Submitting a Monograph
Guidelines for Clinical Verification
Approved July 2020
4. Design / Methods
1. Different research designs and methods are permitted for obtaining clinical material for monograph submission. The main research study types that can be utilized to obtain clinical material for monograph submission are:
2. Clinical Cases / Case Series (Prospective or Retrospective)
3. Observational Studies with comparison data on IHMP-treated and non-treated subjects (including Cohort studies)
4. Experimental Trials (including Randomized Controlled Trials (RCTs))
These study types have been selected to help differentiate varying requirements for data submission for monograph review. For example, all submissions with data generated from human subjects will be required to complete an Ethics Committee or IRB review. However, the specific requirements for ethics compliance (such as the need for informed consent) may vary based upon study design. Furthermore, datasets derived from cohort studies and experimental trials will include data from subjects that were not treated with IHMP. Because of the capabilities inherent in these types of studies, statistical data consistent with study design will be an additional requirement for such data presented for monograph submission.
Each category of data will be associated with inherent strengths and limitations. Case materials based on prospectively collected data, or systematically collected retrospective data, are preferred over data from non-systematically collected cases. Studies with comparative data add the potential for statistical analysis. These studies may, however, artificially limit the number of characteristic clinical features that are essential to understanding the homeopathic clinical picture of the IHMP, e.g., the emergence of an identifiable constellation of clinical features of treatment success with the IHMP. Study design, data extraction methods, and statistical analysis (if used) shall be undertaken with care to enable the elicitation of characteristic clinical features of the homeopathic clinical picture.
Case or case series data may include retrospective (published or unpublished) and prospective data in any combination. On the other hand, experimental trials, e.g., RCTs, and prospective observational studies shall be submitted as separate data. Compilation of data between studies, if feasible and appropriate, may be submitted as additional data.
The general requirements for all data types are given below. Because of the differences between the three main data types, design specific requirements and recommendations are given in separate sections.
- General Requirements
The selected research methodology must be designed to maximize validity, ensure transparency, and protect the rights of any research subjects involved.
4.1.1. Overall Study Design and Plan
Selection of methodology type and research design must be described and justified in detail.
Monograph sponsors shall adhere to guidance provided by the EQUATOR Network and the ICH.
Design or reporting deviations from EQUATOR Network or ICH guidance must be justified in writing as part of the monograph submission. Insufficient justification will result in recommendation to reject data for monograph consideration.
4.1.2. Selection of Study Population
Method and rationale for study population selection shall be reported.
The location and time period of data gathering from study population shall be noted.
4.1.3. Inclusion / Exclusion Criteria
Any criteria used to include or exclude retrieved data or subjects from the study shall be reported.
Inclusion and exclusion criteria shall be used to help minimize variables that are likely to decrease the probability of establishing a homeopathic clinical picture.
Inclusion criteria shall contain variables relevant to known therapeutic actions of the IHMP.
4.1.4. IHMP
Use of a vehicle, preparation, and route of administration for the IHMP shall adhere to general HPUS guidance. Any deviation requires HPCUS approval prior to monograph submission.
4.1.5. Therapeutic Interventions
Only data acquired using a single IHMP during the time of data capture can be used for monograph purposes.
Sufficient data must be provided to verify the identity and receipt of therapeutic intervention as the IHMP.
Sufficient information must be provided to accurately describe the treatment regimen and rationale.
All additional medical and other therapeutic interventions in subjects that occur during the treatment with the IHMP must be recorded and documented as to whether it is likely to have substantially altered the validity of data.
4.1.6. Outcome Evaluation
Outcome assessments shall include global or aggregated measures of subject health. Reporting only single health variable outcomes may not sufficiently delineate the homeopathic clinical picture necessary to define the clinical utility of the medicine.
4.1.7. Data Access
Access to the source data or process of verification for source data for any published material must be provided to permit adequate evaluation of monograph submission.
Copies of any published materials used for obtaining data shall be provided.
