|Year : 2020 | Volume
| Issue : 1 | Page : 24-49
Homoeopathic drug proving researches (1996–2018): A scoping review
Raj K Manchanda1, Anil Khurana1, Peter Fisher2, Bhopal Singh Arya3, Pritha Mehra3, Subhranil Saha4, Munmun Koley5, Meenakshi Bhatia1
1 Central Council for Research in Homoeopathy, New Delhi, India
2 Royal London Hospital for Integrated Medicine, London, UK
3 Dr. D P Rastogi Central Research Institute (Homoeopathy), Noida, Uttar Pradesh, India
4 Homoeopathic Drug Research Institute, Lucknow, West Bengal, India
5 Independent Researcher, West Bengal, India
|Date of Submission||04-May-2019|
|Date of Acceptance||18-Feb-2020|
|Date of Web Publication||9-Apr-2020|
Dr. Pritha Mehra
Dr. D P Rastogi Central Research Institute (Homoeopathy), A 1/1, Sector 24, Noida (Under CCRH), Uttar Pradesh
Dr. Raj K Manchanda
Central Council for Research in Homoeopathy, Janakpuri, New Delhi
Source of Support: None, Conflict of Interest: None
Background: A systematic review on homoeopathic pathogenetic trials (HPTs) from 1945 to 1995 was published in 2007, and the basic question whether the effect produced by homoeopathic drugs in healthy human volunteers is equivalent to placebo or otherwise remained unanswered. There is a need to take up another review of HPTs conducted in the last two decades, to assess the changes in the methodologies adapted and to assess whether the effects produced in apparently healthy volunteers is due to homoeopathic medicines in high dilutions or not. Objective: To seek, collect, review and describe HPTs published during 1996–2018. Materials and Methods: A comprehensive literature search, both electronic and manual, was done using search terms ‘homoeopathic drug proving’ and ‘homoeopathic pathogenetic trial’ with time constraint of 1996–2018 in English language. As per the inclusion and exclusion criteria, the papers were selected for extraction of data in the predefined extraction form. Results: One hundred and forty-seven eligible records (74 peer-reviewed [PR] and 73 non-peer-reviewed [NPR]) of HPTs of 214 drugs were identified and subjected to the extraction of data. Majority of the drug proving records were contributed by the Central Council for Research in Homoeopathy which included 86 records (24 PR and 62 NPR) with the data of 24 and 63 drugs, respectively, and by Riley, one book (NPR) with data of 68 drugs. Heterogeneity was encountered in all aspects – design, conduct, participants and outcome reporting.Conclusion: This preliminary study is the basis for data recovery and for the forthcoming program of systematic review and meta-analysis, which may include the HPTs published in other languages.
Keywords: Homoeopathic drug proving, Homoeopathic pathogenetic trial, Scoping review
|How to cite this article:|
Manchanda RK, Khurana A, Fisher P, Arya BS, Mehra P, Saha S, Koley M, Bhatia M. Homoeopathic drug proving researches (1996–2018): A scoping review. Indian J Res Homoeopathy 2020;14:24-49
|How to cite this URL:|
Manchanda RK, Khurana A, Fisher P, Arya BS, Mehra P, Saha S, Koley M, Bhatia M. Homoeopathic drug proving researches (1996–2018): A scoping review. Indian J Res Homoeopathy [serial online] 2020 [cited 2020 Aug 6];14:24-49. Available from: http://www.ijrh.org/text.asp?2020/14/1/24/282113
| Introduction|| |
Homoeopathic drug proving (HDP), also known as homoeopathic pathogenetic trial (HPT), is a clinical trial aimed at systematic observation and recording of symptoms occurring after the defined administration of a proving substance in a serially agitated non-toxic dilution, prepared according to a homoeopathic pharmacopeia to ‘apparently healthy’ volunteers ('provers') for the purpose of using it as a homoeopathic remedy according to the principle of similarity in a sick person., These provings are considered to play a pivotal role in Homoeopathy since its inception. Results of these trials have been disseminated and applied in clinical practice by physicians, worldwide. Hence, to standardise them and then subjecting these towards vigorous systematic review is the dire need today. The proving substance produces reversible symptoms at physical and psychic levels, which are systematically observed and recorded by the provers and the investigator(s) as well. In quasi-experimental studies (one-group pretest–posttest design), Hahnemann tested such 99 substances. To minimise bias, he recommended the selection of trustworthy and conscientious healthy human volunteers, use of only one medicine in its purest form and in moderate dose, close supervision of the subjects and some rules for controlling confounders as diet, life style, ingestion of medicines and consumption of alcohol and coffee. Naturally, overestimations of pathogenetic effects derived from such studies were predicted  along with the existence of substantial methodological shortcomings and heterogeneity. To overcome such problems, HPTs with defined methodologies began to evolve since 1835.,
