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Considerations for NCCAM Clinical Trial Grant Applications

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Background

Complementary and alternative medicine (CAM) therapies are in widespread use in the United States and throughout the world. The mission of the National Center for Complementary and Alternative Medicine (NCCAM) is, in part, to conduct rigorous research on CAM practices to evaluate the benefits and risks of CAM agents so as to optimize their effect on human diseases or conditions.

CAM Domains
NCCAM groups CAM practices within five major domains: biologically based therapies, manipulative and body-based methods, mind-body interventions, energy therapies, and alternative medical systems.

Biologically based CAM agents are regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA). This regulation includes botanicals and their constituents, vitamins, minerals, and amino acids. The U.S. Food and Drug Administration (FDA) characterizes botanicals and other dietary agents according to their use, not according to their composition. If the intended use is to "promote health," the agent is viewed as a dietary supplement; if the intended use is to treat or prevent a disease, the agent is considered to be a drug.

Applicability of Considerations for Clinical Trial Grant Applications
Products used in NCCAM clinical trials (defined as studies of therapeutic or preventive interventions involving human subjects) must be chosen so that the safety of trial participants is ensured and the endpoints are likely to justify expenditure of Federal funds. This rationale is applicable to all CAM interventions, including biological agents used as drugs or as dietary supplements.

The issues, or considerations, for clinical trials addressed in this document will apply to all NCCAM clinical trial grant applications beginning January 1, 2003.

A clinical trial grant application generally addresses three broad sets of considerations:

These considerations are consistent with the FDA guidelines for botanical drugs found in "Guidance for Industry: Botanical Drug Products Draft Guidance Aug. 2000" and NCCAM's "Policy Announcement of the Quality of Natural Products." They have been approved by the National Advisory Council on Complementary and Alternative Medicine.

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Chemistry-Manufacturing-Control (CMC) Considerations for Botanical Drugs

CMC Requirements for Synthetic/Semi-Synthetic Drugs
In general, CMC requirements for standard synthetic/semi-synthetic drugs are:

Thus, the drug and product are made reproducibly to provide assurance that active ingredients are administered to patients and toxic contaminants are not.

More specific CMC requirements, for example for a plant substance that is later made into a pure drug (e.g., digitalis for heart failure, artemisinins for malaria), are shown in column 3 of Table 1.

Table 1. Chemistry-Manufacturing-Control Considerations for NCCAM Clinical Trials

Subject of Study Study Parameters Study Details Data Required for Proposed NCCAM Trial
      Phase I / II
Trial 		Phase III Trial
Plant Substance Starting material Botanical description X Expanded
    Extraction procedure X Expanded
    Quantity of active moiety   X
    Identity: chemical/biologic assay   X
    Stability   X
Plant Product Manufacturing Reagents/process   X
  Finished product Quantity of active moiety X X
  Product assay Methods/specifications   X
    Identity: chemical/biologic assay X X
    Purity   X
  Storage Describe conditions X X
  Stability Light/heat/time X X
  Excipients List   X
  Impurities List/analyze X X
  Reference standard Standard batch   X
  In-process controls Standard operating procedures   X
  Bioavailability Disintegration/dissolution rate X X
  Microbiology Contamination   X
  Environmental Assessment   X


Plant substance:

Product (capsule, tablet, IV formulation):

Overview of CMC Evidence Needed To Support Clinical Trials for Botanical Drugs
Unlike standard drugs, botanicals have been in use before being studied in a clinical trial. Prior human use gives some assurance that the product will be safe and effective. Some of the CMC information needed for a standard drug is also needed for botanical drugs.

Unlike synthetic drugs, botanical drugs are mixtures of uncharacterized constituents. It is postulated that a mixture provides a therapeutic advantage. For example, unknown constituents may combine in an additive or synergistic way with the known constituents to provide greater efficacy than would be provided by the known constituent alone. For botanical drugs, analysis of the active ingredient(s) may be best approached by analysis for:

The latter two analyses are surrogates for analysis of the unknown constituents that contribute to efficacy.

Information Needed for a Grant Application to NCCAM for a Botanical Drug

Information on a plant product that was the subject of prior human use
Plants are often extracted and processed non-reproducibly. It is important that the product being produced for a clinical trial is similar in analysis to the original product that has been used in humans.

Consider the following example of a botanical drug with three components. Component 1 is potentially toxic and components 2 and 3 are potentially effective at low doses, but also potentially toxic at high doses. Table 2 shows the number of units of each component for two lots of the drug.

Table 2. Example of Component Combinations for a Botanical Drug

  Component 1
  • potentially toxic
 Component 2
  • low dose: effective
  • high dose: toxic
 Component 3
  • low dose: effective
  • high dose: toxic
Lot 1 1 unit 122 units 48 units
Lot 2 12 units 11 units 10 units

If Lot 1 is administered but the lots previously used were comparable to Lot 2, the participants will suffer toxicity from the higher doses of Components 2 and 3. If Lot 2 is administered, but the lots previously used were comparable to Lot 1, the participants will suffer toxicity from the higher dose of Component 1 and efficacy will diminish because of the lower doses of Components 2 and 3.

