws in some bioethical reasonings, Alexandre Mauron, Re- cherche biomédicale, l’éthique sur la brèche, 2419 MED. ET HYG. (Jan. 8, 2003), at

http://www.revmed.ch/article.php3?sid=22762, and Part II, 2420 MED. ET HYG. (Jan. 15, 2003), at http://www.revmed.ch/article.php3?sid=22810; Bioéthique et sciences humaines: quel dialogue, quelles missions ! MED. ET HYG., at !

http://www.revmed.ch/article.php3?sid=22443;

17 When a chapter successively describes Swiss and U.S. regulations, the Swiss subsection usually comes first.

18 In this thesis, I refer mostly to regulations applicable to FDA-governed clinical trials. Trials receiving federal funding, for example from the NIH, follow slightly different rules set forth by the Department of Human Health and Services (“HHS”). See subsection 2.3.2. below.

19 Home page of the FDA, at http://www.fda.gov.

20 See 21 C.F.R. [Code of Federal Regulations] § 312.1 to § 312.145, from

http://www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312. The number of FDA guidelines also far exceeds those of Swissmedic. For 2000 alone, the FDA’s Center for Drug Evaluation and

(27)

The American drug agency, the FDA, has some 9,000 employees, including 700 who only deal with drug applications;

²²

in comparison, the Swiss drug agency, Swiss- medic,

²³

only has 265 employees.

²⁴

The FDA spent some $187 million in 2000 to review new drug applications (“NDAs”);

²⁵

its total budget in 2003 exceeded $1,7 billion,

²⁶

com- pared with CHF 54.5 million for the entire Swissmedic’s operations.

²⁷

According to the FDA’s own slogan, “drug review and approval in the United States now represent the international gold standard.”

²⁸

Second, the United States is a country with a population of over 280 million peo- ple.

²⁹

This is bound to result in more lawsuits. For instance, U.S. courts have issued dozens of decisions pertaining to the conduct of clinical trials in general, and the rights of subjects in particular.

³⁰

In sharp contrast until 2005, there were no reported decisions by Swiss courts.

³¹

The consequence is that many legal questions which are left unan- swered in Switzerland have found a legal solution under U.S. law.

Third, information originating from the United States is infinitely easier to access than information from Switzerland. For example, accounts of abuses in experimental research are broadly divulged to the American public.

³²

The FDA has always acknowl- edged the value of transparency.

³³

In contrast, what happens in Swiss clinical trials tends to stay confidential: there are no lawsuits, no Freedom of Information Act

Review (“CDER”) issued 40 guidelines. Office of Inspector General (“OIG”), FDA’s Review Process for New Drug Applications, A Management Review, at 8, (Mar. 2003) (OEI-01-01-00590), at

http://oig.hhs.gov/oei/reports/oei-01-01-00590.pdf [hereinafter OIG (FDA Review)].

21 This Ordinance is the “OClin,” see note 8 supra.

22 See FDA, Protecting Consumers, Promoting Public Health (Apr. 2000), at

http://www.fda.gov/oc/opacom/fda101/fda101text.html; OIG (FDA Review), supra note 20, at ii.

23 The full name of Swissmedic is the Swiss Agency for Therapeutic Products.

24 E-mail of Dr Michel Ballif, Swissmedic, (Mar. 28, 2004) (on file with author).

25 See OIG (FDA Review), supra note 20, at 2. Of these $187 million, $86 were paid by the industry through

“user fees.” Id. Note that all “$” signs refer to U.S. dollars.

26 See FDA, Budget Proposal for FY 2003, FDA Talk Paper, (Feb. 4, 2002), at

http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01135.html; FDA, Budget Proposal for FY 2004, FDA Talk Paper, (Feb. 3, 2003), at http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01195.html.

27 E-mail of Dr Michel Ballif, supra note 24.

28 Letter of the FDA to the Inspector General (Dec. 24, 2002), printed in OIG (FDA Review), supra note 20, at 25 (emphasis in the original text).

29 See Census Bureau, U.S. Summary 2000, Census 2000 Profile (July 2002), at http://www.census.gov/prod/2002pubs/c2kprof00-us.pdf.

