I. Introduction

NCCIH is committed to the rigorous scientific investigation of natural products used in complementary and alternative medicine. This Policy establishes guidance on the information required by NCCIH for different types of products used in both mechanistic and clinical research including complex botanical products, complex animal products, probiotics, refined products, and placebos. In the context of this Policy, the term "natural product" refers to any substance of natural origin or its synthetic alternative. "Product integrity," as used in this document, refers to the entirety and completeness of information about a product that assures it will meet NCCIH Policy requirements. This information will help provide the investigator and NCCIH with the requisite level of confidence that the research will yield definitive and reproducible results.

This Policy is applicable to all Research Grants (e.g., R01, R15, R21), Competitive Renewals, Center Grants (e.g., P01, P50, and their Pilot Projects), Cooperative Agreements (U's), Contracts (N's), Fellowships (F's), Career Awards (K's), and NCCIH's intramural projects. It applies to all study agents not acquired through a competitive process or developed by NCCIH-supported research-grade product development contractors or grantees. The Policy does not apply to Institutional Training Grants (T32, T35).

Product Integrity Policy Sample Response

II. Guidance for Investigators

A. Information Required in Grant Applications

Sufficient product information must be included in the application to allow the peer reviewers to evaluate the significance, feasibility, and scientific strength of the project. Investigators must demonstrate that their investigative team has the appropriate product and analytical expertise to select the test and placebo agents for study and to insure the product integrity. For example, botanists trained in taxonomy may be required to identify voucher specimens accurately. Experts in natural products chemistry, microbiology, food science, botany, pharmacognosy, analytical chemistry, etc., may need to be consulted in order to provide the analytic rigor with which to evaluate product composition.

In the Research Strategy section of the application, the following information generally should be included or referenced:

• Name of the product (brand name, chemical or taxonomic nomenclature—e.g., genus, species, strain, as applicable)
• Ingredients of the product (both active and inactive)
• Justification/rationale for the product, including supplier; justification for the chosen form of the product (refined, complex, etc.), including parts to be used (e.g., root, stem, leaf) as applicable, and the vehicle and route of administration (e.g. iv, ip, or po);
• Proposed methods for product characterization and standardization
• Rationale for selection and percentages of marker compounds, if applicable.

The following additional information should be provided for human subject studies:

• Justification for the proposed doses/concentrations and dosing schedule
• Any known safety issues regarding the chosen product at this dose
• Brief description of the pharmacokinetics and pharmacodynamics of the known components of the product and any biological or chemical marker(s) of activity (if known and if applicable)
• Description of placebo or vehicle control.

B. Considerations for Clinical Trials

Regulation of products is strictly the jurisdiction of the U.S. Food and Drug Administration (FDA). Therefore, NCCIH will not make any interpretations regarding the appropriate regulatory status for a product used in a human patient population. Investigators proposing clinical studies must contact the FDA to determine if an Investigational New Drug (IND) application is necessary.

Additional resources for clinical researchers include the FDA Guidance for Industry: Botanical Drug Products and the 2006 CONSORT statement (Annals of Internal Medicine. 2006;144(5):364–367). The FDA document (PDF) discusses regulatory policies specific to botanicals and provides information on submitting investigational new drug (IND) applications for botanical drug products. Among the recommendations of the CONSORT statement is a checklist of information that should be included about the intervention when reporting the results. Investigators are encouraged to review these recommendations when designing controlled trials of herbal interventions.

III. Product Information

A. Background

After initial IRG review, applicants with the potential to be supported will be asked by NCCIH to submit additional detailed product information corresponding to the relevant section of this Policy. This notification is a prerequisite for funding, but not a guarantee that an award will be made. The level of detail requested varies depending on the product and its intended use. Submissions in response to this Policy should not exceed 10 pages in length. Requirements listed here may be modified depending on the information available for any particular product. The entirety of the information will be assessed by NCCIH staff in consultation with outside experts where needed. After this evaluation, investigators will be notified whether or not the information is satisfactory. There will be multiple opportunities to submit additional information, if necessary, in order to resolve all issues.

Investigators proposing to use products that have been approved for use by NCCIH in earlier studies or who have obtained an IND for their product should contact NCCIH before submitting to determine what additional information, if any, is required.

Note: A satisfactory designation by NCCIH does not reflect product endorsement.

B. Information for Products Developed During Studies

When new products are developed in the course of an award, product information may be required prior to issuance of a non-competitive renewal award. For example, if one of the specific aims of a project was to generate fractions of a plant extract for use in in vitro or in vivo testing, information on the characterization and standardization of those fractions may be required. The Notice of Grant Award may include terms requiring the reporting of product information for such projects.

