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Guidelines for Homeopathic Drug Provings

Approved April 2015

Appendix A

Proving Report
Monograph sponsors are instructed to follow the requirements outlined in the ICH Harmonized Tripartite Guideline for Structure and Content of Clinical Study Reports. Monograph specific requirements and exclusions from these guidelines are noted in the outline below.

  • When using this template, all sections listed within the guidelines will include the requirements of the ICH guidelines, except where specifically directed by a statement of non-applicability, or by other guidance within the listed element that requests specific deviation or additions to the ICH guidelines.
  • Monograph sponsors must provide adequate information within the Proving Report to demonstrate adherence to all requirements within these Proving Guidelines.
  • Additionally, the Proving Report should include reasoning for any departure from recommendations that are detailed in these Proving Guidelines.
  • Extrapolated or speculative commentary should not be placed into this report except where specifically requested.

Report should include the following sections and subsections:

  1. TITLE PAGE

The following elements are excluded for Proving reports: Indication studied and Development phase of study

  1. SYNOPSIS
  2. TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT
  3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
  4. ETHICS
    1. INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB)
    2. ETHICAL CONDUCT OF THE STUDY
    3. SUBJECT INFORMATION AND CONSENT
  5. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
  6. INTRODUCTION
  7. STUDY OBJECTIVES
  8. INVESTIGATIONAL PLAN
    1. OVERALL STUDY DESIGN AND PLAN – DESCRIPTION
    2. DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS
      • Information reported in this section will be limited to discussion of the following: Percentage of controls used. Discussion of use of control data for any purpose other than bias reduction Discussion of use of control data for any comparative analysis
    3. SELECTION OF STUDY POPULATION
      1. Inclusion Criteria
      2. Exclusion Criteria
      3. Removal of Subjects from Assessment
    4. TREATMENTS
      1. Treatments Administered
      2. Identity of Investigational Product(s)
        Include identifying information about the IPS, manufacturer, and compliance with described manufacturing procedure submitted to the Monograph Review Committee.
      3. Method of Assigning Subjects to Treatment Groups
      4. Selection of Doses in the Study
      5. Selection and Timing of Dose for each Subject
        Homeopathic proving dosing and timing has different selection criteria than therapeutic agents used in trials for treatment outcomes. Please provide a brief description of the criteria used for timing, frequency, and repetition of doses during the Proving.
      6. Blinding
      7. Prior and Concomitant Therapy
        Concomitant therapy with homeopathic agents is not permitted for Provings submitted for monograph review. All information in this section will refer to therapeutic agents that are not homeopathic preparations. Narrative report of any concomitant treatment across the whole group should be included here with reference to table describing individual concomitant treatments within the demographic factors report table.
      8. Treatment Compliance
        Reports of treatment compliance will be limited to how delivery of each dose of IPS to prover was confirmed and recorded.
    5. EFFICACY AND SAFETY VARIABLES
      1. Efficacy and Safety Measurements Assessed and Flow Chart
        Not applicable
      2. Appropriateness of Measurements
        Not applicable
      3. Primary Efficacy Variable(s) Drug Concentration Measurements
        Not Applicable
    6. DATA QUALITY ASSURANCE
    7. STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE
      1. Statistical and Analytical Plans
        Not applicable
      2. Determination of Sample Size
        Adherence to Proving guidelines must be demonstrated.
    8. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
  9. STUDY SUBJECTS
    1. DISPOSITION OF SUBJECTS
    2. PROTOCOL DEVIATIONS
  10. EFFICACY EVALUATION
    1. DATA SETS ANALYSED
      Outcome analysis for Provings will not measure efficacy of the IPS. All other parameters of this part of the ICH guidelines should be followed with respect to the data sets used in outcome analysis.
    2. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
    3. MEASUREMENTS OF TREATMENT COMPLIANCE
    4. EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL SUBJECT DATA
      1. Analysis of Efficacy
        Efficacy measures do not apply to Proving results and this type of analysis is therefore not applicable in Provings. Guidance on analyses types, how outcomes were measured, and the evaluation of safety as described in the ICH guidelines are to be included in the Proving Clinical Study Report. Additionally, all aspects of outcomes analysis as described in Section VI of these guidelines should be reported in this section. Specific information on criteria used for defining highly characteristic symptoms, Proving symptoms, and relative characteristic features should be described in detail.
      2. Statistical/Analytical Issues
        Not applicable.
        1. Adjustments for Covariates
          Not Applicable.
        2. Handling of Dropouts or Missing Data
          Because Provings outcomes are primarily evaluated using qualitative criteria, the effect of dropouts and missing data may be difficult to estimate. Sponsors must report all subjects that drop out of the Proving and the reasons for their leaving the Proving. Extrapolation or modeling approaches to incomplete data sets should not be included in Provings reports.
        3. Interim Analyses and Data Monitoring
          Provings design would generally not include interim analysis.
        4. Multicenter Studies
        5. Multiple Comparison/Multiplicity
