British Homoeopathic Journal October 1996, Vol. 85, pp. 230-236

For debate

How can we get more reliable in format ion from homoeopathic pathogenetic trials? A critique ofprovings

FLAVIO DANTAS, MD, MBA, PHD*

Indeed, a medicine must first of all be essayed in a healthy body, without any foreign admixture; when the odour and taste have been examined, a small dose must be taken, and attention must be paid to every change that occurs, to the pulse, the temperature, respiration and excretions. Then, having examined the symptoms encountered in the healthy person, one may proceed to trials in the body of a sick person.

Albrecht von Haller. Pharmacopoeia Helvetica p. 12. Basel 1771.

Introduction Every homoeopathic prescription, if it is to be called homoeopathic, should be based on comparison between the symptoms presented by the patient and the symptoms the medicine to be prescribed has produced in healthy volunteers. A crucial aspect in this clinical decision relates to the reliability of the symptoms presented in homoeopathic repertories and materia medica textbooks.

Apart from case reports of poisonings and overdosing in the medical literature, experimental trials with healthy volunteers (provings) were the original source material for the homoeo- pathic materia medica Hahnemann produced almost 200 years ago. From his Fragmenta de Viribus Medicamentorum Positivis (1805) to the last edi t ion of Die Chronischen Krankheiten in 1839, Hahnemann published the pathogeneses of 101 drugs.

Recently there has been growing interest in experimental trials in healthy volunteers all over the world. The drug provings group of the European Committee for Homoeo- pathy is formulating a minimum standard for homoeopathic drug proving protocols. The Brazilian Medical Homoeopathic Association (homoeopathy is a recognized medical specialty in Brazil) is conducting several trials with physicians studying homoeopathy in post- graduate courses. In the USA, several provings

* Professor of Medical Ethics and Homoeopathy, Department of Clinical Medicine, Federal University of Uberl~ndia (Brazil) and Visiting Research Fellow, The Royal London Homoeopathic Hospital NHS Trust.

have been conducted in the last five years', 2 and a workshop on the methodology of provings was sponsored by the Council on Pharmacy of the Homeopathic Pharmacopoeia Convention of the United States in 1995. Several experimental pathogenetic trials have been conducted in India under the guidance of the Central Council of Research in Homoeopathy. 3,4

Homoeopathic trials in non-patient volunteers are conducted along Hahnemann's guidelines and also several other experimental designs and procedures. This paper attempts to extend the debate on the reliability and quality of data generated by homoeopathic medicine trials in non-patient volunteers, doing so from a theo- retical and methodological perspective. It is also an invitation to do rigorous experimental studies using homoeopathic medicines and contribute to a reliable and valid body of homoeopathic knowledge to be applied in clinical care and research.

'Proving' an archaic term H a h n e m a n n used the word Priifung for homoeopathic trials in healthy volunteers? The term is normally translated into modern English as ' test ' . Translation of Priifung as 'proving' is based on an archaic use of the te rm ' p r o v e ' and should be changed to improve communica t ion with healthcare professionals who are unfamiliar with old homoeopathic terminology. According to the ninth edi t ion of The Concise Oxford Dictionary (COD), ' to prove' has an 'archaic meaning--no longer in ordinary use, though retained for special purposes----of testing the qualities of, try'. Nowadays 'to prove' means

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to demonstra te the truth by evidence or argument (COD). The term 'proving' is not cited separately in the COD.

We propose using the term Homoeopathic Pathogenetic Trial (HPT) for Hahnemann's Priifung, i.e. an exper imental trial using homoeopa th ic medic ines in non-pat ient volunteers. 'Pathogenet ic ' means causing disease or abnormality and is synonymous with morbific, morbigenous, nosogenic and nosopoietic (Stedman's Medical Dictionary, 26th edn) or 'pertaining to pathogenesis ' (Dorland's Medical Dictionary), with patho- genesis defined as the development of morbid conditions or of disease. 'Pathogenetic' thus gives a better definition of the main purpose of the trial . ' H o m o e o p a t h i c ' spec i f ies Hahnemann's original idea of using diluted medicines in non-patient volunteers in good, stable health. Also, 'trial' is more consistent with the German Priifung. The Oxford-Duden German Dictionary translates Pri~fung as 'examination' ( 'a detailed i n s p e c t i o n ' ~ O D ) and klinische Priifungen as clinical trials. More accurate translations were made in French (experimentation pathog~n~tique), Portuguese (experimentaq(to patogen~tica) and Spanish (patogenesia, experimentaci6n pura).

