(Lecture given at the Conference on "EU-Gesetze und Naturheilverfahren" on 15 Nov. 1996, organized by the Zentrum zur Ookumentation van fur Naturlieilverfahren e.V.)

Dr. Paul Lannoye's report to the European Parliament(1) is Europe's most widely discussed political paper about Complementary Medicine. It's general statement is: medical pluralism has to be established throughout the European Community.

Medical pluralism means that medicine is not a monolithic block but consists of different directions(2) - e.g. phytotherapy, homeopathy and anthroposophical medicine - and these directions of therapy need to be judged and evaluated according to their own criteria.

This medical pluralism is being opposed by many representatives of orthodox medicine. They believe that there is a declining quality in the spectrum of judging the efficacy of treatment. One extreme in this spectrum is me everyday clinical judgment of the physician is deemed unreliable. The other extreme is the randomized double-blind trial being questioned as the only proof of efficacy. For example, a member of the German Medizinischer Dienst writes: "The question whether a remedy is efficacious or not can never be solved with single cases... Controlled double-blind trials with large groups of patients and long periods of observation are indispensable."(3) This attitude - that everyday clinical judgment of the physician is unreliable and valid judgment of efficacy is possible only in controlled clinical trials - is methodological monism.

Wherever methodological monism becomes the basis of drug regulation, can be eliminated because most of the remedies of have not been subjected to controlled trials. There are many reasons for this: Complementary Medicine mainly is done by practitioners; Complementary Medicine has been excluded from academic institutions; in Complementary Medicine, patients and doctors are highly skeptical against controlled clinical trials. Therefore, when Methodological Monism is introduced as the general, obligatory standard in the European Community, no medical pluralism can be established. There are contradictory positions: Methodological Monism stands against Medical Pluralism. For the future perspectives of medical pluralism, the decisive question is whether methodological monism is justified or not. The following outlines reasons for a double position.

Methodological monism is not justified - Medical pluralism is legitimate

Central argument - the Placebo Effect

Fifty years ago in the history of medicine, clinical judgment of physicians lost its credibility and controlled clinical trial gained overwhelming dominance. The first conference on placebos was the Cornell Conference on The Use of Placebos in 1946. This conference was opened by E. F. DuBois saying: "As a matter of fact, I think we can show that the study of the placebo is the most important step to be taken in scientific therapy."(4)

It is interesting to read the protocol of that conference and learn why the participants were convinced that placebos could be therapeutically effective. The protocol says: "The enormous success of homeopathy, where drugs are given in great dilution (in sugar pills) so dilute that they could not possibly have any pharmacologic action, is a good example. Its success and therapeutic results are probably better than those in the case of some of the regular drugs that are given in huge doses by the rival practitioners. At least, it has demonstrated very clearly what can be done by placebos."(5) Then, the participants reported what kind of efficacy placebos can have, e.g. against sleeping problems or gastric problems. After this, different placebos were named, e.g. Gentiana or Valeriana. These are phytotherapeutic remedies with specific effects against the ailments mentioned.

One needs to see what happened at this conference. The placebo discussion had been initiated in 1946 because orthodox medical doctors observed therapeutic successes of homeopathy and phytotherapy and because these successes did not fit into their theoretical framework about reality and medicine. They were not open to accepting that it had specific therapy effects. They were looking for a pseudo-rationalization of these therapy successes, and they invented the argument of the "placebo effect", using a word that has been around for a long time. This is an historical fact and can be read in the protocol of that conference.

In 1955, Henry K. Beecher published a paper. The Powerful Placebo.(6) This work has been seminal; it became world famous. It has been responsible, as Robert says,(7) for the double-blind trial becoming the universal standard of therapy judgment. In this publication, Beecher quantified the placebo effect: on the basis of 15 clinical trials including 1082 patients, he summarized that 35% of patients with a variety of different diseases could be satisfactorily treated by placebos alone with "true therapeutic effects." Thus, the existence of the placebo effect has been scientifically established.

Of course, the consequences for the clinical judgment of the physician have been fatal. When a large percentage of patients can be successfully treated with placebos alone, the physician cannot know whether a particular therapy success comes along due to his specific therapeutic measures or whether it only reflects a placebo. In short, with the placebo argument being true, the physician cannot judge the specific efficacy of his therapies. Thus, there cannot be valid clinical judgment.