          Not applicable.
        6. Use of an “Efficacy Subset” of Subjects
          Not applicable.
        7. Active-Control Studies Intended to Show Equivalence
          Not applicable.
      3. Examination of Subgroups
        • Such analysis is not applicable to Provings unless sample size is large.
          Tabulation of Individual Response Data
          Pertinent individual response data is an essential element of all Provings
          submitted for monograph report. Detailed response data should be
          formed into a table including all subjects. This table should include:
          • Subject identification number
          • Notation of receipt of Verum or Control
          • Number of doses received
          • Date of Proving initiation for each subject
          • Dates and times doses received
          • Date of last journal entry / data entry for each subject
          • Number of Proving symptoms observed
          • Number of characteristic symptoms observed
          • Number of highly characteristic symptoms observed
        • In addition, a detailed record of all symptoms recorded during the Proving for each subject should be included. Each symptom recorded should include identifying nomenclature for the type of symptom according to labeling criteria in Section IV of these guidelines.
      4. Drug Dose, Drug Concentration, and Relationships to Response
        Not applicable.
      5. Drug-Drug and Drug-Disease Interactions
      6. By-Subject Display
        This information should be included within 11.4.3, if applicable.
      7. Efficacy Conclusions
        • Not applicable. In place of Efficacy Conclusions, please add a synopsis of the outcomes from the Proving including any highly characteristic symptoms with descriptions and number, and a listing of the primary Proving symptoms that displayed the highest degree of characteristic features. An overall symptom picture can be presented here.
  11. SAFETY EVALUATION
    1. EXTENT OF EXPOSURE
    2. ADVERSE EVENTS (AEs)
      1. Brief Summary of Adverse Events
      2. Display of Adverse Events
      3. Analysis of Adverse Events
      4. Listing of Adverse Events by Subject
    3. DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS
      1. Listing of Deaths, other Serious Adverse Events and Other Significant Adverse Events
      2. Deaths
      3. Other Serious Adverse Events
      4. Other Significant Adverse Events
      5. Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events
      6. Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events
    4. 12.4. CLINICAL LABORATORY EVALUATION
      1. Listing of Individual Laboratory Measurements by Subject (16.2.8) and Each Abnormal Laboratory Value (14.3.4)
      2. Evaluation of Each Laboratory Parameter
        1. Laboratory Values over Time
        2. Individual Subject Changes
        3. Individual Clinically Significant Abnormalities
    5. VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY
    6. SAFETY CONCLUSIONS
  12. DISCUSSION AND OVERALL CONCLUSIONS
    Discussions as to efficacy are not appropriate for Provings. Other findings and conclusions should be included in these sections
  13. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT
    1. DEMOGRAPHIC DATA
    2. EFFICACY DATA
      Efficacy data are not applicable. Table of outcomes should be provided here. Outcomes should be tabulated by Highly Characteristic Symptoms first, followed by those symptoms with the highest amount of characteristic qualities in a descending order according to the analysis by the Proving Supervisor. Each symptom or observation reported should be described in original language of the prover, labeled for New (N), Improved (C+), Worsened (C-) or Recurrent (R), and described for date of onset relative to Proving initiation and dosing.
    3. SAFETY DATA
      1. Displays of Adverse Events
      2. Listings of Deaths, Other Serious and Significant Adverse Events
      3. Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
    4. Abnormal Laboratory Value Listing (Each Subject)
  14. REFERENCE LIST
  15. APPENDICES
    1. STUDY INFORMATION
      1. Protocol and protocol amendments
      2. Sample case report form (unique pages only)
      3. List of IECs or IRBs (plus the name of the committee Chair if required by the regulatory authority) – Representative written information for subject and sample consent forms
      4. List and description of investigators and other important participants in the study, including brief (1 page) CVs or equivalent summaries of training and experience relevant to the performance of the clinical study
      5. Signatures of principal or coordinating investigator(s) or sponsor’s responsible medical officer, depending on the regulatory authority’s requirement
      6. Listing of subjects receiving test drug(s)/investigational product(s) from specific batches, where more than one batch was used
      7. Randomization scheme and codes (subject identification and treatment assigned)
      8. Audit certificates (if available)
      9. Documentation of statistical methods
        If Used.
      10. Documentation of inter-laboratory standardization methods and quality assurance procedures if used
      11. Publications based on the study
      12. Important publications referenced in the report
    2. SUBJECT DATA LISTINGS
      1. Discontinued subjects
      2. Protocol deviations
      3. Subjects excluded from the efficacy analysis
      4. Demographic data
      5. Compliance and/or drug concentration data (if available)
      6. Individual efficacy response data
        Not Applicable.
      7. Adverse event listings (each subject)
      8. Listing of individual laboratory measurements by subject, when required by regulatory authorities
    3. CASE REPORT FORMS
      1. CRFs for deaths, other serious adverse events and withdrawals for AE
      2. Other CRFs submitted
    4. INDIVIDUAL SUBJECT DATA LISTINGS (US ARCHIVAL LISTINGS)
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