In summary, an HPT is an experimental trial to investigate the effects of potentially toxic or pathogenic substances, diluted and serially agitated according to homoeopathic pharmacopoeias, in non-patient volunteers who are in good, relatively stable health. It is one of the sources of data used to build homoeopathic pharmacology or materia medica and deserves a more thorough assessment and continuous refinement.

Accurate and useful information An HPT aims to produce valid and useful data concerning the object ive and subject ive changes--mental, general or local--a particular medicine can provoke in apparently healthy human beings. A homoeopathic medicine is a potentially toxic or pathogenic substance that has been prepared according to the specifications of homoeopathic pharmacopoeias (including trituration or dilution and succussion). The critical relevance of Hl~s can be deduced from the need for accurate comparison between the symptoms the patient presents and the supposedly reliable symptoms reported in homoeopathic materia medica, many of them from HPTs.

Hahnemann considered a true materia med- ica to be a collection of the authentic, pure, reliable effects of simple medicinal substances in themselves (Organon w completely excluding all conjecture, anything asserted or entirely fabricated (w 144). 6 He also stated that

the curative virtues of medicines cannot be apprehended by specious a priori sophistry, or from the smell, taste, or appearance of the medicines, or from chemical analysis, or by treating disease with one or more of them in a mixture. (w

Only reliable symptoms should be included in the homoeopathic materia medica. That is the clear message present in all editions of Hahnemann's Organon. He would not permit transgression of this golden rule in gaining knowledge of the 'individual disease-producing powers of medicines which are to act as counter-diseases for the cure of natural diseases'. 7 (w Thus he was against paying healthy volunteers to participate in homoeo- pathic trials and tried to dissuade physicians from doing long distance or mail trials on the grounds of unreliability and uncertainty of results, and thus their uselessness. (w ~

Avoidance of guesswork and imagination, and the need to record findings only after close questioning were always stressed in the different editions of the Organon. Hahnemann also said that

Anybody publishing the results of such experiments for the medical world becomes responsible for the reliability of the experimental subject and the accuracy of his reports, and rightly so, since the well-being of suffering mankind is at stake. (Note to w 6

In this spirit he condemned a proving of Osmium by a homoeopathic physician from Leipzig, saying that he ' invented all the printed symptoms ... for the sake of snapping up a bookseller's fee '?

Hahnemann was also aware of the power of suggestion and recommended that

In the investigation of these drug-symptoms all suggestion must be as rigidly avoided as in the examination of the symptoms of disease. (w 115) 7

To obtain symptoms that are as accurate as possible, every subject had a pocket-size notebook in which to write down sensations and changes immediately after they occurred. The volunteers were required to repeat the

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description of the changes without referring to this notebook during the personal interview with him. If the accounts varied he advised the director of the trial to confront the subject with both versions and invite him to choose and confirm the statement that was nearest to the truth. (w 116)

Hahnemann met the subjects participating in his trials, mostly friends and people who attended his lectures, 8 daily or every two or three days to question them about their symptoms. He was aware of the impossibility of absolutely and perfectly healthy volunteers and also r ecommended that any minor ailments appearing during the trials which experimenters might feel to be dubious or unconfirmed should be added in parentheses. 9 In the preface to his Materia Medica Pura he suggested the rejection of all symptoms developed after some extraordinary circumstance which might affect the results.

