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Because clinical trials attach importance to all adverse effects, whether minor or major, whether frequent or rare, they are able to ascertain a long list of such effects (see further

subsection 9.1.2. below)

. Of course, the list can never be exhaustive and may even include effects wrongly attributed to the drug. This is to be expected given that a large clinical trial enrolls “only” a few thousand subjects. Hence an adverse reaction that occurs only in 1 out of 5’000 patients will probably not be detected.

537

Likewise, clinical trials may not suffice to exclude or validate a causal link between an adverse effect and the intake of a drug. As a result, the adverse effect may end up listed in the label of use, even though causality is not guaranteed.

536 See Federal Food, Drug, and Cosmetic Act of 1938 (“FDCA”), Pub. L. No.75-717, 52 Stat. 1040 (codified as amended 21 U.S.C. §§301 et seq.).

Between 1905 and 1930, U.S. drugs were reviewed by a private organization, the American Medical Associa-tion, and more precisely its Council on Pharmacy and Chemistry. See HARRYM. MARKS, THEPROGRESS OF EXPERIMENT, SCIENCE AND THERAPEUTIC REFORM IN THE UNITEDSTATES, 1900-1990, at 22-41 (Cambridge History of Medicine, 1997).

537 See DEUTSCHE BANK, PHARMACEUTICALS FOR BEGINNERS, 35 (Mar. 12, 2003).

4.1.1.2. Proving efficacy

Clinical trials must demonstrate that a drug is effective.

538

Although commentators of-ten use these two terms interchangeably,

539

efficacy and effectiveness are slightly differ-ent concepts.

540

According to one set of definitions, a drug is efficacious when it has the desired effects, which is generally to cure the patient; a drug is effective when it has its intended effects, which can be less than a cure.

541

According to another definition, a drug is said to be efficacious in reference to results obtained in controlled settings such as those of a clinical trial; its effectiveness is determined based on results obtained from ordinary medical practice.

542

Yet, another definition set forth by the FDA distinguishes the two terms in the following manner: “the term efficacy refers to the findings in an adequate and well-controlled clinical trial … and the term effectiveness refers to the regulatory determination that is made on the basis of clinical efficacy and other data.”

543

Regardless of the definition retained, these two terms have a very close meaning. There are therefore used synonymously in this thesis.

4.1.1.2.1. Historical background of the efficacy requirement

This efficacy/effectiveness requirement was first introduced in the United States. Before 1962, drugs could be withdrawn from the market only if the FDA could prove that the drugs were indeed ineffective and, thus in the language of the statute, misbranded.

544

An analogous process was followed in other countries.

545

538 See 21 C. F.R. § 314.126(a) on adequate and controlled studies (“Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is ‘substantial evidence’ to support the claims of effectiveness for new drugs.”).

539 For example, the English translation of the LPTh (proposed on Swissmedic’s website; see supra note 7) uses

“effective” for the French “efficace,” but uses sometimes “efficacy” sometimes “effectiveness” for the French

“efficacité.”

See Grow, supra note 249, at 82-83. See FDA (Effectiveness), supra note 529, at 18-19. In the European Union, the term “efficacy” is more often encountered than the term “effectiveness” but both are in use. See Medicinal Products for Human Use: Guidelines, Volume 3C of EudraLex, at

http://pharmacos.eudra.org/F2/eudralex/vol-3/home.htm#3c.

540 A synonym of efficacy is efficaciousness; it is however rarely used.

For biologics, the term “potency” is generally used (instead of effectiveness). See FDA (Effectiveness), supra note 529, at 4.

541 See Grow, supra note 249, at 82; Jennifer Kulynych, Will FDA Relinquish the “Gold Standard” for New Drug Approval? Redefining “Substantial Evidence” in the FDA Modernization Act of 1997?, 54 FOOD& DRUGL.J.

127, at 133 (1999), at http://www.fdli.org/pubs/Journal%20Online/54_1/art12.pdf.

542 See, e.g., Office of Technology Assessment (“OTA”), The Effectiveness of Drug Abuse Treatment: Implica-tions for Controlling AIDS/HIV Infection (Sept. 1990), at 119, at

http://www.wws.princeton.edu/cgi-bin/byteserv.prl/~ota/disk2/1990/9041/9041.PDF; NBAC (Developing), supra note 254, at 28.

543 FDA (Effectiveness), supra note 529, at 1 n.2. See also Sarah M. R. Cravens, The Usage and Meaning of

“Clinical Significance” in Drug-Related Litigation, 59 WASH. & LEEL. REV. 553, at 565-68 (Spring 2002).