30 Court decisions on the reimbursement of experimental treatments by insurance plans are not taken into account.

31 In its ATF 114 Ia 350, the Swiss Supreme Court had to decide, in abstracto, whether a Geneva law requiring informed consent (for ordinary medical interventions and for medical research, though under different terms) was constitutional. The Court did not rule on a concrete case involving clinical trials. In its decision of July 4, 2003 (2A.450/2002), the Court had to rule on the admissibility of an ethic committee. Once again, it was not a decision on a specific clinical trial (see also infra note 2135). Finally, in August 2005, the Swiss Supreme Court had decide whether a non-interventional study falls within the definition of a clinical trial and therefore is subject to prior review and clearance by Swissmedic (2A.522/2004).

32 It is also significantly easier to trace back regulation of clinical trials in U.S. history than in Swiss history.

There is little historical information available about the IOCM, while the FDA has done excellent work in con- serving historical data and making them easily available. See, e.g., FDA, FDA History, at

http://www.fda.gov/oc/history/default.htm.

33 See as early as 1973, Peter Barton Hutt, Philosophy of Regulation under the Federal Food, Drug and Cos- metic Act, 50 FOOD& DRUGL.J. 101, at 104 (1995), initially published in 28 FOODDRUGCOSM. L.J. 177 (1973).

(28)

(“FOIA”),

³⁴

and scant investigative journalism.

³⁵

This explains why the section on U.S.

scandals is much more detailed than its Swiss counterpart

(see subsections 2.2.2. and 2.3.1.

below)

.

Finally, there is a tendency in Switzerland to defer to the opinions of the FDA and, to a similar degree, to those of the European Medicines Agency (“EMEA”).

³⁶

It is in- creasingly perceived as an anomaly that a small country like Switzerland should have a full-fledged regulatory drug system. This is particularly obvious with respect to mar- keting authorizations.

³⁷

With respect to clinical trials, the question is whether Switzer- land could justify regulations that would differ from those of the United States or the European Union. Could it claim that it knows better or that local circumstances warrant different solutions? In my view, the answer is no. Swiss clinical trial regulations should – and will – grow to resemble those of leading industrialized nations – even if this hurts Swiss national pride. Reference to the ICH guidelines

(see further subsection 4.3.1. below)

illustrates this point: The substantive provisions of the Swiss Ordinance on clinical trials are generally less precise, less clear, and less complete than those of the ICH.

³⁸

A more elegant solution would have been to include in this Ordinance only provisions that add to (e.g., procedural rules), or perhaps contradict, the ICH Guideline.

³⁹

By and large, Swiss, U.S., and E.U. regulations have a lot in common.

⁴⁰

When legal provisions are essentially similar, the corresponding reference is simply given in a foot- note.

⁴¹

However, when Swiss regulations do differ from those of the United States or of

34 In the United States:5 U.S.C. § 552, at http://www.nih.gov/icd/od/foia/efoia.htm. In December 2004, over- coming some difficulties, the Swiss Parliament succeeded in adopting a Federal Law on the transparency of the administration (”LTrans“), but the law has not yet entered into force.

35 The same is apparently true for other European countries. See for instance in France, M. Ezratty, Opening of Symposium, 4 (special issue) INTERN. J. OF BIOETH. 8 (Mar. 1993).

36 Home page at http://www.emea.eu.int. This name was changed from "European Agency for the Evaluation of Medicinal Products." See whereas (2) of the Regulation 726/2004 of the European Parliament and of the Council of 31 March 2004, laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, OJ L 136, 30.4.2004, p.1-33, at

http://pharmacos.eudra.org/F2/eudralex/vol-1/REG_2004_726/REG_2004_726_EN.pdf.

37 Why should Swissmedic duplicate the work that has already been conducted thoroughly in the United States or in the European Union? It makes little sense. Agencies throughout the world are supposed to receive essentially the same files on which they then base their opinions. Hence, the key difference is how they will interpret them. In most cases, all agencies reach the same decision as to whether a marketing authorization should be granted. There are only few instances of disagreement. Do they justify the time and money spent by Swissmedic? This question goes beyond the scope of this thesis and therefore needs not be further ex- plored – although, in my opinion, the answer is no.