IV. Requested Product Information

Investigators should provide the following information upon NCCIH's request. Guidance on five categories of products is provided. If the study product is not included in one of the five categories, you should contact NCCIH staff. The items listed under each section and subsection (in vitro studies, animal studies, human studies) are meant to serve as guidelines and may be modified by NCCIH staff depending on the product and/or the details of the study.

A. Complex Botanical Products

(e.g., plants, macroscopic fungi, algae)

• For single-herb products, information on the raw material and final product is needed.
• For multiple-herb products, information is needed for each individual botanical within the preparation, as well as for the mixture as a whole.

In vitro studies

1. Identify the source plant for the product using the scientific taxonomic nomenclature and author citation (e.g., Ginkgo biloba L.). Describe the parts of the plant from which the product is derived.
2. If an extract is used, identify the extraction solvent.
3. Name the supplier of the product. Include the brand name of the product, if applicable.
4. Present data on the characterization (e.g., chemical profile or fingerprint) of the final product as thoroughly as the state of the science allows.
   • Identify active and/or other relevant marker compound(s) used for standardization.
   • Provide any information relevant to the standardization process (including process control, as well as chemical and/or biological standardization of ingredients).
   • Information from suppliers MUST be confirmed through independent analysis either by a third party lab or by the investigator (if they have appropriate facilities and expertise).
5. Provide a Certificate of Analysis from the supplier to show compliance to their specifications for content and any other supporting information relating to the batches to be used in the study. This should include data on the analysis of the product for contaminants/impurities such as pesticides, heavy metals, and residual solvents.
6. Provide data on batch-to-batch reproducibility. These data may be required separately for the botanical alone, the vehicle alone, and the final product, as appropriate.
7. Present a plan to monitor the stability of product samples from all batches used during the course of the study.
   • The plan should include:
     1. How you plan to store the botanical, vehicle, and/or final product
     2. What analyses will be conducted, the methods to be used, and how frequently and by whom the analyses will be done
     3. Investigator's tolerances for chemical and/or biological variability, and what will be done if variability exceeds those limits.
   • In addition, sufficient material must be retained from each batch to allow independent analysis, should NCCIH request samples. Samples should be retained a minimum of one year after all results arising from the study have been published.

Additional Information for Animal Studies

1. Describe the method of authentication of the raw material and where and how an authenticated voucher specimens of the plant material is reserved. Ideally, an original herbarium specimen should be deposited in a publicly accessible herbarium where conditions and staff are appropriate for the conservation of the specimen. At a minimum, a voucher or reference sample culled from the same batch of the plant material should be deposited in a secure, climate-controlled facility at the investigator's institution.
2. Describe the manufacturing process. This should:
   • Include details of the extraction such as solvent(s), ratio of plant to solvent, time and temperature
   • Alternatively, if the test agent is not an extract, but is an infusion, tincture, or volatile oil, describe its preparation with the same level of detail as an extract
   • Provide information about the formulation of the final product (e.g., excipients, chow/feed composition, etc.)
   • Provide documentation to show the product was manufactured under GMP guidelines.
3. If the product is combined with a diet, a Certificate of Analysis and specifications for the vehicle will also be necessary to assure purity, consistency, absence of bioactive components (e.g. soy), and/or reproducibility of the vehicle. Furthermore, analysis of the formulated diet may be required to assess consistency, stability, etc. of the product in this matrix.

Additional Information for Human Studies

1. Submit copies of correspondence with the FDA indicating you have discussed whether or not an IND is required for this proposed study.
2. Provide a letter from the supplier stating their commitment to provide the product and cooperate with the IND application process, if required.
3. If the source plant is collected from wild populations, provide evidence that it was collected in compliance with applicable international, national, and/or local guidelines.

B. Complex Animal Products

(e.g., fish oils, bee pollen, marine invertebrates)

• For single-species preparations derived from animals, information on the raw material and final product is needed.
• For multiple-species preparations derived from animals, identity and quality information is needed for each individual ingredient, as well as for the mixture as a whole.