544 See, e.g., Grow, supra note 249, at 21.

545 See in Switzerland, W. Wilbrandt, Wandlungen in der Beurteilung von Arzneimitteln, in 75 ANS DE CONTRÔLE INTERCANTONAL DES MÉDICAMENTS [75 YEARS OF INTERCANTONAL CONTROL OF DRUGS] 129, at 130 (1975); P. Geiser, Arzt und Arzneimittelsicherheit, in 75 ANS DE CONTRÔLE INTERCANTONAL DES MÉDICAMENTS [75 YEARS OF INTERCANTONAL CONTROL OF DRUGS] 121, at 122 (1975).

The result was that many, if not most, drugs were simply worthless.

546

A scientific review of U.S. drugs performed between 1966 and 1969

547

(the DESI study) showed that a “substantial numbers of drugs were being marketed [in the U.S.] for which efficacy could not be shown. The panels evaluated some 16,500 claims made on behalf of 4,000 drugs and found that seventy percent of the claims were not supported by substantial evidence of effectiveness. Only 434 drugs were found effective for all their clinical uses.”

548

More than a thousand drugs were withdrawn from the market for lack of effi-cacy.

549

In 1962, the U.S. Food, Drug and Cosmetic Act (“FDCA”) was amended following bills presented by Senator Estes Kefauver and Representative Oren Harris. Initially, the main purpose of the bills that later became the Kefauver-Harris Amendments was to pro-tect “the public against unreasonably high-priced drugs” and to reduce – what was already at the time considered to be – excessive profits achieved by pharmaceutical companies.

550

Protecting patients from ineffective drugs was initially only a secondary concern. Moreover, legislators viewed ineffective drugs not so much as a health risk, but as economic treachery: Misled patients were thought to be swindled.

551

Addition-ally, “[p]roof of efficacy in a new drug application again was offered as a tactic to lower consumer costs, through assuring doctors that they could prescribe an available generic drug without fear that it might be less effective than its brand name counterpart.”

552

The introduction of the efficacy requirement in 1962 was far from self-evident. It was opposed by various groups, including the American Medical Association (“AMA”).

553

For the AMA, the assessment of a drug’s efficacy should have remained the exclusive province of doctors.

554

The trade group of pharmaceutical companies (called at the time the Pharmaceutical Manufacturers Association or “PMA”) supported only limited changes in the way drugs were approved.

555

They wanted to get rid of the

“patent medicine” industry (i.e., secret remedies peddled by shady characters) without hurting their own business.

556

546 Even though most drugs were either worthless or harmful, they enjoyed tremendous popular success. To-wards the end of the 19th century, “no fewer than 2,060 million – mainly digestive – pills were taken annu-ally in the UK, or one a week for every man, women, and child.” T. A. B. Corley, The British Pharmaceutical Industry Since 1851, at 3, (Centre for International Business History, University of Reading, 1999-2000), at http://www.rdg.ac.uk/Econ/Econ/workingpapers/emdp404.pdf.

547 See, e.g., FDA, CDER, A Brief History of the Center for Drug Evaluation and Research, http://www.fda.gov/cder/about/history/Histext.htm and also FDA Oral History Program, Interview with J.

Richard Crout, at http://www.fda.gov/oc/history/oralhistories/crout/default.htm#desi.

548 See, e.g., Warner-Lambert v. Heckler, 787 F.2d 147, at 149 (3d Cir. 1986); Weinberger v. Hynson, Westcott &

Dunning, 412 U.S. 609 (1973), at http://laws.lp.findlaw.com/getcase/US/412/609.html.

549 See David J. Horowitz, FDA proposes incentives to remove illegal Rx drugs, 9 (5) NEWS ALONG THE PIKE(Dec.

3, 2003), at http://www.fda.gov/cder/pike/nov2003.htm.

550 See Grow, supra note 249, at 9.

551 Id. at 11, 38 and 51.

552 Id. at 10.

553 Id. at 16.

554 Id. at 17 and 75-77.

555 Id. at 35-36 and 71-73.

556 While the first patent medicines of the early 19th century were indeed protected by a patent, subsequent patent medicines were kept secret. See Elizabeth L. Davoli, Patent Medicines: Ethnic or Socioeconomic Indi-cators? at 3 (paper presented in 1998), at

http://www.uark.edu/campus-resources/archinfo/SHACdavoli.pdf.

The Kefauver-Harris Amendments were ultimately successful owing to the jolt

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