In the first edition of the Organon of the Rational Art of Healing (1810), Hahnemann asserted that

The rational nature of the art of medicine manifests itself pre-eminently in the rejection of all systematic and other prejudices, in the refusal to act without good grounds, in the adoption of every possible measure to achieve the desired action, and in confining attention as much as possible to that which can be definitely ascertained. (w 7

In the last paragraph on experimentation with homoeopathic medicines in the last (6th) edition of Organon, Hahnemann called on careful and reliable observers to experiment on themselves. With growing numbers of trials he anticipated that 'the healing art will then approach the mathematical sciences in certainty'. (w An analysis of his intentions and a historical perspective make it quite clear that only the best evidence from HPTs would be accepted by Hahnemann as reliable and useful in homoeopathic clinical practice and research. He was deeply concerned with the reliability and validity of his Priifungen. From the currently fashionable perspective of evidence-based medicine, we can conclude that from the beginning of homoeopathy Hahnemann proposed the best possible evidence-gathering methodology on which to base homoeopathic knowledge.

Hypothesis tested A trial can be described as controlled only if

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it includes a method of elimination that makes it possible to discover differential effects of a factor believed to be important for the occurrence of the phenomenon. The presence of the original substance in the homoeopathic medicine should be the only factor associated with changes and symptoms in healthy volunteers in a controlled trial. The control medicine must be a similar preparation which is identical in all other respects except that there is no original and specific substance to be mixed and succussed with the vehicle. The only di f ference between placebo and testing medicine thus is contact of the original substance with the vehicle of the pharmaceutical preparation.

This allows the specific effects of the homoeopathic medicine to be tested in at least two groups of subjects or in the same group using a multiple-phase design. If the placebo is not diluted or succussed, or both, there will be two or more variables and the possible claims for pathogenetic effects cannot properly be associated with the presence of the original substance in the preparation. The objection may be raised that this means testing the pathogenesis of ethanol (or saccharum lactis). This may be partly true if there is no proper comparison group or set of data. The issue here is the specificity of a homoeopathic medicine in inducing particular changes or symptoms in non- patient, healthy volunteers. It follows that all HPTs should use a diluted and succussed placebo control if they are to determine the specificity of drug effects in healthy volunteers.

Common and differential features of HPTs and phase 1 trials The current drug approval process in the US and EU involves three phases of clinical testing (plus postmarketing studies). Phase 1 trials use a few normal volunteers primarily to assess tolerance of a new drug (safe dosage range and exclusion of any extremely common toxic reactions peculiar to humans) and to obtain basic phar- macokinetic data. HPTs and Phase 1 clinical trials have similarities and also differences that range from goals to measurement of the effects in subjects. Table 1 summarizes some of the common and differential features of HPTs and Phase 1 clinical trials.

Just as there are different phases for clinical trials of drugs it is possible also to devise different types of HPT with different functions,

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Similarities Non-patient volunteers Observation of subjective and objective changes produced in the volunteers by the drug or medicine (toxicologic reactions or pathogenetic effects) Multiple or more specific end-points (exploratory trials first) Controlled experiment (different designs, usually with unbalanced assignment) Necessary phase for future drug or medicine prescription by physicians Small number of subjects (20-100)

Differential features HPT Phase 1 clinical trial

Use of sub-material or ultramolecular First test of new drugs in humans doses of potentially toxic or pathogenic substances commonly with well-known toxic effects

Expectation that trial will produce symptoms and so generate new indications for clinical use of the homoeopathic medicine

The more reliable symptoms, the better

High level of detail for every reported symptom

Tendency to produce type B (unpredictable, idiosyncratic) reactions but without potential serious effects

Designed primarily to reduce the risk of serious toxicity and avoid confounding pharmacologic and disease effects; also to assess pharmacokinetics

Close monitoring of objective changes (laboratory tests)

The fewer symptoms, the better

Raw symptoms, not so much attention to modalities or detailed symptomatology

May provide data on toxic symptoms to be used homoeopathically

Apt to produce type A (dose-related, common) reactions

TABLE 1. Similarities and differences between HPTs and phase 1 clinical trials.

e.g. exploratory versus confirmatory trials. The important point is that there are similarities and differences between phase 1 clinical trials and HPTs and both can learn from one another. Data on highly toxic drugs derived from phase 1 clinical trials can serve to stimulate a trial using this drug in a homoeopathic preparation and the careful observation of changes used in HPTs could be incorporated in modern phase 1 clinical trials.