See, e.g., interpellation by Swiss Parliamentary member Simonetta Sommaruga of March 22, 2002, and answer of the Swiss Federal Council on June 14, 2002, at

http://www.parlament.ch/afs/data/f/gesch/2002/f_gesch_20023168.htm.

38 The ICH E6 Guideline is made applicable under Article 53.1 LPTh and Article 4.1 OClin.

39 Ummel and Mandofia made a similar point with respect to the former IOCM regulation and its accompanying Good Clinical Practices; both texts had to be read in conjunction; they overlapped and partly contradicted each other. See Marinette Ummel & Marina Mandofia Berney, Le règlement sur les médicaments au stade d’essai clinique de l’OICM et la protection des sujets de recherche, 93 SJZ 61 (1997) [hereinafter Ummel &

Mandofia]. The same can be said of the OClin and the ICH E6.

40 To simplify the text, I sometimes refer to the United States, the European Union and Switzerland as three regions.

41 Citation format follows the U.S. “Bluebook.” (a uniform system of citation, 17^th ed). However, references to Internet (URL) addresses do not strictly follow rule 18.2.1.(b) of the Bluebook. Instead, they are indicated with a simple “at.” Moreover, footnotes from cited material are always omitted.

(29)

the European Union, the differences are explained in a distinct subsection. Divergences are slightly more frequent vis-à-vis U.S. law for two reasons. First, Swiss regulators are particularly careful to maintain compatibility with E.U. law.

⁴²

Second, the FDA tends to act as a pioneer. It usually takes the Swiss agency – Swissmedic

⁴³

– and the European central authority – the EMEA – a few years to emulate the example set by the FDA.

⁴⁴

1.4. Plan of the thesis

This thesis is divided in three parts.

Part I goes over general issues, starting with an historical overview. It then analyzes the definition of clinical trials and reviews the scope of existing Swiss regulations. It explores economic aspects related to clinical trials. Information in this subsection should contribute to a more accurate understanding of the role and importance of clini- cal trials.

Part II contains the technical and scientific standards governing clinical trials. It de- scribes the role played by all key participants in clinical trials. It presents the various means currently utilized to achieve reliable clinical trial results by minimizing sources of bias.

⁴⁵

It provides “medical” notions that jurists may not be acquainted with.

Part III focuses chiefly on legal provisions. It is the part with the greatest focus on Swiss statutory provisions. Part III is further divided into four sections, respectively reviewing the procedures governing trial approvals, the rights of human research sub- jects (i.e., volunteers in a clinical trial), reporting obligations during a clinical trial, and publication policies after trial completion.

A list of abbreviations and a glossary are provided. Words that are defined in the glossary are indicated in the main text with an asterisk. A short index at the end of the thesis should make it possible to rapidly find particular issues.

You will notice that this text is replete with footnotes, especially in the first two parts of the thesis. To highlight those that contain interesting citations, – as opposed to footnotes only containing supporting data or references to legal norms –, I have put in bold type their footnote reference. I went to great efforts to systematically provide the

42 See, e.g., decision of the Swiss appeal commission for pharmaceuticals, JAAC 67.58, at point 2.3.1. (Dec. 23, 2002), at http://www.vpb.admin.ch/franz/doc/67/67.58.html. See more generally, Articles 4.2, 9.1, 11.2.a, 14.1, 53.1 LPTh and Article 26.1 OClin referring to international norms. See also subsection 4.3.3. below.