- Specific Requirements Cases / Case Series
4.2.1. Sampling / Selection of Cases
For prospectively collected case material, the rationale for subject selection for treatment shall be clearly defined.
The association between selection method and known data on IHMP shall be detailed. Known data on IHMP as well as starting material may include:
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- Proving data
- Toxicology data
- Traditional use data (for starting material), or
- Clinical use data
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Retrospective case material may be obtained in two different ways:
a) Review and synthesis of published clinical cases that are in the public domain
b) Retrospectively retrieved unpublished cases:
i. Treated under the responsibility of the PI, or
ii. Treated by other clinicians
Both possibilities mentioned above either alone, or in combination with each other, can be utilized for monograph submission.
Monograph sponsor shall provide the following information for any case data retrieved from publications:
a) Method for selection of cases from the literature (including search parameters, inclusion and/or exclusion criteria, and database(s) searched)
b) Sufficient evidence to verify the identity of therapeutic intervention as the IHMP for such data
c) Total number of case reports selected for submission of monograph
d) Name and quality of the publication(s) concerned, i.e., peer-reviewed, well-recognized, indexed, etc.), and
e) Journal policy, as well as likelihood of use, with regard to informed consent of published cases
If required for the proper evaluation of retrospectively retrieved unpublished case material, the HPCUS may request access to additional de-identified original patient case data.
4.2.3. Case Report Requirements
All case reports submitted as clinical data for monograph evaluation must meet the following requirements:
h) Compliance with appropriate clinical guidelines ,
i) All medical and other therapeutic interventions in subjects that occur during the period of treatment with the IHMP must be recorded.
j) Subjective and objective data within the case report must include an indication of date (and time if appropriate) when data was collected and when entered into the record.
k) Timeline with regard to treatment of subject must be included
4.2.4. Follow-up Duration
Duration of follow-up shall be sufficient to demonstrate clinical response for the given complaint(s). Use of the IHMP in treatment of both acute and chronic clinical conditions is acceptable for monograph purposes.
4.2.5. Outcome Evaluation
Individual case score using the HPCUS Case Outcome Assessment Tool is required for all submitted cases (see Table 1 Section 4.4.7.).
Recommend only submitting cases with a HPCUS Case Outcome Assessment Tool score of eight or higher.
Only cases where IHMP use was associated with a likely improvement in the outcome will be considered for final review.
The use of historical comparison data and/ or other available literature on the expected course of the disease for supporting the outcome evaluation is recommended.
Use of validated diagnosis specific and general outcome evaluation tools is recommended.
The HPCUS reserves the right to reject material deemed insufficient in quality or reliability and recommends the monograph sponsor consult the HPCUS prior to the monograph submission when considering the use of such material.
4.2.6. Quantity of Cases for Monograph Evaluation
During the HPCUS monograph review process, known information on the IHMP, type(s) of case material submitted, individual case quality, and qualitative coherence (similarity) between cases will determine the absolute number of cases sufficient for monograph approval.
When sponsors are submitting case material as the primary clinical data for monograph evaluation, a minimum of three cases using the IHMP as the primary intervention and having sufficient quality must be submitted.
- Specific Requirements for Observational Studies
Observational studies (including cohort studies) may include data on non-IHMP treated patients that can be used for comparative purposes. With regard to the IHMP treated cases, the case report requirements and case report quality and outcome evaluation are the same as described in Section 4.2 above, unless otherwise noted.
Observational studies with comparison data can be designed to help validate the prognostic value of symptoms and signs used to select a homeopathic medicinal product. Such studies overcome some of the limitations associated with experimental trials as referred to below in Section 4.4, while adding further validity to the identification of the homeopathic clinical picture of the IHMP. The conduct of such studies is therefore recommended.
The following additional requirements and recommendations apply to observational studies.
4.3.1. Outcome Evaluation
A full description and reasoning for any statistics used in evaluating the outcomes shall be included.
