National Center for Complementary and Alternative Medicine (NCCAM)

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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are consistent with the FDA guidelines for botanical drugs found in “Guidance for Industry: Botanical Drug Products Draft Guidance” and NCCAM’s “Natural Product Integrity—Policy and Guidance.” 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:

  • Synthesis of the drug
  • Manufacturing of the product that is administered to the patient
  • Control of these processes.

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:

  • Description of the plant
  • Procedure by which a part of the plant is extracted
  • Quantity of active ingredient in the extract
  • How the active ingredient is identified
  • Stability of the active ingredient (at least over the time of the trial).

Product (capsule, tablet, IV formulation):

  • How the product is manufactured
  • Quantity of active ingredient in the product
  • How the active ingredient is identified
  • Impurities in the product, including microbials, pesticides, heavy metals, and adulterants
  • Storage conditions and physical-chemical stability of the active ingredient during storage
  • Specifications of a reference batch and the controls during the manufacturing process such that each batch is similar to the reference batch
  • Bioavailability of the active ingredient (disintegration and dissolution, or breakdown, in physiologic solutions in vitro, absorption in vivo)
  • Whether the environment is contaminated, for example, with carcinogens, as the product is being made.

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:

  • One or more hypothesized active ingredients
  • A chemical constituent that constitutes a sizable percentage of the total ingredients
  • A chemical fingerprint of the total ingredients.

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:

  • Analysis of commonly accepted or supposed active ingredient(s) via chemical or biological parameters
  • Analysis of a sizable chemical constituent (analytical marker compound)
  • Analysis via chemical fingerprint (analytical markers)

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:

  • Analysis of commonly accepted or supposed active ingredient(s) via chemical or biological parameters
  • Analysis of a sizable chemical constituent (analytical marker compound)
  • Analysis via chemical fingerprint (analytical markers)
  • Analysis for lack of contamination by pesticides, heavy metals, and synthetic drug adulterants
  • The breakdown or dissolution of the analyzed components in physiological solutions
  • List of inert substances (excipients) added to the product
  • Storage conditions and stability over the length of the trial.

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

Plant substance:

  • Botanical description
  • Statement that the plant is cultivated according to Good Agricultural Practices or harvested according to Good Wildcrafting Practices
  • Extraction procedure
  • Quantity and identity of active ingredient(s) and of sizable chemical constituent

  • Statement that extraction and analytic procedures are performed under Good Manufacturing Practices (GMP) (e.g., that the manufacturing processes and their controls provide the appropriate levels of assurance for the important quality characteristics of the product).

Plant product:

  • Manufacturing methods
  • Analysis of commonly accepted or supposed active ingredient(s) via chemical or biological parameters
  • Analysis of a sizable chemical constituent (analytical marker compound)
  • Analysis via chemical fingerprint (analytical markers)
  • Analysis for lack of contamination by pesticides, heavy metals, synthetic drug adulterants
  • The breakdown or dissolution of the analyzed components in physiological solutions
  • In-process controls for manufacturing process
  • List of inert substances (excipients) added to the product
  • Description of the reference batch
  • Storage conditions and stability over the length of the trial
  • Environmental impact statement
  • Statement that the plant product is manufactured and analyzed according to Good Manufacturing Practices (e.g., that the manufacturing processes and their controls provide appropriate levels of assurance for the important quality characteristics of the 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).

  • Efficacy is demonstrated in vitro and in animal models
  • Toxicity overall is investigated after single and multiple doses in two species
  • Reproductive toxicity is investigated in females and in males
  • Cardiovascular toxicity is investigated in the dog
  • Target organ toxicity is investigated as needed
  • Mutagenicity is determined in vitro and in vivo
  • Carcinogenicity for long-term preventive agents is determined in two species
  • Plasma levels corresponding to acute and chronic toxicity are determined
  • Plasma levels corresponding to other toxicity tests and to efficacy tests may be determined
  • Pharmacokinetic investigation requires prior experiments to identify metabolites and to assay drug and metabolites in biological fluids.

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)

  • Phase I studies are designed to determine safety associated with increasing doses in normal volunteers, as a precursor to phase II and phase III trials. In addition, phase I studies investigate toxicity and drug levels in states in which drug levels might be altered: the fed versus the fasted state, or in renal or hepatic impairment. Mechanisms of action are also investigated in phase I.

  • Phase II studies evaluate the efficacy of a range of doses in individuals with disease. Phase II studies typically start by evaluating the maximum tolerated dose determined in the phase I normal volunteer studies. If the maximum dose is effective, dose-ranging downword would be investigated. If the phase I dose is ineffective, dose-ranging upward generally is performed. Phase II dose-ranging studies use a relatively small number of patients per dose group. Placebo or standard intervention control groups are highly recommended in phase II protocols in order to begin to evaluate efficacy.

  • Phase III studies are expanded trials of safety and efficacy. They are performed after preliminary evidence suggesting efficacy for the intervention has been obtained. Phase III studies are intended to gather the additional information about efficacy and safety needed to evaluate the overall benefit-risk ratio of the intervention and to provide an adequate basis for general clinical use. Phase III studies usually include large numbers of participants (several hundred to several thousand), and involve statistical comparison of the intervention to standard and/or placebo interventions.

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:

  • Neurological—lack of neurological symptoms
  • Skin—clinical evidence of lack of allergic reactions
  • Musculoskeletal—lack of arthritis or myalgias
  • Gastrointestinal—clinical evidence of tolerability
  • Liver—SGOT or SGPT, alkaline phosphatase, total bilirubin
  • Kidney—BUN or creatinine
  • Endocrine system and metabolism:
    • albumin or total protein
    • uric acid
    • CPK
    • glucose
    • cholesterol
    • amylase or lipase
    • sodium/potassium
    • calcium
  • Cardiovascular—EKG, blood pressure
  • Hematopoietic—complete blood count.

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)

  • Safety data, as described in the previous section, are necessary. If the study population is larger compared to the populations of prior trials, the reasons the agent is likely to be safe to treat the novel population should be given.

  • Efficacy data from phase II trials.

  • Evidence from dose-ranging trials showing that the dosing regimen is likely to be the optimum regimen with respect to safety and efficacy.

“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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