Problems and strategies with HPTs The controlled investigation of the pathogenetic power of medicines was one yardst ick in Hahnemann's writings. Early on in the Organon he referred to the main methodological problems of HPTs, namely --truthfulness of volunteers (w 126) - - u s e o f medicines with different powers

(w

- -deal ing with individual differences (w 129). Hahnemann took several measures to minimize

these, including --select ion of trustworthy and conscientious

heal thy human volunteers (wel l -known friends and sympathizers of homoeopathy)

- - u s e of only one medicine in its purest form and in moderate doses

---close supervision of subjects --recommendations for controlling confounding

variables such as diet, life style, ingestion of medicines, and consumption of alcohol and caffeine-containing drinks.

It is well accepted that, even with the best of scientific intent ions--as we can infer from Hahnemann's recommendations--researchers can unintentionally introduce bias which results in expected outcomes. Hahnemann could not have ant ic ipa ted some of the sys temat ic

234 British Homoeopathic Journal

Methodological flaw Consequences Minimization strategies

Absence of control group Overestimate of medicine effects (volunteers' usual symptoms + random symptoms + medicine symptoms)

Use of well-known friends and lecture audiences as volunteers ('believers')

Overestimate of medicine effects (placebo effect to please the master/investigator)

Volunteers infoimed that they were using a medicine to observe effects on them

Overestimate of medicine effects (expectancy + conditioning effects)

Recording all complaints, symptoms and changes observed during action of the medicine even if the person had noted similar symptoms in himself a considerable time before

Overestimate of medicine effects (false cause fallacy--post hoc ergo propter hoc + naturally occurring symptoms)

Absence of masking in volunteers Overestimate of medicine or in trial supervisors effects (selective perception

+ investigators' effect)

Close supervision and daily (or 2-3 days) interview with subjects + daily recording in a pocket notebook

Overestimate of medicine effects (Hawthorne effect* + recall bias)

Sudden prohibition of coffee, tea, spices and alcoholic drinks (or medicinal drugs)

Overestimate of medicine effects (effects of abstinence, surfacing of hidden symptoms ...)

Vague definition of healthy volunteers ~ inclusion of non-healthy volunteers

Overestimate of medicine effects (volunteers recording symptoms related to prior and current disease)

No random assignment of subjects

Overestimate of medicine effects (investigators' effect)

Use of comparative placebo group

Use of non-subservient volunteers + placebo comparison + masked volunteers

Masked placebo and medicine use + standardization of unbiased instructions

Use of a comparable group using placebo + comparison between symptoms in the two groups and from a pre-observation period + pre-defined criteria for selection of pathogenetic effects

Double masking of volunteers and supervisors + causal judgement by volunteers

Moderated supervision + improved selection of subjects + standard questions

Observation of volunteers as usual; definition of clear exclusion criteria for heavy drinkers or recently prescribed for drug users

Prospective definition of healthy volunteers with clear statement of inclusion and exclusion criteria for volunteers + use of validated questionnaire

Randomization

TABLE 2. Methodological flaws in Hahnemann's HPTs and proposed minimization strategies.

* Tendency for people to change their behaviour (usually in a positive or beneficial way) when receiving special attention and interest in studies, regardless of the nature of the intervention. The effect was named after studies done at Western Electric, Hawthorne, Illinois, in the 1920s when workers exposed to increased, decreased or the same intensity of illumination showed consistently higher output compared to previous records. The experiments are reported in Roethlisberger FJ, Dickson WJ. Management and the Worker. Cambridge MA: Harvard University Press 1939.

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errors that might result in unacceptab le results and in unreliability and overestimation of medicine effects in general. Table 2 shows the main flaws in Hahnemann's proposal for HPTs and suggests how these may be minimized according to current scientific knowledge.