A systematic review of HPTs from 1945 to 1995 has been published, in which it has been reported that the HPTs were found suffering from design flaws, heterogeneity and low methodological quality, and above all, whether homoeopathic medicines in high dilutions can provoke effects in healthy volunteers remained inconclusive. Since then, many more HPTs have been published across the globe. There is a need to evaluate the collective outcome of these studies in terms of their methodology and the quality of information generated and to make further recommendations for undertaking similar studies. Hence, another systematic review and meta-analysis of these studies have been planned. Two institutions, namely Central Council for Research in Homoeopathy (CCRH), under the Ministry of AYUSH, Government of India, in association with Royal London Hospital of Integrated Medicine, are collaborating to take up the systematic review and meta-analysis of the HPTs published in these two decades, i.e., from 1996 to 2018; however, keeping in mind the possibilities of heterogeneity, initially, a scoping review has been performed. This is a preliminary paper wherein an up-to-date and comprehensive systematic categorisation of the international HDP literature published in English language in the last two decades has been covered. An ‘eligible’ record for full data extraction is defined as any substantive report of HDP in healthy humans published in books, research journals or bulletins. In a series of papers planned to follow, eligible HPTs will be short-listed and will ultimately be appraised for internal validity (risk of bias) against pre-defined criteria (not yet determined) and included in appropriate meta-analysis models if data permit. Majority of the proving elicits qualitative data; hence, meta-analysis might seem to be inappropriate; still, a considerable number of experiments dichotomizes the outcome reporting in terms of incidence rates (i.e., producers of proving symptoms) in the verum and control groups those can be pooled successfully in meta-analysis models. Thus, if the data allow, meta-analysis of proving may prove to be successful venture to test whether homoeopathic potentised medicines can produce symptoms beyond mere placebo.
The objective of this self-audit is to seek, collect, review and describe HPTs published during 1996–2018 to identify the caveats and improve the adopted methodologies.
| Materials and Methods|| |
Trials were sought by manual search of books, research bulletins and journals and electronic search into eight major bibliographic bio-medical databases (PubMed, ScienceDirect, Cochrane, Virtual Health Library, LILACS, BioMed Central, Wiley Online Library and ChiroACCESS), three major trial registries (ClinicalTrials.gov, ISRCTN and CTRI) and one specialised homoeopathic database – CORE-Hom [Table 1]. Search terms used were “homoeopathic pathogenetic trial” and “homoeopathic drug proving” in English language with year restriction used as 1996–2018. The inclusion and exclusion criteria considered were as follows:
- Written information of HPTs in English language from 1996 to 2018 in the public domain
- Prospective, double-blind, randomised, placebo-controlled studies using diluted and potentised homoeopathic medicines
- Studies in which a non-randomised method of sequence generation and/or a single-blinded approach is used
- Trials having a cross-over design, only data from the first randomisation period have been considered due to concerns over carryover effects.
- Studies in which mother preparations (tincture, solution, powder) are used
- Studies where Homoeopathy is combined with another intervention
- 'Dream provings’ and ‘meditation provings'
- Studies in which no data are provided or data are otherwise not extractable
- Self-experiments, repeat or redundant publications and translations and papers dealing with theoretical/methodological aspects of HPTs and papers not reporting any experimental results
- Publications before 1996 and after 2018 were excluded
- Proceedings, posters or reports of homoeopathic meetings – congresses, seminars, symposiums, workshops, etc., and private reports of HPTs by homoeopathic companies and data claimed by non-peer-reviewed (NPR) websites
- Repeat publications, translations and papers dealing only with theoretical or methodological aspects of HPTs and not reporting any experimental data.