Beecher's The Powerful Placebo justified breaking with traditional "experiential" medicine, ignoring clinical judgment and clinical experience, and installing the double-blind clinical trial as a decision instrument for drug regulation. In fact, researchers from Beecher's group have influenced the legislation of the United States to replace the physician's experience by controlled clinical trials for matters of drug registration, beginning with the Kevauer Bill of 1962.(8)

In 1995, a book was published by Gunver Sophia Kienie, The So-Called Placebo Effect: Illusion, Facts, Reality (original: Der sogenannte Placeboeffekt: Illusion, Fakten, Realitdt),(9) in which the complete original literature of Beecher's publication has been reanalyzed with a surprising result: in none of the 15 trials Beecher had referred to was there the slightest reason to suppose any placebo effect. There are many factors which can imitate placebo effects: natural history of the disease, regression to the mean, concomitant treatments, obliging reports, experimental subordination, severe methodological defects in the studies, misquotes, etc. However, with great plausibility there was no placebo effect analyzed in 800 papers. All this literature gave the same picture: nowhere has the existence of any therapeutic placebo effect been convincingly demonstrated.(10)

These investigations have been published only recently; but they have aroused resonance and recognition. After an article was published in June, 1996 in Forschende Kompletdrmedizin,(11) four other medical journals spontaneously wished to reprint this article. Even representatives of the German Society of Medical Documentation and Statistics expressed respect. At the 1996 Congress of the German Society for Gynecology and Obstetrics (Deutsche Gesellschaft fur Gynakologie und Geburtsheilkunde) Gunver Kienle's recent placebo publications have been honored with the Hevert award because of their "eminent importance for the whole of medicine." This issue will soon be discussed at a placebo conference at the National Institute of Health in Washington.

The placebo argument has lost its scientific value. This is important for medicine because the clinical judgment of the physician regains autonomy, and this must have consequences on drug regulation.

The physician's judgment of efficacy

Most remedies of Complementary Medicine have been available for decades. To no demand controlled clinical trials for regulatory purposes implies that physicians are not able to judge whether their therapeutic measures help or do not help. With this insinuation, the physician could be forced to accede to a posteriori-controlled trials, which would mean the best therapist is the physician who subordinates to the results of controlled clinical trials without making sure his treatments do or do not help his patient (it being assumed that the only valid and reliable judgment of efficacy is possible through controlled trials and not through his judgment). Considering the absurdity of this, one need only think of the many treatments that have a dosage calibration according to the patient's reactions: insulin therapy in diabetes, treatment of hypertension, pain therapy, psychiatric therapies and many more. These therapies could not be handled without the physician judging the effects of his treatment.

When discussing the judgment of efficacy, a central problem is the exclu- sive orientation toward medical statistics. The professionalism of medical statistics blocks the awareness of other forms of efficacy judgment which are not statistical, which can be applied to single cases, and which are not less valid than so-called controlled clinical trials. Medical statistics are a powerful source of dogmatism. One is dealing with an example of what, in The Lancet, has been called the "extra-ordinary capacity of the profession for self-delusion."(12)

Up to now, the exclusive statistical orientation has prevented investigation of the structures of the individual physician's judgment as well as the methods of non-statistical judgment of therapy. Valid, non-statistical methods of efficacy judgment exist in single patients.(13) It is these methods that have been used by practitioners (without methodological reflection) for ages.

Why controlled clinical trials cannot be decisive criteria for drug regulation

Double-blind clinical trials tend to produce false-negative results

Blinding of clinical trials should prevent false-positive results. However, for several years we have known that blinding itself can produce the opposite: false-negative results.(14) It has been believed that randomization and blinding neutralize all possible influences upon observation and reporting of effects, but this is not true. In fact, when blinding a trial, several factors have the tendency to be stronger in the group of lesser-treated patients, thus possibly concealing the efficacy of the test drug. Of course, when a test method is fallible in itself (with a one-sided tendency to false-negative results) it should not be declared an obligatory instrument of efficacy judgment.