In vitro Studies

1. Identify the study agent using the scientific taxonomic nomenclature (e.g., genus, species, variety, if applicable) and author citation. Describe the parts of the animal from which the product is derived.
2. If an extract is used, identify the extraction solvent.
3. Name the supplier of the final product. Include the brand name of the product, if applicable.
4. Present data on the characterization of the product (e.g., chemical profile or fingerprint) as thoroughly as the state of the science allows.
   • Identify active and/or other relevant marker compound(s) used for standardization.
   • Provide any other information relevant to the standardization process (including process control, as well as chemical and/or biological standardization of ingredients).
   • Information from suppliers MUST be confirmed through independent analysis, either by a third party lab or by the investigator (if they have appropriate facilities and expertise).
5. Describe the specifications and provide a Certificate of Analysis from the supplier to show compliance to their specifications for content and any other supporting manufacturer information relating to the batches to be used in the study. Provide data on the analysis of the product for contaminants/impurities such as pesticides, heavy metals, and residual solvents.
6. Provide data on batch-to-batch reproducibility. These data may be provided separately for the extract alone, the vehicle alone, and the final product, as appropriate.
7. Present a plan to monitor the stability of product samples from all batches used during the course of the study.
   • The plan should include:
     1. How you plan to store the test agent, vehicle, and/or final product
     2. What analyses will be conducted, the methods to be used, and how frequently and by whom the analyses will be done
     3. Investigator's tolerances for chemical and/or biological variability and what will be done if variability exceeds those limits.
   • In addition, sufficient material must be retained from each batch to allow independent analysis, should NCCIH request samples. Samples should be retained a minimum of 1 year after all results arising from the study have been published.

Additional Information for Animal Studies

1. Describe the manufacturing process. This should include:
   • Details of the extraction such as solvent(s), solvent to raw material ratio, and time and temperature
   • Information about the formulation of the final product (e.g., excipients, chow/feed composition, etc.)
   • Documentation to show product was manufactured under GMP guidelines.
2. Describe how freedom from disease communicable to humans or animals is assured; include documentation from manufacturer, if available.
3. If the product is combined with a diet, a Certificate of Analysis and specifications for those vehicles will also be necessary to assure purity, consistency, absence of bioactive components, and/or reproducibility of the vehicle. Furthermore, analysis of the formulated diet may be required to assess consistency, stability, etc. of the product in this matrix.
4. Describe the methods by which the test agent is derived from the source materials. Describe the procedures for ensuring that discomfort, distress, pain, and injury will be limited. Describe the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices, where appropriate. Describe any method of euthanasia to be used.

Additional Information for Human Studies

1. Submit copies of correspondence with the FDA indicating you have discussed whether or not an IND is required for this proposed study.
2. Provide a letter from the supplier stating their commitment to provide the product and cooperate with the IND application process, if required.
3. If the source animal is collected from the wild, provide evidence that it is not on an endangered species list and that it was captured and handled in compliance with international, national, and/or local guidelines.

C. Probiotics

In vitro and Animal Studies

1. Identify each strain in the study agent using the scientific taxonomic nomenclature (e.g., genus, species, strain).
   • The method to identify strain should be disclosed. Species and strain recognition should rely on molecular methods (e.g., 16S RNA, pulsed field electrophoresis [PFGE], DNA fingerprinting) to assure absence of pathogenic variants, undesirable metabolites, and toxicity.
   • Nomenclature should conform to the Approved Lists of Bacterial Names or Validation Lists, published in the International Journal of Systematic and Evolutionary Microbiology (or the International Journal of Systematic Bacteriology, prior to 2000).
   • For synbiotics, separate information for the prebiotic must be submitted according to the requirements enumerated in Section D of this Policy.
   • Document the absence of virulence genes or antibiotic resistance genes.
2. Name the supplier of the product.
3. Provide information on the analysis of the product for contaminants/impurities, including microorganisms other than the test strain.
4. Describe the specifications and provide Certificates of Analysis to show compliance to specifications for purity and content from the supplier/manufacturer or other supporting manufacturer information, relating to the batches to be used in the study. The method to quantify/enumerate the organism should be provided. If multiple strains are blended into the product, methods must show how counts for each strain will be obtained.
5. Provide data on short- (at a minimum) and long-term (if available) viability (of live microorganisms) or potency (in activated microorganisms).
6. Provide data on batch-to-batch reproducibility. These data may be provided separately for the test agent alone, the vehicle alone, and the final product, as appropriate.
7. Show that the chosen strain is sensitive to two clinically relevant antibiotics.
8. Present a plan to monitor stability of product samples from all batches used during the course of the study. The plan should include:
   • How you plan to store the test agent, vehicle, and/or finished product
   • What analyses will be conducted, the methods to be used, and how frequently and by whom the analyses will be done
   • Investigator's tolerances for variability of probiotic viability and what will be done if variability exceeds those limits.

   In addition, sufficient material must be retained from each batch to allow independent analysis, should NCCIH request samples. Samples should be retained a minimum of 1 year after all results arising from the study have been published.

9. Identify the international culture collection in which the strain is deposited.
10. Provide information on the finished formulation of the product. Disclose the identity and quantity of all ingredients and identify any possibly bioactive ingredients other than the defined probiotic strain(s) (and prebiotic). Define the active or hypothetically active property (e.g., active cells, bacterial enzymes, cell components). Identify antigenic material (e.g., milk protein) in probiotic products. Provide documentation to show the product was manufactured under GMP guidelines.

Additional Information for Human Studies

1. Name the manufacturer and s