A data extraction form was developed to collect relevant information on the intervention, dosage, study design and schedule, volunteers and overall results as reflected in the HDP reports. Methodological analysis remains to be appraised in future publications. For each medicine, the name, dilution(s), dose, repetition and duration were extracted. The study design was assessed in terms of randomisation, sequence generation of subjects, allocation concealment, masking (blindness), use of placebo, comparative group and parallel or cross-over. Study schedule was checked for pre-trial observation ('run-in') period with or without placebo and washout period (post-treatment observation). For study population, data were sought for the total number of verum and control group volunteers, sex and age. For the presentation of results, we extracted information on reported incidence of symptom(s) per group and enlisting of observed pathogenetic effects (proving symptoms). Proving symptoms were defined as any change in normal objective and/or subjective state of mind or body as experienced by the prover, or as observed by proving investigator and/or others occurring during proving period, which are possibly related to the proving substance., Reporting adhered to the PRISMA extension guidelines for scoping reviews.
| Results|| |
Selection and characteristics of sources of evidence
After screening for entries in different databases and books, a total of 5054 records of drug proving were identified. After applying year restriction (1996–2018), the number was reduced to 2932. The details of the search results from electronic databases and manual search are given in [Table 1]. Then, 394 reports on HDPs were retrieved excluding the redundant entries and irrelevant ones. Again, 256 papers were excluded dealing with theoretical and methodological aspects of HDPs, editorials and commentaries, reviews, conference reports, guidelines, protocols, reprint articles, private reports, proving done in mother tincture form and websites. Finally, 147 eligible papers were subjected for extraction of data [Table 2] and [Table 3]. Among these, 82 were published research papers and rest were published in the form of books presenting homoeopathic proving reports of total 207 drugs.
|Table 2: Non-peer-reviewed clinical studies of homoeopathic drug proving; 1996-2018|
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|Table 3: Peer-reviewed clinical studies of homoeopathic drug proving; 1996-2018|
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Under the NPR publications:
- CCRH published proving data of 74 drugs in the form of research papers published in NPR CCRH Quarterly Bulletin, six volumes of Drug Provings and New Drugs Proved by CCRH books
- Riley's book contained HPTs of 68 drugs
- Koster published one article but names of 15 drugs proved are not clearly mentioned
- One research paper was published by Maishi containing proving data of one drug.
Cardiospermum halicacabum has been proved by CCRH and Reily; thus, names of 214 drugs are enlisted in [Table 4].
|Table 4: Alphabetical list of the 214 homoeopathic drugs proved during 1996-2018|
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Among the 74 peer-reviewed (PR) research papers, the proving data of 74 drugs has been published between 1996 and 2018 [Figure 1], CCRH published 24 HPTs, Shah published four HPTs, and the rest were from different countries. Proving of Galphimia glauca, Okoubaka aubrevillei, Ozone, Sulphur, Bryonia alba and Calendula officinalis has been published by two different authors, and proving of Belladonna has been published by three different authors. The names of 74 drugs published in PR journals are added in [Table 4]. The list of references of the studies included, excluded papers and unrecovered literature are mentioned in Appendices 1-3 [Additional file 1] (available in online version of this article), respectively.
|Figure 1: PRISMA flowchart: Inclusion and exclusion of records reporting HDPs and HPTs in Homoeopathy. PR: Peer-reviewed; NPR: Non-peer reviewed; HDPs: Homoeopathic drug provings; HPTs: Homoeopathic pathogenetic trials|
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Results of individual sources of evidence
Among the searched literature, the trials were found to have methodological differences –
- observational (pre–post or repeated measure), observational and self-experimental (pre–post),
- single/double blind,
- placebo controlled or single arm, parallel arm (two or more) or crossover (inter- or intra- group),
- using different dilutions of the same medicine or one medicine in a single dilution,
- different study schedules – pretrial observation ('runin') period with or without placebo and washout period (posttreatment observation) with inconsistent duration, and
- different dilutions were used – 3X, 6X, 4C, 6C, 12C, 30C, 90C, 200C, and 200K in variable dosage, order, frequency and durationZ
This has been reflected in [Table 2] and [Table 3].
