Submitting a Monograph
Guidelines for Homeopathic Drug Provings
Approved April 2015
4. Design / Methods
- Overall Study Design and Plan
Research design type must be described and justified in detail.
While retrospective information may be placed in the introduction, toxicology section, and/or pre-Proving information, all data for Proving analysis will be prospective in nature.
Number of Centers involved in a Proving will be noted (mono- or multi-center are equally acceptable).
Randomized, Double Blind, Placebo Controlled design is recommended.
If blinding to Investigational Proving Substance (IPS) identity for subjects, supervisors, and principal investigator is not possible, use of control (placebo) is required.
The control used should be indistinguishable by the subjects and supervisors from the verum form of IPS and vehicle of the verum form of IPS.
In randomized controlled Provings, a minimum of 20% of the Proving subjects at the initiation of the proving should receive control (placebo) to help minimize bias in the Proving.
Use of control (placebo) is recommended in all Provings. (1), (2)
- Selection of Study Population
A Proving will be conducted with the widest range of subjects possible.
Limitation of Proving subjects from ages 18 years to 75 years is recommended.
Inclusion of male and female subjects to ensure that representative data on both genders can be collected is recommended.
The location and setting of the Proving should be noted.
- Inclusion / Exclusion Criteria
Criteria must be established to exclude certain subjects from the Proving to help minimize health risks, to remove potentially confounding factors from the Proving, and to ensure that subjects are capable of providing accurate information while recording their subjective symptoms.
Criteria must be defined before Proving initiation and subject selection and approved by Ethics or Institutional Review Board.
Pregnancy testing of all women within 1 week prior to administration of the IPS and exclusion of pregnant subjects is required.
Exclusion of subjects <18 or >75 years of age is recommended. If such subjects are included, this must be accompanied by a suitable rationale and Ethics or Institutional Review Board approval.
Exclusion of mentally incompetent subjects or individuals with inability to give an adequate history is required.
Exclusion of subjects with serious mental-emotional disorders (Psychosis, Major Depression, Bipolar Disorder or similar) is recommended.
Exclusion of subjects with planned medical / dental treatment during the Proving period including herbal or dietary supplements, procedures, or medications that are likely to interfere with, or substantially alter responsiveness to IPS (such as hormonal contraceptives or systemic corticosteroids for example) is recommended.
Exclusion of subjects under current homeopathic treatment within the past 45 days is recommended.
Exclusion of subjects with lifestyle practices (such as current alcohol or drug addiction) that are likely to substantially alter responsiveness to IPS is recommended.
- IPS Characteristics
Attenuation or concentration will be selected to ensure safety of test subjects based upon the maximum dosing possible during the Proving.
Attenuations lower than 12C should not be used if the safe human dose of IPS is not known.
Attenuations greater than 30C are not recommended for Provings.
Use of a vehicle, preparation, or route of administration that does not adhere to HPUS guidance requires HPUS approval prior to monograph submission.
IPS is recommended to be prepared and administered in a manner adhering to the HPUS.
Process for randomization will follow international Good Clinical Practice standards (15), (16), to ensure unbiased allocation to verum and control groups prior to distribution of IPS, if control (placebo) utilized.
- Dosing Frequency
Timeline for repetition of dosing shall be established prior to Proving initiation as approved by the Ethics or Institutional Review Board.
IPS dosing frequency greater than three times daily is not recommended.
- Criteria for Non-Repetition of Dose
Non-repetition criteria shall be explicitly defined in the Proving protocol prior to initiating the Proving.
Non-repetition criteria will include the initial development of proving symptoms by a subject (requires definition in the protocol).
Criteria for non-repetition of dose are recommended to include stopping IPS dosing in subjects with no discernible response after 1 week.
Blinding to treatment allocation when placebo control is utilized should include all of the following:
a) Principal Investigator
b) Proving Coordinator
d) Subjects (Provers)
Blinding to IPS under study should include the maximum number of the following permitted by Ethics or Institutional Review Board:
a) Principal Investigator
b) Proving Coordinator
Un-blinding should only occur:
a) During the Proving, for individual subjects, in the event of a Serious Adverse Event. (see Section 6.3 for required elements of un-blinding process)
b) If the PI or Ethical / Institutional Review Board determines un-blinding is medically necessary for subject safety reasons.
c) After all data is locked into a final, unalterable database following the final evaluation of all subjects and correction of any subject entries.
- Therapeutic Intervention during Proving
All medical and other therapeutic interventions in subjects that occur during the Proving must be recorded.
Investigator will make a determination on any such intervention during the Proving to determine if such treatment is likely to have substantially altered the validity of subsequent Proving symptoms in the subject. Events related to such treatment must be handled according to Adverse Events process within Section 6 of these guidelines.
- Number of Subjects / Sample Size
Sufficient sample size must be selected to ensure that a minimum of 10 subjects receive verum and complete the proving per protocol.
Subject withdrawal rates greater than 10% are sub-optimal and must be accompanied by specific explanation.
Proving sample size is recommended to include at least 20 subjects.
- Subject Replacement
Subjects who withdraw or are removed prior to the administration of the IMP should be replaced; subjects who withdraw after IMP administration—but before the data code is un-blinded—may be replaced.
- Supervisor and Subject Interaction
Face to face subject evaluations are required during intake and exit visits.
Subjects must be provided instruction and the means for emergency contact with the supervisor.
Additional face-to-face or telephonic interactions with subjects during the Proving are recommended at least weekly.
Subject education is recommended to include the following:
a) How to record symptoms
b) Reporting adverse events
c) Interim contact procedure
- Definitions to be Included in Proving Timeline
Run-in period (including Pre-Proving data collection)
Run-in period recommended to last at least 7 days.
Subject reporting / interview frequency and duration
a) Subject reporting / interview frequency and duration recommendations:
b) Subject interview is recommended to be at least weekly.
c) Duration of subject reporting is recommended to span at least 6 weeks.
d) In person evaluation by the supervisor or principal investigator should be conducted at the final evaluation or exit point of the Proving for each subject.
e) Subject diary entry schedule is detailed in section 5.3.
- Follow-up period
Final follow up of subjects is recommended to extend at least 3 months.
(1) Walach H. Response: potential nonlocal mechanisms make placebo controls in pathogenetic trials difficult. Homeopathy, Volume 96, Issue 4, October 2007, Page 278.
(2) Walach H, Sherr J, Schneider R, Shabi R, Bond A, Rieberer G. Homeopathic proving symptoms: result of a local, non-local, or placebo process? A blinded, placebo-controlled pilot study. Homeopathy, Volume 93, Issue 4, October 2004, Pages 179-185.