Stanford University Research Compliance Office
Guidance for Sound Study Design in Clinical Trials
GUI-17m
Background Information:
• • • • • • Name and description of the investigational product(s). Summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial. Summary of the known and potential risks and benefits, if any, to human participants. Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s). Description of the population to be studied. References to literature and data that are relevant to the trial, and that provide background for the trial.
Trial Objectives and Purpose:
A detailed description of the objectives and the purpose of the trial.
Trial Design:
• • A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial. A description of the type/design of trial to be conducted (e.g., double-blind, placebocontrolled, parallel design) and a schematic diagram of trial design, procedures, and stages. A description of the measures taken to minimize/avoid bias, including (for example): (a) Randomization (b) Blinding A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labeling of the investigational product(s). The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any. A description of the “stopping rules” or “discontinuation criteria” for individual participants, parts of trial, and entire trial. Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any. Maintenance of trial treatment randomization codes and procedures for breaking codes. The identification of any data to be recorded directly on the case report forms (i.e., no prior written or electronic record of data), and to be considered to be source data.
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File:GUI01017 rev1 01/06
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Stanford University Research Compliance Office
Guidance for Sound Study Design in Clinical Trials
GUI-17m
Selection and Withdrawal of Participants:
• • • Participant inclusion criteria. Participant exclusion criteria. Participant withdrawal criteria (i.e., terminating investigational product treatment/trial treatment) and procedures specifying: (a) When and how to withdraw participants from the trial/investigational product treatment. (b) The type and timing of the data to be collected for withdrawn participants. (c) Whether and how participants are to be replaced. (d) The follow-up for participants withdrawn from investigational product treatment/trial treatment.
Treatment of Participants:
The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for participants for each investigational product treatment/trial treatment group/arm of the trial. • • • • • • • • • • Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial. Procedures for monitoring participant compliance.
Assessment of Efficacy:
Specification of the efficacy parameters. Methods and timing for assessing, recording, and analyzing efficacy parameters.
Assessments of Safety:
Specification of safety parameters. The methods and timing for assessing, recording, and analyzing safety parameters. Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses. The type and duration of the follow-up of participants after adverse events.
Statistics:
A description of the statistical methods to be employed, including timing of any planned interim analysis(ses). The number of participants planned to be enrolled. In multicenter trials, the number of enrolled participants projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification. The level of significance to be used.
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File:GUI01017 rev1 01/06
Stanford University Research Compliance Office
Guidance for Sound Study Design in Clinical Trials
GUI-17m
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Criteria for the termination of the trial. Procedures for accounting for missing, unused, and spurious data. Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in the protocol and/or in the final report, as appropriate). The selection of participants to be included in the analyses (e.g., all randomized participants, all dosed participants, all eligible subjects, evaluate-able participants).
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Special Considerations for Minimization of Risks Through Research Design:
In designing and conducting research, the protocol director should minimize risks by using procedures that are consistent with sound research design and do not expose participants to unnecessary risks. Whenever appropriate, the protocol director should utilize procedures that are already being performed on the participants for diagnostic or treatment purposes. Where this is not the case and the research procedure carries a high level of risk with no potential benefit to participants, the protocol director should be prepared to justify why the procedure is necessary to achieve the research objectives, or why enrollment should not be limited to those already scheduled for the procedure for non-research purposes. Minimization of risks is of critical importance in designing and conducting research on vulnerable populations Certain types of clinical protocols may require special attention from the protocol director to minimize risks. Several examples are described below. Example #1. Placebo-Controlled studies A protocol that involves removing participants from the standard medication for their disease or condition, and randomizing them to receive either an investigational agent or a placebo, may raise issues of participant safety. If some participants will receive no potentially beneficial drug for all or a significant portion of the trial, the protocol director should specify in the protocol and consent form the nature and severity of the associated risk to those participants. Depending upon the degree of risk, the protocol director should consider modification of study design to minimize the risk. Modification of Study Design to Minimize Risk The study design might be modified to define a benchmark for unacceptable worsening of the participant's disease or condition, together with a monitoring plan for timely detection of participants who reach the benchmark and a "rescue mechanism" for ameliorating the participant's condition once the benchmark is reached. Alternatively, the protocol director might consider modifying the research design to include a cross-over design (from placebo to investigational drug and vice versa). Other design options include restricting eligibility to individuals who refuse, or have been shown not to respond to, the standard medication, or who have only a mild form of the disease or condition. In situations where the standard treatment is tolerated by and known to prevent serious harm such as death or irreversible morbidity in the participant population, the IRB may determine that a placebo design is not acceptable.
File:GUI01017 rev1 01/06
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Stanford University Research Compliance Office
Guidance for Sound Study Design in Clinical Trials
GUI-17m
Example #2. Active Control Studies. Research designs in which some participants receive the investigational agent but are removed from standard therapy for serious conditions may raise similar issues, as the investigational treatment may turn out to be ineffective. Unless there is strong reason to expect that the investigational drug will be at least as good as the standard therapy, consideration should be given to one of the design modifications discussed above. Example #3. Deliberate Induction of Undesirable States. A further example where protocol directors should consider special measures to minimize risk is research that deliberately induces an undesirable state or condition in participants - e.g., a panic attack or allergic attack or a condition of airway narrowing - in order to learn more about the undesirable state or condition. The IRB will scrutinize thoroughly the design aspects of such research to ensure that adequate measures have been instituted to minimize participant risks.
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