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.
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”)
7and the Swiss Ordinance on clinical trials (“OClin”)
8constitute the main subject matter of this thesis.
9I 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.
10The 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 is-sued 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 thera-peutic 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 re-spectively subsection 8.2. and 8.6.5.).
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
11is a much abridged version of key inter-national guidelines.
12One 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.”
13For 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;
14I 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.
15Lastly, 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 compul-sory 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.