Monograph sponsors shall utilize statistical methods, e.g., likelihood ratios , to help define the relative predictive value of symptoms and signs as indicators of treatment success in the selection of the IHMP for clinical use.
- Specific Requirements for Experimental Trials
Controlled Trial (RCT) is an experimental trial that is designed to minimize potential unknown confounders of the outcome via random allocation to the intervention and control treatments. The aim is to evenly distribute the known as well as unknown determinants of outcome between the groups with the exception of the treatment of interest. While this research design is excellent for determining efficacy of a specific intervention in a well-defined group of subjects with regard to a specific endpoint, it is of limited value in homeopathic prescribing where the “confounders,” i.e., individual subject characteristics, are the actual variables of interest, as they lead to the development of a homeopathic clinical picture for the IHMP.
For monograph purposes, experimental trials designed solely to demonstrate the efficacy of the IHMP with regard to a single- or multiple-therapeutic outcomes are of limited value as they do not provide the broader clinical characteristics of the IHMP necessary for homeopathic use. This does not preclude the use of RCT data in support of a new monograph approval, but such trials must be designed with a view to assess the value of characteristic features of the IHMP as modifiers of the treatment effect.
Trial designs that may be able to contribute to assessment of characteristic features of the IHMP include:
- Individualization in the selection of patients based on a limited set of characteristic symptoms of the IHMP, e.g., see study by Yakir et al.
- Limited individualization of the subject population, combined with collection of individual homeopathic characteristics of each subject at baseline, and subsequent analysis to determine if these clinical features modify the treatment effect, e.g., see study by van Haselen.
Experimental trials need to comply with relevant ICH Good Clinical Practice (GCP) requirements.
The following requirements and recommendations apply to experimental trials for monograph purposes.
4.4.1. Pre-approval
If an experimental trial is planned for monograph purposes, the monograph sponsor must submit the trial design specifications to the HPCUS for PRC review prior to conducting the trial.
Experimental trials that were conducted prior to planned submission of the IHMP for monograph purposes will be considered, if such trials adequately conform to HPCUS guidelines.
4.4.2. Trial Design
Any trial submitted for monograph purposes must be designed with a goal of identifying the homeopathic clinical picture of the IHMP.
Rationale for trial design shall be explained in detail.
Qualitative and quantitative measures (such as found in Mixed Methods research) that help to clarify treatment selection process are recommended.
4.4.3. Comparison Group
If a crossover design is used, the length of the washout period shall be established before the trial and justified by the sponsor due to variations in duration of action of homeopathic medicines.
Single case experimental designs (e.g., N of 1 trial) that make use of intra-individual crossovers will be considered, provided that a clear rationale for its use is provided.
‘Trials within Cohorts’ (TwiCs) designs (also referred to as “Cohort multiple randomized controlled trial designs”) , will be considered, provided that a clear rationale for use is provided.
4.4.4. Inclusion / Exclusion Criteria
Rationale for subject selection must be explained in detail.
Subject selection criteria based on previously identified clinical features of the IHMP are recommended to be used as inclusion criteria.
4.4.5. Secondary Analysis
Any secondary analysis shall be accompanied by relevant statistical evaluation of the factors of interest.
If secondary analysis involves characteristic features (rubrics for treatment selection) that were not identified before the trial, qualitative analysis of the rubric and IHMP selection process must be provided.
Secondary analysis for potential clinical predictors of IHMP therapeutic use is recommended.
4.4.6. Trial Report Requirements
The CONSORT guideline and their extensions and other relevant guidelines3 shall inform the reporting process.