In Complementary Medicine controlled clinical trials are not practicable in most cases

In most cases, there are many reasons why controlled clinical trials cannot be done in Complementary Medicine.(15) For example, blinding often is impossible because of technical reasons, e.g. with mistletoe injections, with etheric oils, amaroids, teas, etc. Strictly demanding double-blind trials for the registration of these substances would exclude them from medical usage regardless of their benefit. Blinding is impossible in neural therapy since a double- blind trial cannot be done without bodily injury. Even without blinding, other problems remain: long-term clinical trials for chronic disease would be impossible. Hawley and Wolfe showed(16) that out of 122 studies for long-term therapy in polyarthritis, only 57 had been controlled; and out of these, only 2 studies went longer than one year, and none went longer than two years. There is not sufficient compliance from the patients for long-term studies - they drop out of the trials - so for merely technical reasons there is no chance for "proofs" of efficacy for Complementary Medicine in chronic diseases. Moreover, Complementary Medicine is primarily used by practitioners who do not have the infrastructure necessary for clinical trials. In Complementary Medicine, both patients and physicians are resentful of controlled trials.

Official demands/or controlled trials in Complementary Medicine are unethical in most cases

The ethical basis for clinical research is the declaration of the World Health Organization in Geneva, Helsinki and Tokyo: "Concern for the interest of the subject must always prevail over the interests of science and society."(17) Therefore, a randomized trial needs equal chances. At the beginning of a trial, there should not be any reason to assume that one treatment will be superior to the other; otherwise the trial would not be ethical. However, meta-analyses show that these equal chances probably do not really exist. For example, from the data of a meta-analysis by Dickersin et al.(18) of about 945 published and non-published trials (it was corrected against publication bias), one can conclude: there were better results in the verum group in 65.3% (47.5% with p<0.05); but for the control group, only in 8.9% (3.8% with p<0.05). Similar results are shown through the data of a metaanalysis by Juhl et al.(19) There was a verum group superiority in 61% compared to a control group superiority in 1.6%. These results generally indicate that patients in control groups are disadvantaged. (For a complete survey on ethical problems of randomized controlled trials, see(20).)

This ethical problem primarily affects affects remedies of Complementary Medicine that have been used by physicians for decades and applied because physicians have had therapeutic successes and have been convinced of their efficacy. In this case, authorities cannot afterward demand controlled trials as a prerequisite for registration. According to German constitutional judge (Verfassungsrichter), Gerhard Leibholz, it is illegitimate to demand controlled trials for Complementary Medicine: "Ein vom Hersteller zu erbringender Nachweis der Wirksamkeit des Arzneimittels ist jedenfalls fur die 'Naturheilmittel' verfassungswidrig."(21)

Summary

To establish Medical Pluralism in Europe political instruments will not suffice. Politics will need assistance from science, in particular from methodology. It will be necessary to overcome Methodological Monism. A double strategy is necessary: (1) one needs to show that the general demand for controlled clinical trials is not justified, and (2) one has to substantiate the overall reliability of the clinical judgment of the clinician.

It may also be appropriate to have a three-part coalition: (1) the people's interest in unconventional Complementary Medicine; (2) unconventional, innovative politicians; and (3) unconventional, innovative scientists.

Helmut Kiene, MD Institut fur angewandte Erkenntnistheorie und medizinische Methodologie Muselgasse 10 D-79112 Freiburg i. Brst. Germany

References & Bibliography

1. Lannoye, P. Europaisches Parlament. Ausschuss fur Umweltfragen, Volksgeundheit und Verbraucherschutz. Entwurf eines Berichts zm Status der Alternativmedizin. 3 March 1994. Doc-DE\Pr\245773.

2. Zentrum zur Dikumatatnion fiir Naturheilverfahren e.V.: Dokumentation der besonderen Therapierichtungen und natiirlichen Heilweisen in Europa. Band I-V. Im Auftrag des Niedersachsischen Mmisteriums fur Wirtschaft, Technologie und Verkehr. VGM-Verlag Luneburg1991.

