How to Submit Monographs to the HPUS

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FDA’s Revised Draft Enforcement Document states the Agency considers only products that use substances monographed in the Homeopathic Pharmacopoeia of the United States (HPUS) as homeopathic. This statement has created interest in what steps are necessary to submit a monograph to the Homeopathic Pharmacopoeia Convention of the United States (HPCUS) for inclusion in the pharmacopoeia.

Eligibility Criteria [1]

To be eligible for inclusion, appropriate documentation must be provided so the HPCUS can determine the submitted homeopathic drug is safe and effective, and it has been prepared according to specifications of relevant sections of the HPUS. Further, the therapeutic use of the submitted homeopathic drug needs to be established by either:

  • a homeopathic drug proving with subsequent clinical verification, or
  • published documentation providing the drug’s symptom picture, (including subjective and any available objective symptoms), or
  • at least two adequately controlled double blind clinical studies using the drug as the single intervention; accompanied by sufficient statistical analysis and adequate description of the symptom picture, or
  • data gathered from clinical experience or documented in medical literature, which provides the subjective and objective symptom picture plus pre- and post-treatment information.

Once submitted, the documentation is given to two HPCUS committees: the Monograph Review Committee (MRC) consisting of experts in botany, chemistry, toxicology, manufacturing, and quality control, and the Pharmacopoeia Revision Committee (PRC) which is composed of homeopathic clinicians. The MRC reviews the submitted technical documentation to determine if the drug is adequately identified, prepared according to the HPUS, and its safety profile is appropriately described. The PRC reviews the clinical submission to ascertain if the therapeutic utility of the submitted homeopathic drug is substantiated by the documentation.

Each committee forwards their recommendation to the Board; the Board reviews the recommendations in relation to the submission and makes the final determination whether the substance should be added to the HPUS or not. In the event the MRC and PRC recommendations differ, the two committees may meet in a joint session; this can lead to resolving the differences. The sponsor of the monograph submission may also be asked for additional information or clarification as necessary.

There are three guideline documents that will be of help to those contemplating submissions to the HPUS. Each is briefly described below; a much deeper reading of each is necessary to understand the detail of information to be submitted. All three guidelines provide similar criteria:

  • Requirements that must be met for approval of the monograph; non-compliance with these requirements will likely cause non-approval of a monograph submission, unless the deviations are justified and approved by the committee(s) in advance; and
  • Best Practice Recommendations are suggested methods or particular points that should be considered when conducting development and documentation.

Technical Information Requirements for Monograph Review [2]

This guideline assists monograph sponsors to assemble and present sufficient and appropriate chemistry, manufacturing and controls (CMC) plus safety information. While the information may seem voluminous, the level of detail is on a par with what is expected of any company to comply with good GMP and maintain a documentation program. These requirements also guide MRC reviewers in ensuring that expected standards are met:

  • The definition, description, nomenclature and general properties of the raw material is adequately described;
  • The manufacturing processes and control of materials are identified where appropriate; the quality, storage conditions and stability of the raw material, are, as needed, clearly stated; and
  • The safety of the starting material is established on a basis that allows calculation of appropriate attenuations levels.

Examples of the information when describing the starting material include: physico-chemical properties; natural habitat/geographical distribution; part of plant/stage of development; age, health status and cultivation of donor animals; distribution controls imposed by regulatory authorities;
safe handling practices (not an exhaustive list).

Examples of quality parameter information include: macroscopic and/or microscopic description; photo of voucher specimen; chromatographic or spectrographic fingerprint; acceptable limits of heavy metals, residual pesticides, 
foreign material or other adulterants;
total ash;
moisture content (not an exhaustive list).

Details regarding safety should include information on acute and repeat dose toxicity as well as genotoxicity, carcinogenicity, reproductive toxicology, local tolerance, antigenicity, immunotoxicity, and dependence. Much of this information can be submitted from literature sources; these are the usual expected categories of information as explained during the AAHP June 2019 Summit presentation on Toxicology.

HPCUS Proving Guidelines [3]

Published literature on homeopathic provings was considered in the development of these guidelines, which will help monograph sponsors design and conduct a Homeopathic Drug Proving that meets standards for approval. These also help guide reviewers in ensuring:

  • Compliance with the Proving design and execution requirements;
  • Proper analysis to evaluate the sufficiency of the Proving results; and
  • Compliance with all legal, ethical, and publication requirements.