Table 1: HPUS Clinical Outcome Assessment Tool
| Criteria | Yes | No | Not Sure or N/A |
|---|---|---|---|
| 1. Was there an improvement in the main symptom or condition for which the homeopathic medicine was prescribed? | +2 | -1 | 0 |
| 2. Did the clinical improvement occur within a plausible timeframe relative to the drug intake? | +1 | -2 | 0 |
| 3. Was there an aggravation of symptoms? (See Section 10 Glossary of Terms for definition) | +1 | 0 | 0 |
| 4. Did the effect encompass more than the main symptom or condition, i.e. were other symptoms ultimately improved or changed? | +1 | 0 | 0 |
| 5. Did overall wellbeing improve? (suggest using validated scale) | +1 | 0 | 0 |
| 6. (A) Direction of cure: Did some symptoms improve in the opposite order of the development of symptoms of the disease? | +1 | 0 | 0 |
| I) (B) Direction of cure: Did at least two of the following aspects apply to the order of improvement of symptoms: – from organs of more importance to those of less importance – from deeper to more superficial aspects of the individual – from the top downwards | +1 | 0 | 0 |
| 7. Did “old symptoms” (defined as non-seasonal and non-cyclical symptoms that were previously thought to have resolved) reappear temporarily during the course of improvement? | +1 | 0 | 0 |
| 8. Are there alternate causes (other than the medicine) that – with a high probability – could have caused the improvement? (Consider known course of disease, other forms of treatment, and other clinically relevant interventions) | -3 | +1 | 0 |
| 9. Was the health improvement confirmed by any objective data? (E.g. lab test, clinical observation, etc.) | +2 | 0 | 0 |
Maximum Score = 12
Minimum Score = – 6
1) EQUATOR Network website. Reporting guidelines for experimental studies. http://www.equator-network.org/?post_type=eq_guidelines&eq_guidelines_study_design=experimental-studies&eq_guidelines_clinical_specialty=0&eq_guidelines_report_section=0&s. Accessed September 09, 2020.
2) Gagnier JJ, Kienle G, Altman DG, et al.; and the CARE group. The CARE guidelines: consensus-based clinical case report guideline development. J Clin Epidemiol. 2014;67:46-51. Doi: 10.1016/j.jclinepi.2013.08.003
3) van Haselen RA. Homeopathic clinical case reports: Development of a supplement (HOM-CASE) to the CARE clinical case reporting guideline. Complement Ther Med. 2016;25:78-85. Doi: 10.1016/j.ctim.2015.12.019
4) Lamba CD, Gupta VK, van Haselen R, et al. Evaluation of the modified naranjo criteria for assessing causal attribution of clinical outcome to homeopathic intervention as presented in case reports. Homeopathy. 2020; Doi: 10.1055/s-0040-1701251. Online ahead of print.
5) Rutten L, Rutten M. Fundamentals of Statistics and Clinical Research in Homeopathy. 1st edition. New Dehli, India: B Jain Publishers; 2016.
6) Yakir M, Kreitler S, Brzezinski A, Vithoulkas G, Oberbaum M, Bentwich Z. Effects of homeopathic treatment in women with premenstrual syndrome: a pilot study. Br Homeopath J. 2001;90(3):148-153. Doi: 10.1054/homp.1999.0491
7) Van Haselen R. Development of a Prognostic Factor Prediction Model in Patients with Musculoskeletal Pain Treated with Homeopathy: An Individual Patient Data Meta-Analysis of Three Randomized Clinical Trials. Complementary Medicine Research 2020 [DOI: 10.1159/000508716].
8) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Efficacy Guidelines. https://www.ich.org/page/efficacy-guidelines. Accessed September 09, 2020.
9) Relton C, Burbach M, Collett C, et al. The ethics of ‘Trials within Cohorts’ (TwiCs): 2nd international symposium. London, UK: 7-8 November 2016. Trials. 2017;18(Suppl 2):244. Doi: 10.1186/s13063-017-1961-0
10) Velden JM, Verkooijen HM, Young-Afat DA, et al. The cohort multiple randomized controlled trial design: A valid and efficient alternative to pragmatic trials? Int J Epidemiol. 2017;46(1):96-102. Doi: 10.1093/ije/dyw050