Applicants requesting $500,000 or more in direct costs in any year (excluding consortium facilities and administrative costs, or F&A) must contact the NIDCD Clinical Trials Program at least 8 weeks before submitting the application with the following information:
- Investigator(s) name(s) and institution(s).
- Include the names and specialties for the clinicians responsible for administering the intervention and monitoring safety.
- A brief description of the general trial design, including:
- Phase (e.g., Phase I, Phase II, or Phase III).
- Trial type/design (e.g., placebo-controlled, double-blinded randomized, parallel design, open-label, dose-escalation).
- Study arms.
- Study population.
- Sample size (total and number in each arm).
- Randomization scheme, if applicable.
- Schema, e.g., a study flow chart or diagram.
- A schedule of evaluations, e.g., visits and evaluations/procedures completed at each.
- Study duration (from the enrollment visit to the last study visit).
- Primary hypothesis to be investigated in the clinical trial.
- Primary and secondary objectives.
- Primary and secondary endpoint measures.
- A detailed description of the intervention and control (including dose, duration, administration route, associated administration procedures, and components if applicable).
- Justification for this clinical trial: What are current practices/standards of care and outcomes for current practices? What impact will this clinical trial have in driving the field as well as clinical practice?
- For a preliminary (Phase I/II) clinical trial application, indicate why this clinical trial is necessary and how it will guide the development of the Phase III trial (essential information and data to be collected, if any; how this data will be used to inform future studies, etc.).
- For a Phase III/pivotal clinical trial application, provide a summary of studies that led to the proposed clinical trial and data from Phase I and II studies/summaries of evidence for the potential safety and efficacy for each proposed intervention.
- Number of clinical sites (specify domestic, international, or both).
Please include the following information to justify the size and developmental phase of your clinical trial:
- Section 3.1.3 (of U01 Clinical Trial Application) Potential Benefits of the Proposed Research to Research Participants and Others
Note: Pertinent results for preliminary studies should be clearly presented in the application to justify intervention, dose selection, and design of the study.
Provide a discussion of studies that led to the proposed clinical trial and information or data from preliminary studies to address the need for and feasibility of the trial, as well as evidence of the safety and potential efficacy for each proposed intervention; dose selection; and administration route/procedures including:
- Safety
- A summary of the risks associated with the intervention.
- A summary of safety findings from nonclinical in vitro/in vivo/animal studies.
- A summary of relevant clinical research and any history of human use or exposure to the study intervention; if applicable, include information on use in other countries and clinical pharmacology studies.
- Discussion of important literature and data relevant to the safety profile of the intervention.
- A safety summary of the specific intervention dose and duration.
- Any relevant treatment issues or controversies.
- Efficacy
- A summary of findings from nonclinical animal studies that have potential clinical significance.
- A summary of relevant clinical research and any history of human use or exposure to the study intervention, including use in other countries, that support the potential efficacy of the intervention as well as the proposed intervention dose. Note: a summary to justify the specific intervention dose and duration must be included.
- Discussion of important literature and data that are relevant to the trial and that provide background for the trial.
- Applicable clinical, epidemiological, or public health background or context to support the importance of the clinical trial.
- Safety
- Statistics
- Provide information about the research team’s statistician and how this person will be involved in the application, in study design, and in study implementation.
- Selection of primary outcome and effect size:
- What would be considered successful clinical outcomes for this treatment? How would this intervention have direct impact on patients on a day-to-day basis and throughout their lives? What is the selected primary endpoint (endpoint and time of endpoint)? How does the selected primary endpoint provide evidence for this? Is this the endpoint used to obtain Food and Drug Administration (FDA) approval for similar products?
- What is the proposed effect size for the primary endpoint? Clarify how this effect size is clinically relevant.
- Clarify the scaling score of the primary endpoint. What is the range of the scaling score and how does the scaling score result translate to efficacy of treatment? What change from baseline or what threshold value on the scaling score represents what level of daily function for a patient? If a threshold value on the testing corresponds to a level of function compatible with independent living, how many participants from a prior study (or studies) reached that threshold?
- Statistical Design and Power (of U01 Clinical Trial Application)
Provide details on the sample size determination, including information needed to validate your calculations, and judge the feasibility of enrolling and following the necessary number of participants. In particular, specify all of the following:
- Number of subjects anticipated to be enrolled.
- Expected effect size.
- Outcome measure used for calculations.
- Statistical method used with respect to each outcome measure.
- Null and alternative hypotheses.
- Type I error rate (alpha).
- Power level (e.g., 80% power).
- Assumed event rate for dichotomous outcome (or mean and variance of continuous outcome) for each study arm, justified and referenced by historical data to the extent possible. Also, provide information to support the clinical relevance of the selected effect size.
- Statistical method used to calculate the sample size, with a reference for it and for any software used.
- Anticipated impact of dropout rates, withdrawal, crossover to other study arms, missing data, etc., on study power.
- Method for adjusting calculations for planned interim analyses, if any.
- Discuss whether the sample size provides sufficient power for addressing secondary endpoints or exploratory analyses.
- Feasibility for patient recruitment and anticipated enrollment per month and per year, including whether the team has had prior success in recruiting/enrolling the study population for these types of studies and the plan to identify participants. Provide information on existing pools of potential subjects to validate the enrollment projections. When providing this information, correlate the specific eligibility criteria with the potential patient pool data. Clarify how the data on the existing pool of subjects correlate with the feasibility projections presented for each individual site.
- Will this intervention/indication be regulated by the FDA, e.g., an investigational new drug (IND) or investigational device exemption (IDE)?
- If yes, provide feedback from the FDA. Note: section 4.6.a of the U01 application requires a description of the availability of Investigational Product (IP) and IND/IDE status.
- If no, provide the reason that FDA oversight is not required. Provide documentation to verify the clinical trial is exempt from an IND or IDE requirement.
- Specify the intervention brand name and manufacturer. Provide a summary of FDA-approved indications (including age, dose, and administration) for the intervention.
- Projected direct cost per year including:
- PHS 424 Form (complete form, including justification; each subcontract should have a separate set of budget and justification pages).
- Capitation estimate (cost per subject).
- Anticipated application submission date.
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