Synthesis of results
Thus, the study reporting was heterogeneous. The proving symptoms’ incidence rates per group were also searched in each of these trials, and it was found that none of the NPR studies and only six PR studies reported this outcome completely. PR papers were subject to selective reporting, preferably for the verum group only in most occasions. Continuous outcomes were also reported in terms of number of symptoms produced and mean difference between groups. Pathogenetic effects are enlisted in most of the studies [Table 2] and [Table 3]. However, the question that whether the results of provings are due to the placebo effect is yet to be answered subsequent to the upcoming programme of meta-analysis.
| Discussion|| |
Our search findings and initial data extraction have provided an expanded and refined view of the HDP literature. Like any event, this literature search cannot be regarded as completely successful, especially in the context that a significant part of proving literature is in the German language that was not assessed in this study. Full texts of 30 articles could not be recovered. The efforts will be made to do so and, if possible, to present all the recovered data in a standardised database. Owing to the narrative nature of this review, any conclusion regarding whether the results of provings are due to the placebo effect cannot be arrived at and is possible subsequent to the upcoming programme of meta-analysis, if feasible at all. There is a need to undertake similar exercise in publications in other languages, e.g., Spanish, German, Dutch, French, Portuguese and Russian, to the extent possible. Like the earlier systematic review, groundwork scrutiny has again discovered substantial heterogeneity in the HDPs, especially in terms of study design or methodology, study population, intervention used, and outcome reporting. Most of the trials were randomised, double-blind, placebo-controlled, parallel arm design (HPTs); still, other study designs were also adopted. There were lacunae in the studies undertaken by CCRH, especially under-reporting, that is, the incidence rate of proving symptoms (=symptom producers) were not reported till 2007 papers. After that, selective reporting was identified in the verum group only, but inconsistently, till 2014. Since 2015, the incidence has been reported in both groups. Even though there were variations in reporting, the HPTs done by CCRH seem to be relatively homogenous.
The earlier systematic review concluded that the HPTs were of low methodological quality and were suffering from substantial heterogeneity. Although we are in the process of developing psychometrically valid tool/criteria aimed at evaluating methodological qualities of HPTs consistently, overall heterogeneity of the studies still emerges. In contrast with the earlier systematic review by Dantas et al., this scoping review limits itself to systematic data extraction and charting only. We restrained from doing methodological quality scoring of the identified trials, because the scoring system – i.e., Methodological Quality Index (MQI) proposed by Dantas et al. has not been validated formally. Further, our review was confined to the drug proving research trials published in English only, whereas Dantas et al. covered studies published in German, Dutch, French, Spanish and Portuguese also. In both the reviews, the authors of both the papers abstained from conducting meta-analysis due to substantial heterogeneity of data. One of the major problems in today's proving is that different countries are following different protocols for drug proving. Different schools have evolved with different lines of thought. This lack of uniformity generates substantial amount of heterogeneous data and poses a considerable threat to the reliability of the study findings. Previous systemic review of HPTs of 50 years published in six different languages covers 156 HPTs on 143 medicines, whereas in this scoping review of HPTs of 20 years, systemic review published in English language only includes 147 HPTs on 214 drugs. Thus, there has been a paradigm-shift in the last two decades towards conducting more HPTs than earlier. As we are in the process of developing tools for transparent assessment of internal validity of the trials, formal quality assessment of the HPTs will be done in the upcoming systematic review in the near future. The problem of heterogeneity can be resolved to a great extent by paying attention to the basic framework of protocol development and reporting following harmonised guidelines having enough scientific rigors. In comparison with the ‘polychrest’ ones, much importance has been given to rare or indigenous drugs. The authors believe that the research priority should not change from fragmentarily proved drugs or indigenous drugs, but the focus on the methodology adopted and transparency in reporting the results should increase. Further, focus should be to validate the signs/symptoms/syndromes developed during proving or claimed to be effect of proving substance.