In the development of these guidelines, various standards were consulted, including those of the HPUS, the FDA, the International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the Homeopathic Medicinal Product Working Group (HMPWG) of the European Union Heads of Medicine Agency, and the EU-Notice to Applicants (NTA) guidance on homeopathic drug manufacturing. Basing the HPUS guidance on those sources helps ensure that new monographs accepted into the HPUS will withstand scrutiny from various regulatory agencies.

The guidelines cover various aspects of Homeopathic Drug Provings, including: personnel qualifications and training; proving controls (blinding and randomizing); selection of study population and inclusion/exclusion criteria; basis for selection of attenuation used, as well as frequency of administration. The guidelines cover aspects of data collection and analysis with a focus on understanding general proving symptoms verses specific characteristic symptoms. A well-designed Homeopathic Drug Proving creates an opportunity to develop a coherent remedy picture for the monograph submission substance.

Of particular interest is the section that notes any symptom or condition occurring in a subject during the Homeopathic Drug Proving and clinically unexpected reactions considered to be an adverse event. This concurs with both FDA and ICH-GCP adverse event definitions for clinical trials in humans. Based on decades of experience with provings, this section continues by confronting causality considerations and addressing the question of what is an expected homeopathic symptom and/or aggravation, and what is an independent adverse (especially serious) event that must be addressed during the course of the Homeopathic Drug Proving.

Clinical Data Guidelines [4]

This guideline defines how different types of clinical data can be used in a monograph submission. The monograph review primarily focuses on information derived from historical or modern provings, toxicological data, and data from generally accepted homeopathic literature. If the information from these sources is insufficient to establish a reasonable understanding of the safety and potential utility of the IHMP, additional information and/or clinical data may be required by the HPCUS for monograph approval. In the right circumstances, this information can be submitted on its own.

The requirements for the quality and quantity of clinical data for new monographs are described in this guideline, and help monograph sponsors ensure that the gathering and the preparation of clinical data meets standards for monograph review. This document closely parallels the information in the HPCUS Proving Guidelines (see previous section). However, instead of addressing design and analysis of Homeopathic Drug Proving data, this guideline addresses other methods permitted for obtaining clinical material for monograph submission. The main research study types to obtain clinical material for monograph submission are:

  • Clinical cases/case series (prospective or retrospective);
  • Observational studies with comparison data on homeopathically-treated and non-treated subjects (including cohort studies); and
  • Experimental trials (including randomized controlled trials).

Due to the characteristics inherent in these types of studies, statistical data consistent with the study design is an additional requirement for such data submission. Each category of data is 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, but may artificially limit the number of characteristic clinical features that are essential to understand the symptom picture of the homeopathic products.

The HPCUS will evaluate clinical data submitted by a monograph sponsor in a manner consistent with the fundamental tenets of homeopathic medicine and with an aim to minimize bias. While the method of evaluation will vary according to the type of data, the overall assessment goal remains the same: the clinical data must demonstrate a sufficient number of assessable outcomes to provide a homeopathic clinical picture (indications) for the homeopathic product.

These requirements are not overly burdensome and have been successfully utilized by multiple companies to successfully submit monographs; since 2005, more than two dozen new monographs have been added to the HPUS through this process. Readers interested in the particulars of the monograph submission requirements are strongly encouraged to read the individual guidelines on the HPUS website (links given below). This abbreviated overview cannot replace a careful review of the documents with their clarity, explanations, specifications, and details. Each also contains a glossary of helpful terms to support a consistent vocabulary when communicating with the HPCUS regarding monograph submissions.

[1] For more details, please see the HPUS Criteria For Eligibility.

[2] For details, see http://www.hpus.com/private/HPCUS-Technical-Submission-Guidelines-2014.pdf (accessible by subscription)

[3] HPCUS Proving Guidelines  http://www.hpus.com/HPCUS-Proving-Guidelines-2015.pdf (accessible by subscription)

[4] http://www.hpus.com/HPCUS-Clinical-Data-Guidelines-Draft-08-2018.pdf