43 See Swissmedic’s home page in English, at http://www.swissmedic.ch/?lang=2.

44 The regulation of orphan* drugs is a good example. To encourage pharmaceutical companies to develop treatments for these rare diseases, the United States offers them special periods of exclusivity (a monopoly right somewhat similar to a patent). The European Union subsequently adopted an analogous system of in- centives. See Regulation (EC) No 141/2000 of the European parliament and of the Council of 16 December 1999 on orphan medicinal products, in particular at whereas n° (2) and (8), at http://europa.eu.int/eur- lex/pri/en/oj/dat/2000/l_018/l_01820000122en00010005.pdf [hereinafter Regulation 141/2000/EC]. See also European Forum for Good Clinical Practice (“EFGCP”), The EFGCP News, at 7 (Spring 2002), at http://www.efgcp.org/webitems/doc/newsletters/2002_Spring.pdf. Switzerland intends to amend the existing OASMéd to facilitate the development of orphan drugs; the changes would take effect in 2005 or 2006.

45 “Bias is any influence that distorts the outcome [of a clinical trial, leading to] erroneous conclusions.” Vari- ability, probability and power, 4 STATISTICS IN DIVIDED DOSES (May 2002), at

http://www.ukmi.nhs.uk/Research/Documents/STATSDIVIDEDNO4.pdf. See further subsection 6.3.

(30)

URLs for cited documents.

⁴⁶

URLs are however highly perishable information and I apologize in advance for the inevitable frustration caused by outdated Internet ad- dresses.

⁴⁷

Given the very large number of references, the bibliography I have included only lists the books and articles most often cited.

Finally, I endeavored to take into account materials published until the end of June 2004.

⁴⁸

However, important legal changes under Swiss law have been incorporated if they occurred before July 2005.

46 In addition, some websites require user registration (e.g., Medscape), while others require subscription (e.g., the New England Journal of Medicine).

47 My website (www.pharmalaw.org) also contains some of the material cited in this thesis (e.g., IOCM documents).

48 Several Swiss ordinances, including the one on clinical trials, underwent (usually minor technical) changes, which went into force on September 1, 2004. These minor modifications are mentioned in the footnotes, usually referring explicitly to the 2004 revision (e.g., under the 2004 OClin revision …).

(31)

2. Historical overview of clinical trial regulations

Drug and clinical trial regulations are an achievement of the second half of the 20

^th

century. While experimentation on animals was well developed already in the mid- 1800s,

⁴⁹

scientific experimentation of drugs on human beings was rare until the begin- ning of the 20

^th

century.

⁵⁰

Physicians relied on their own intuition … with the result that most remedies were at best ineffective.

⁵¹

Scientific experimentation on human beings took off in the 1960s. Concomitantly, reports of experiments started to receive widespread publicity in medical and layman journals.

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.

⁵³

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

“guinea pigs.”

⁵⁴

Protection of research participants enrolled in clinical studies

⁵⁵

(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)].

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

(see subsection

2.3.

below)

.

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

⁵⁶

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

⁵⁷

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.

⁵⁸

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.

⁵⁹

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 experimentation. Instead of a purely scientific-medical view point, the Nuremberg Code introduces a legal and ethical perspective.

⁶⁰

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.

⁶¹

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

below)

. 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^HENAZI 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].

(33)

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,

⁶²

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

⁶³

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

⁶⁴

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

⁶⁵

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

⁶⁶

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.

⁶⁷

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

⁶⁸

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

⁶⁹

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 experimentation 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 informed 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 experiment…. 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).

(34)

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

⁷⁰

Although the Nuremberg Tribunal purported to codify preexisting ethical princi- ples,

⁷¹

there had not been any previous comprehensive (national or international) regulation of clinical trials.

⁷²

At best, one could cite a few isolated national regulatory attempts.

⁷³

The earliest guidelines were adopted by pre-war Prussia at the start of the 20

^th

century.

⁷⁴

Ironically, the most comprehensive and humane text was a 1931 Nazi Guideline;

⁷⁵

its ethical principles reached even further than the Nuremberg Code.

⁷⁶

In the United States, a few courts had taken into consideration the lack of informed con- sent by the patient to rule on malpractice cases brought against doctors trying experi- mental treatments.

⁷⁷

Paradoxically given the American influence on the entire process, the Nuremberg Medical Trial and the ensuing Code received little press coverage in the United States.

Consequently, for the next two decades, researchers saw the Code’s relevance as fun- damentally limited to Nazi Germany.