Since publication of the earlier systematic review, two different drug proving schools emerged and focused on different areas of interest. One of these schools preferred to keep HDPs for collecting new symptoms epistemologically separated from those designed to quantitatively test hypotheses about the generation of new symptoms. They continued carrying out HDPs in single arm, pre–post, interventional design without placebo control. This study design is criticised for its inherent limitations, e.g., the placebo effect, the therapeutic relationship with the clinician (empathy, compassion, social desirability, etc.), the regression effect towards the mean and the effects of undisclosed interventions, if any. The other school considered HDPs as phase 1 clinical trials  and continued performing studies in double-blind, randomised, placebo- controlled, parallel arms design. This school generated heterogeneous data – either due to the absence of any standardised generic protocol for HPTs or due to under-reporting to a considerable extent. Both the schools, especially the former, adopting their own ideologies, generated an enormous display of symptoms – both generals and particulars. To some extent, the HPTs and phase 1 clinical trials are similar but overall clearly distinct from each other. Differences exist in terms of trial objectives, eligibility criteria, dosage of investigational medicinal product (IMP), endpoints and analysis of efficacy and safety. Similarity exists in terms of study designs – both single-arm trials as proof of concept and randomised, double-blind, parallel group or cross-over designs are adopted. Conventional phase 1 trials are actually non-therapeutic exploratory trials in usually healthy human subjects who can generally expect no therapeutic benefit from the IMP. These trials are performed to obtain pharmacokinetic, pharmacodynamic, toxicokinetic, safety, and tolerability data using dose escalation or repeat dose method following definite GCP/ICH guidelines with no obvious placebo control.
The standardisation of a proving process and the quality of proving studies have been major considerations for research over the years. HPT guidelines and protocols are being developed and continuously being updated,,,,,, and very recently, the latest harmonised guideline has been outlined by CCRH. Checklist for quality assessment of HDPs needs to be developed further and adopted in adherence with the proposed one. Still, some issues remain unaddressed, e.g., pre-defining dosage of the IMP in HPTs, which may contribute to the low prior probabilities to such an extent that it may make no sense. Although a low theoretical prior probability is a questionable argument for rejecting further trials, because prior chance combined with Bayes’ theorem demonstrates that extremely low priors are consecutively increased by new evidence that is positive. However, the (prior) chances of producing symptoms with inert substances and toxic/poisonous substances in same dosage may influence the outcomes. Other potential sources of bias (e.g., age, sex, demographics, ethnicity, socio-economic status, food, religion and cultural practices) can be evaluated by undertaking intercontinental studies. The investigators should try to stick to the adopted strategies to minimise heterogeneity and generate reliable drug pictures in the future.
| Conclusion|| |
This scoping review helped in the identification of the HPTs/HDPs conducted between 1996 and 2018 and organised illustration of the trials in terms of study design, interventions, volunteers and overall results. Despite a clear trend of gradually improving quality in terms of adopted study designs, much heterogeneity still existed in study planning, execution and reporting. The 147 accepted records are the first for data recovery and assessing and analysing the possibility of conducting a systematic review and meta-analysis, which may include the HPTs published in other languages and is aimed at evaluating methodological qualities of the HPTs using valid criteria and statistical pooling of the trial results if the data permit.
We deeply acknowledge Dr Chaturbhuja Nayak, Former Director General, CCRH, Dr Alok Kumar, Former Director General In-Charge, CCRH, Dr Vikram Singh, Deputy Director, CCRH, Dr V A Siddiqui, Former Assistant Director (H), CCRH, and Dr Rajpal, Scientist-4, CCRH for their contribution towards the monitoring of Drug Proving Research Programme of the Council. As this article has maximum research papers from the Council, the authors are grateful to the Drug Proving Masters for data collection for these trials. We gratefully acknowledge the active co-operation and participation made towards the study by the provers and the supporting staffs.
Financial support and sponsorship
The project was funded by Central Council for Research in Homoeopathy, under the Ministry of AYUSH.
Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]