This example illustrates the wide variation in composition that may be found in identically labeled botanical products. For this reason, analysis of the product being proposed for study in a clinical trial must be performed and shown to be similar to the analysis of the botanical with prior human experience, if prior clinical data are being used to justify the proposed trial.

Therefore, the following information is needed for products previously used in humans:

Plant substance:

Description of the plant:
  • genus
  • species (cultivar if appropriate)
  • country(s) of origin
Plant extraction procedure

Plant product:

Information on the plant product proposed for Phase I/II studies (See Table 1, Column 4)

Plant substance:

Description of the plant:
  • genus
  • species (cultivar if appropriate)
  • country(s) of origin
  • time of harvest
Plant extraction procedure

Plant product:

Information on the plant product proposed for Phase III studies (See Table 1, Column 5)

Plant substance:

Plant product:

Information Needed for a Grant Application for a Non-Botanical Biological Agent
The information for non-botanical biological agents, such as vitamins, minerals, or amino acids is the same as that for botanicals, except for the items that are relevant only for plant products.

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Non-Clinical Considerations for Biological Agents

Information Needed for a Synthetic Drug
Non-clinical information generally needed to support an Investigational New Drug application for a standard synthetic drug consists of in vitro and animal data on efficacy, toxicity, and pharmacokinetics/mechanisms (See Table 3).

Table 3. Non-Clinical Considerations for NCCAM Clinical Trials

Study Type Study Parameters Details of Study Information Needed for Proposed NCCAM Trial
      Phase I / II
Trial 		Phase III Trial
Efficacy In vitro Mechanisms * **
  In vivo animal Two species * **
Toxicity Single dose Two species * **
  Multiple dose Two species * **
  Reproduction Segment 2, segment 1 * **
  Mutagenicity In vitro, in vivo * **
  Carcinogenicity In mice, rats * **
  Cardiovascular toxicity In dogs * **
  Special target toxicity As needed * **
Pharmacokinetics (ADME) Metabolite synthesis Chemical or biological * **
  Assay methods In vitro, in vivo * **
  In vitro metabolism Metabolism, drug-drug * **
  In vivo metabolism Metabolism, drug-drug * **
  In vivo kinetics Absorption, excretion * **
  Distribution Radiolabel distribution * **
    Protein binding * **
  Toxicokinetics Two species * **
  Efficacy kinetics In vivo models * **

* Literature review needed
** Data highly encouraged

Information Needed for a Grant Application to NCCAM for a Biological Agent
Non-clinical information for a biological agent is not absolutely required. However, non-clinical information, as described in the previous section, is strongly encouraged because it can materially support the proposed clinical dosing regimens in the grant application.

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Clinical Considerations for All CAM Interventions

Information Needed for a Standard Intervention (See Table 4, Column 3)

Neither phase I /II nor phase III trials should be omitted in a product evaluation program. In spite of present use, without phase I/II trials, it is unlikely that an optimum dose will be found. Without phase III trials, it is difficult to have statistical confidence in safety or efficacy data.

Table 4. Clinical Considerations for NCCAM Clinical Trials

Study Type Study Parameters Study Details Data Required for Proposed NCCAM Trial
      Phase I / II
Trial 		Phase III Trial
Phase I Toxicity Single dose    
    Multiple dose X X
    Impaired populations renal/hepatic   Desirable
  Pharmacokinetics (PK) Fed versus fasted   Desirable
    Drug-drug interactions   Desirable
  Toxicokinetics Compare to toxicity data    
    Compare to animal data    
Phase II Efficacy Multiple dose   X
Phase III Efficacy, toxicity, PK Pivotal trials: adults    
    Other trial populations:
  • children
  • renal/hepatic impaired
   

Information Needed for Phase I/II Trials of CAM Agents (See Table 4, Column 4)

Safety data for agents with prior human experience
In lieu of non-clinical data, the data from prior human experience must convey confidence in the clinical safety of the product. By organ systems, examples of relevant parameters of safety are:

Additionally, more intensive investigation may be conducted of any organ system likely to be particularly effected by the product.

If prior human experience is modest and the values of these parameters are not well described, evaluation of these parameters should be included in the protocol being proposed. In particular, these parameters could be first evaluated in a small percentage of participants. If normal, the protocol could proceed to enroll the rest of the participants. In this way, the lack of prior experience would be compensated by experience generated in the initial period of the trial being proposed.

Information Needed for Phase III Trials (See Table 4, Column 5)

"Primary Aim" of Clinical Protocols
Clinical protocols should have one "primary aim." The technical reason for one primary aim is that the sample size calculation is based on it. A single primary aim focuses the protocol and the person-hours expended on it. If unforeseen circumstances constrain resources, fulfillment of the primary aim becomes the focus of the remaining resources.

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