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• Introduction
• Characterization of the Treatment Modality or Product
• Data from Pilot, Phase I, and Small Phase II Clinical Studies
• Validation of Clinical Trial Parameters and Trial Design
  
  
• Resources

Introduction

Clinical trials are essential for understanding the safety and efficacy of interventions. Complementary and Alternative Medicine (CAM) modalities encompass a broad range of intervention techniques, such as acupuncture, botanicals, biofeedback, chiropractic, homeopathic treatments, massage, Reiki, and the like. (For more information on what constitutes CAM, see nccam.nih.gov/health/whatiscam)

Every year, NCCAM receives many inquiries about Phase II or III clinical trial applications. Unlike many synthetic drugs, less is generally known about CAM modalities that are being proposed for Phase II and III clinical trials.

Thus, we are asking applicants seeking support for Phase II and III clinical trials of CAM modalities to consider the following questions. The information provided here does not replace or supersede guidance already on the NCCAM Web site about clinical trial grant applications, but provides a central overview with links to more detailed guidance and policy located elsewhere.

In general, investigators should consider whether there is an adequate empirical base about the CAM therapy in question for the outcome(s) of interest to move forward with a large Phase II or III clinical trial. If not, they could decide to investigate and address basic background information necessary before considering an application for a phase II or phase III clinical trial. Research grant mechanisms, such as the R21 or R01, can be used to generate this information. Please note that NCCAM offers an exploratory/development grant mechanism for clinical studies (grants.nih.gov/grants/guide/pa-files/PAR-06-091.html). This mechanism also provides investigators with the opportunity to design rigorous feasibility studies and developmental projects that will serve as the basis for planning and scientifically justifying larger clinical trials.

Below we array a number of issues in the form of questions to consider in paving the way toward a clinical trial. They are intended to apply to interventions for all CAM modalities. These issues are divided into three broad categories:

1. Characterization of the Treatment Modality or Product
2. Data from Pilot, Phase I, and Small Phase II Clinical Studies
3. Validation of Clinical Trial Parameters and Trial Design

At the end of each of these sections, links are given to more detailed NCCAM policies and guidance related to the content of the section.

In addition, at the end of this document, we have provided a more extensive list of issues for those investigators interested in clinical trials involving natural products.

1. Characterization of the Treatment Modality or Product

Has the product or treatment modality been well defined or characterized?

• Has testing for stability been conducted?
• Can the investigator assure lot-to-lot reproducibility or standardization of treatment across all individuals who will be providing the treatment?

What is known about the mechanism of action?

• While it is not essential to know the mechanism of action prior to conducting a clinical trial, such information can be very useful.

Are there in vitro and/or animal model data on the proposed product or treatment modality?

(See also the section at the end of this document on natural products.)

Links to NCCAM Policy or Guidance:

• Biologically Active Agents Used in CAM and Placebo Materials
  nccam.nih.gov/research/policies/bioactive.htm
  
  
• Considerations for NCCAM Clinical Trial Applications nccam.nih.gov/research/policies/clinical-considerations.htm

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2. Data from Pilot, Phase I, and Small Phase II Clinical Studies

Are there existing data on safety and toxicity?

• Are there safety data available from previous clinical trials or long-term use?
• Have safety studies been done at a range of doses?
• Note: When there is a reasonable likelihood of either toxicity or efficacy over the time period of the proposed study, a placebo control group is recommended. Similarly, a placebo control should be included to control for placebo effects that are often found in CAM clinical studies.

What is known about side effects to particular organs or systems, such as:

• Neurological
• Skin
• Musculoskeletal
• Gastrointestinal
• Liver
• Kidney
• Endocrine system and metabolism
• Cardiovascular
• Hematopoietic

If toxicity has been determined, what are the data on plasma levels corresponding to acute or chronic toxicity?

Are there data on:

• Reproductive, cardiovascular, target organ toxicity?
• Mutagenicity from in vitro experiments? In vivo studies?
• Carcinogenicity?

What is known about the pharmacokinetics and bioavailability?

• Have metabolites been identified?

Are there dose ranging data?

• What is the optimal dosage schedule?
• Do we need to learn more to identify the optimal duration and frequency of treatment?

What is known about efficacy?

• Which doses and what formulation were used to assess efficacy?
• What systems were used to generate efficacy data - in vitro experiments, animal models, human studies?

Are there data to establish the anticipated benefit of treatment?

What is known about the risk/benefit balance of the proposed treatment?

• Are there data on the rate of success?
• Are there data on the type and rate of complications?