3. Wolk, Wofgang. Paramedizinische Therapie und Rechtsprechung. MedR 1995.12:492-496.

4. Conferences on Therapy: The Use of Placebos in Therapy. NY State { A/led. Aug. 1946: 1718-1727

5. Ibid.

6. Beecher, H.K. The Powerful Placebo. Journal of Anthroposophic Medicine 1995.159:1602-1606.

7. Roberts, H.A., Kewman, D.G., Mercier, L., Hovell, M. The Power of Nonspecific Effects in Healing: Implications for Psychosocial and Biological Treatments. Clinical Psychology Reviews 1993.13:375-391.

8. Temin, P. Taking Your Medicine: Drug Regulations in the United States. Harvard University Press. Cambridge, Mass. and London, England. 1980.

9. Kienie, G.S. Der sogenannte Placeboeffekt: Illusion, Fakten, Realitat. Schattauer Verlag Stuttgart 1995.

10. Kienie, G.S., Kiene, H. Placeboeffekt und Placebokonzept - eine kritische methodologische und konzeptionelle Analyse von Angaben zum Ausmafi des Placeboeffekts. Forsch Komplemenfdrmed, 19963:121-138.

11. Ibid.

12. Editorial: Breast Cancer: have we lost our way? The lancet 199 (Feb. 6); 341:343-344.

13. Kiene, H., Schon-Angerer, T. Single Case Causality Assessment as a Basis of Clinical Judgment Alternative Therapies in Medicine and Health, 1996. In press.

14. Kiene, H. A Critique of the Double-Blind Clinical Trial. Alternative Therapies in Medicine and Health. 1996; 2:74-80; 59-64.

15. Kiene, H., Kalisch, M. Wissenschafftliche Dogmen bei der Machzulassung von Arzneimittein in der Bundesrepublik Deutschland. Aurelia Verlag Baden-Baden 1995.

16. Hawley, D., Wolfe, F. Are the Results of Controlled Clinical Trials and Observational Studies of Second Line Therapy in Rheumatoid Arthritis valid and Generalizable as Measures of Rheumatoid Arthritis Outcome:Analysis of 122 Studies. Journal of Rheumatology; 1991; 18: 1008-1014.

17. Weltarztebund: Deklaration von Helsinki 1964 (erweitert Tokio 1975, Venedig 1983, Hong Kong 1989). In: Klinische Arzneimittelprufungen in der EG. EG-GCP-Note for Guidance. Edition Cantor Verlag, Aulendort; 1992; p. 93-97.

18. Dickersin, K., Chan, S., Chalmers, T.C., Sacks, H.S., Smith, H. Publication Bias and Clinical Trials. Controlled Clinical Trials, 1987; 8:343-353.

19. Juhl, E., Christensen, E., Typstrup, N. The Epidemiology of Gastrointestinal Randomized Trials. New England Journal of Medicine, 1977; 296:20-22.

20. Kiene, H. Kornplementarmedizin-Schulmedizin: der Wissenschaftssreit am Ende des 20. Jahrhunderts. Schattauer Verlag Stuttgart, 2 August 1996.

21. Leibholz, G. Arzmeittelsicherheit und Grundgesetz. Rechtsgutachten. 50 Seiten. Zu beziehen durch die Arztliche Aktionsgemeinschaft fur Therapiefreiheit e.V. Pforzheim. Homung, J. Zur Problematik der Doppelblindstudie. Therapeutikon, 1989; 3: 696-701. Kienie, G., Kiene H. Placebo effect and placebo concept: a critical methodological and conceptual analysis of reports onthe magnitude of the placebo effect. Alternative Therapies, 1996; 2(6): 39-54.

Kirsch, I., Weixel, L.J. Double-blind versus Deceptive Administration of a Placebo. Behavioral Neuroscience, 1988; 102(2): 319-323.

Klejinen, J., de Craen, A.J.M., van Everdingen, ]., Krof, L. Placebo Effect in Double-blind Clinical Trials: A Review of Interations with Medications. The Lancet, 1994 344:1347-1349.

Lindahl, 0., Lindwall, L., Is All Therapy Just a Placebo Effect? Metamedicine, 1982. 3: 255-259. Moerman, D.E., General Medical Effectiveness and Human Biology: Placebo Effects in the Treatment of Ulcer Disease. Medical Anthropology Quarterly, 1983; 14: 3-16.