⁷⁸

The Code was also viewed as extremely strict,

70 See, e.g., GEORGEJ. ANNAS ET AL., INFORMEDCONSENT TOHUMAN EXPERIMENTATION: THESUBJECT’SDILEMMA, at 7 (Ballinger Publishing Company 1977), chapter 1 (Origins of the Law of Informed Consent to Human Experi- mentation) [hereinafter Annas (Dilemma)].

71 The Tribunal was not entitled to formulate original legal norms. Pursuant to the principle of legality and non- retroactivity, it had to apply existing legal principles. See Jay Katz, The Consent Principle of the Nuremberg Code: Its Significance Then and Now, in THENAZI DOCTORS AND THE NUREMBERGCODE227, 236 (Oxford Uni- versity Press 1992) [hereinafter Katz].

72 See Delon Human & Sev S. Fluss, The World Medical Association’s Declaration of Helsinki: Historical and Contemporary Perspectives, (July 2001), at 4, at

http://www.wma.net/e/ethicsunit/pdf/draft_historical_contemporary_perspectives.pdf [hereinafter Human &

Fluss]; Sharon Perley et al., The Nuremberg Code: An International Overview, in T^HENAZIDOCTORS AND THE NUREMBERGCODE149, 150 (Oxford University Press 1992); Jay Katz, supra note 71, at 228.

73 See, e.g., Grodin (Historical Origins), supra note 66, at 124-26 (Oxford University Press 1992); Sharon Perley et al., supra note 72, at 150-51 (Oxford University Press 1992).

74 See Vollmann & Winau, supra note 57. The authors discuss a first 1891 Prussian Directive prohibiting tuber- culosis experimentation on unwilling prison inmates. A few years later, a Prussian doctor – Albert Neisser – was accused of having injected syphilis to unwitting patients so as to test his investigational vaccine. Neisser was fined for not having obtained prior consent from his patients. Following the scandal, the Prussian Par- liament appointed a commission to investigate unethical conduct by physicians. The Commission issued a report stating basic principles of ethical research. The report was followed in 1900 by a ministerial directive which mandated prior informed consent for experiments taking place in hospitals. However, the directive was not legally binding. See also Grodin (Historical Origins), supra note 66, at 127-28; Marinette Ummel, La réglementation de l’expérimentation humaine et l’organisation des commissions d’éthique médicale en Suisse, at 3-6, Thèse genevoise médecine, n° 9219 (1991) (on file with the Library of the Medical School at the University of Geneva) [hereinafter Ummel (1990)]; Pierre Dayer, Limites de la recherche sur l’homme, 20 CAHIERS DE LA FACULTÉ DE MÉDECINE 57, at 58 (1991) [hereinafter Dayer (Limites)].

75 See Vollmann & Winau, supra note 57. The Guideline was still in effect during the second World War. See also Grodin (Historical Origins), supra note 66, at 129-32; Katz, supra note 71, at 227.

76 For Grodin, the 1931 Guideline was “visionary in [its] scope and depth.” Supra note 66, at 131.

77 See Annas (Dilemma), supra note 70, at 2-3 (in the United States, in addition to three cases from 1767, 1871 and 1895, there has been only “dozen additional cases … prior to World War II, and almost all dealt with them in a substantially similar manner, i.e. treating any departure from standard medical practice as

‘experimentation,’ and treating experimentation as something improper.” Id. at 3.).

On the 1960s U.S. malpractice crisis, see OLIVIER GUILLOD, LE CONSENTEMENT ÉCLAIRÉ DU PATIENT, AUTODÉTERMINATION OU PATERNALISME? 33 (Editions Ides et Calendes, 1986) (with reference to informed consent and liability issues).

78 Jay Katz puts it very well: “It was a good code for barbarians but an unnecessary code for ordinary physician-scientists.” Katz, supra note 71, at 228. See also JAMESH. JONES, BADBLOOD, THETUSKEGEESYPHILIS EXPERIMENT 179-80, and 188 (The Free Press 1981) [hereinafter JONES(TUSKEGEE)]; Ruth R. Faden et al., US Medical Researchers, the Nuremberg Doctors Trial and the Nuremberg Code: A Review of Findings of the