Links to NCCAM Policy or Guidance:

• Considerations for NCCAM Clinical Trial Applications
  nccam.nih.gov/research/policies/clinical-considerations.htm
  
  
• Guidance on Designing Clinical Trials of CAM Therapies
  nccam.nih.gov/research/policies/guideonct.htm

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3. Validation of Clinical Trial Parameters and Trial Design

Design:

Can the investigator demonstrate feasibility of conducting the study?

Is the design appropriate to address the hypotheses posed?

Is there a reason for the investigators not to use a double blind design?

Will a placebo control be used?

• If so, what will the placebo consist of (e.g., invasive control or sham versus non-invasive control, such as placebo, standard therapy, wait list, etc.)?
• Is more work needed to refine the control?
• Note: When there is a reasonable likelihood that the natural history of the disease leads to either toxicity or efficacy over the time period of the proposed study, a placebo control group is recommended.

Will the design call for a comparative treatment arm?

• If so, what will that consist of? Is this a well-accepted treatment by the field?

Are both a placebo arm and comparative treatment arm needed?

Is the dose proposed for the study sufficiently high to maximize the probability of assessing efficacy?

If there are no data to suggest that the proposed dose is likely to give maximum efficacy, or if there are no data to identify the highest tolerated dose that can be tested, the applicant should evaluate a range of dosages to establish the appropriate dose for the study or clearly explain why the optimal dose cannot be established.

• Note: Use of a suboptimal dose that is safe but ineffective does not serve the larger goals of the CAM community. Any given study can only draw conclusions concerning the dose that was tested. If that dose proves ineffective, the community may conclude incorrectly that all doses of the intervention are ineffective, and patients will be denied possible benefit from the intervention.

Is a run-in period needed?

• If so, how long does this need to be?

Does the design call for standardized or individualized treatment?

• Regardless of which is chosen, the applicant should justify their choice.
• If the investigator is proposing individualized treatment, a plan should be provided to ensure that the individualization process is reproducibly administered and standardized across subsets of subjects as appropriate and can be replicated by other investigators.

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Patient population:

Have appropriate inclusion and exclusion criteria been identified?

• How will these be determined?

Can the investigator demonstrate capability to recruit and retain the type and number of subjects needed?

• What is the subject pool?
• What is the estimated dropout rate?
• Note: Reviewers often look for this information.

Will subjects tolerate randomization?

Endpoints:

What are the appropriate endpoints for a clinical trial?

• Note: Mechanism studies can be useful in the identification and specification of study endpoints, especially functional and physiological measures, which in turn will strengthen the design of clinical trials.

What surrogate markers will be used in clinical studies?

• Are these well accepted in the field?

What will be the primary outcome measure for the study?
What are the secondary outcome measures?

Have endpoints been demonstrated to be clinically useful (e.g., validity, reliability, etc.)?

How appropriate are commonly used assessment procedures (i.e., quality of life, functional, and physiological measures) for the proposed study?

Sample size

Are there sufficient data on effect size to estimate power and sample size?

Considering the primary and secondary outcome measures, has the total number of subjects (n) been determined so that the study has statistical power to answer the main hypotheses posed?

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Resources

Does the investigator need additional time and/or resources to develop realistic protocol(s)?

Links to NCCAM Policy or Guidance:

• Considerations for NCCAM Clinical Trial Applications
  nccam.nih.gov/research/policies/clinical-considerations.htm
  
  
• NCCAM Terms of Awards for Clinical Trials
  nccam.nih.gov/research/policies/terms-of-awards.htm

Questions Related to Clinical Research on Natural Products:

If an herbal or botanical product is proposed:

What is known about any potentially toxic components?
Are there data on overall toxicity with:

• A single dose?
• Multiple doses?

If toxicity has been determined, are there data on plasma levels corresponding to acute or chronic toxicity?

Are there toxicity data available on systems such as:

• Reproductive system?
• Cardiovascular system?
• Target organ?

Are there data on mutagenicity from:

• In vitro experiments?
• In vivo studies?

Are there data on carcinogenicity?

What is known about safety, including side effects for:

• Neurological system
• Skin
• Musculoskeletal system
• Gastrointestinal system
• Liver
• Kidney
• Endocrine system and metabolism
• Cardiovascular system
• Hemotopoietic system

What is known about active ingredient(s), including quantity in product?

Has the investigator contacted the FDA to determine if the proposed study requires an IND?

Investigators are strongly urged to consult NCCAM's Interim Policy on Biologically Active Agents Used in CAM while designing studies of such agents.

Links to NCCAM Policy or Guidance:

• Considerations for NCCAM Clinical Trial Applications
  nccam.nih.gov/research/policies/clinical-considerations.htm
  
  
• Interim Policy on Biologically Active Agents and Placebo Materials Used in CAM nccam.nih.gov/research/policies/bioactive.htm

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