Taken together these flaws are sufficient to provoke serious doubts concerning the validity of the specific pathogenetic symptoms reported in Hahnemann's writings. His data may be true, though Hughes seriously questioned some of the findings in particular volunteers, m but they do not stand up to cr i t ical scrut iny f rom a methodological perspective. Numerous findings in the medical and homoeopathic literature also show that ' n o r m a l ' or supposed ly healthy people may report symptoms without the use of medicines ' ' when using placebo in phase 1 clinical trials ~2 ~ or in HPTs. ~5~'6 Repeated aggravations were reported in the only patient using placebo who completed a one- year follow-up in a double-blind proctocolitis trial. '7 When subjects have been exposed to dummy treatment, thinking they were receiving a new medicine, the results show a variable incidence of symptoms similar to side-effects that were present in the pretreatment period and could be found, if sought, during history- taking and physical examinations. TM

The methodological flaws of Hahnemann's trials were recognized early and new designs tested. A century ago, a group of homoeo- pathic medical doctors in Baltimore proposed that every trial in non-patient volunteers should be preceded by a pre-observation peri- od to prepare the volunteer to pass judgement upon the pathogenetic value of the many manifestations that are likely to occur during the trial. '9 From 1901 to 1903, Bellows co- ordinated a multicentre double-blind trial of Belladonna (mostly in mother tincture) using placebo control in 11 USA centres2 ~

'Results can always be improved by omit- ting controls' states Muench's Second Law. 2' The absence of a control group in HPTs is a cardinal sin that increases the likelihood of non-medicine symptoms and false positive results. The flaws shown in Table 2 require a comparative control group to be used in every HPT. In addition, subjective and functional symptoms are the most frequently reported changes in HPTs and this is the setting in which blinding is most vital. 22 It is easy to understand the prolific and growing production

of s y m p t o m s in H a h n e m a n n ' s M a t e r i a Medica Pura if one accepts that volunteers generally tend to behave in accordance with investigators' expectations and conditioning. 23,24 The influence of researchers on data collected can be reduced by random assignment. The deliberate or subconscious use of unbalanced attention to subjects or interpretation of subjective changes can be minimized by using the double-blind (or masking) technique.

It is no longer accepted that every symptom exper ienced by a human volunteer after ingestion of a medicine administered by a physician with the aim of collecting symptoms is exclusively due to the action of that medicine. In controlled, clinical trials, Chalmers et al. found non-randomized studies yielded larger estimates of treatment effects than studies using random allocation. 25 A similar conclusion was reached by Schulz et al. when comparing trials with inadequate or unclear allocation concealment with those where adequate measures to conceal allocation were taken. 26 The incorporation of current controlled trial techniques can lead to identification of fewer, more reliable, idiosyncratic or type-B reactions instead of the plethora of common symptoms reported in uncontrolled HPTs. It follows immedia te ly- - i f this is t rue-- that we will need a different approach for selection of pathogenetic symptoms, based mainly on accepted criteria for the causal nature of an association and complemented by the judge- ment of the investigator.

Mclntyre and Popper, introducing their paper about a critical attitude in medicine and the need for a new ethics, wrote:

Mistakes occur in medicine as in other walks of life. Their consequences may be trivial, but often they are serious, and they may be catastrophic .... Steps may be taken to correct errors but in many instances the mistake is irrevocable; the only benefit is the prevention of similar errors in future, z7 Radical i m p r o v e m e n t in pa thogenet ic

information is a vital point in the current agenda for homoeopathic practitioners and clinical researchers that deserves a painstaking and dedicated world-wide effort. We need sensitive designs and robust methodological procedures for homoeopathic pathogenetic trials.

Acknowledgements During the preparat ion of this paper the

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author was suppor ted by a pos tdoc to ra l fellowship from CNPq (Conselho Nacional de Desenvolvimento Cientffico e Tecnol6- gico do Bras i l ) bu t e n d o r s e m e n t by this agency is not implied. The author thanks Jonathan Davidson for his comments and Peter Fisher for his comments and language editing.

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