Carefully designed eligibility criteria ensure that the intended study population is enrolled and that trial participants for whom participation may be harmful are not included. Ambiguity may result in inconsistent application across sites; overly restrictive criteria may limit the real-world applicability of results or impede trial participant recruitment.

Each criterion should be evaluated in terms of its utility in 1) defining the population, 2) excluding trial participants for whom there are safety concerns, 3) avoidance of confounding of efficacy measures, and 4) identifying contraindicated medications or procedures. If the criterion does not have utility by these measures, the rationale for retaining it should be further considered.

1. Describe the specific population needed for the trial to evaluate the intended question. If this specific population is not enrolled, will trial results be brought into question?
2. Are there trial participant populations that must be excluded from enrollment due to specific safety concerns with administration of the product to that population?
3. Evaluate the impact of “getting it wrong” with regard to eligibility. If a trial participant is found to not meet a criterion, what is the impact on the trial (e.g., if removed, replaced, considered treatment failure)?
4. Is the trial intended to evaluate effectiveness and safety of the investigational product in a real-world population that would be likely to receive the product after approval?
5. What are the commonly accepted criteria for diagnosing and evaluating patients:
   a.  With the disease under study?
   b.  With comorbid conditions that are exclusionary?
6. Have PPAO and participating investigators provided imput as to the feasibility of implementing criteria?

Randomization, when appropriately executed, addresses selection bias and permits a valid basis for making comparisons between, and drawing statistical inferences about, study groups.The integrity of randomization rests on both sponsor and site-level processes. For example, the sponsor or its designee generates and programs randomization schemes, and must ensure adequate allocation concealment; site staff must administer the treatment to which a trial participant was randomized.

1. Is the study randomized?
2. If the study is randomized, consider:
   1. Who will generate and implement the randomization schema?
   2. What is the method by which randomization will occur?
   3. Are any specific approvals needed to randomize a trial participant?
   4. Who is permitted to randomize trial participants?
   5. How and by whom will randomization errors be managed?

Masking may minimize biases that result from differences in management, treatment, assessment of trial participants, or interpretation of results that arise as a result of trial participant, investigator, or study staff knowledge of treatment assignment. Prespecified controls should be considered to prevent unblinding and to deal with potential unblinding events should they occur. Designs that require some staff (whether at the sponsor or site level) to be unmasked while maintaining masking for others present opportunities for inadvertent unmasking and may require additional controls.

1. What is the impact of unmasking for this study? Does it pose a risk to interpretation of study outcomes?
2. Does the study design:
   1. Require that some site staff members be unmasked while others remain masked?
   2. Require that some sponsor or contract or academic research organization (CRO/ARO) staff members be unmasked while others remain masked?
   3. Require study data to be unmasked for periodic interim reviews/analyses (e.g., for a data monitoring committee [DMC] or adaptive design)?
   4. If so, the process(es) and responsibilities for maintaining masking in these scenarios should be described.

The acceptability of the control (if used) in the study may affect the willingness of trial participants to participate in the study and the interpretation of perceived value and reliability of the study’s conclusions by different stakeholders (e.g., patients, regulators, payers).

1. Consider the type(s) of control(s) to be used in the study (e.g., placebo/sham procedure, standard of care, historical) and the rationale for selection.
2. Is there clinical equipoise? Do PPAO and treating physicians agree that there is clinical equipoise?
3. Is a control group feasible, especially from the PPAO and treating physician perspective?
4. Identify controls that may be preferred by different stakeholders (regulators, payers, PPAO).

There are a variety of viewpoints and interests involved in designing a trial. The minimum data set that is sufficient to address study endpoints and meets the needs of various stakeholders should be that which is collected (data parsimony).

1. What data points are critical to addressing the question(s) posed by the trial?
2. How will these critical data points be generated, collected, and reported?
3. What is the distinction between exploratory endpoints and primary and secondary endpoints?
4. Does the need for exploratory data endpoints unduly burden data collection?
5. Have PPAO and participating investigators provided input as to which data points are the most important to them?

Clearly defining study endpoints and describing how endpoint data are to be collected and reported will support consistent trial implementation across sites and prevent errors that may interfere with analysis and bring into question study conclusions. In defining endpoints, prospective attention should be given to the degree of objectivity in assessment of endpoints, the potential for simple external verification (e.g., death certificates, central and/or bioanalytical laboratory data), and potential for unbiased adjudication or review of endpoint data.

1. Is/are the endpoint(s) commensurate with the scientific question/objectives of the study?
2. Will the endpoint have a clinically meaningful impact on patient care or provide a unique building block for future research?
3. Are standardized and generally accepted endpoint definitions and methods to ascertain endpoints available?
4. If there are multiple primary endpoints, verify and describe how each is necessary to address/directly link to the scientific question posed by the study.
5. Consider the characteristics of the primary endpoint(s), including
   • How is the endpoint defined?
   • Is it assessable?
   • How and by whom will the endpoint(s) be ascertained (e.g., investigator, centrally, third party uninvolved in the study)?
   • If the endpoint is to be adjudicated, what were the criteria to determine that adjudication was necessary?
   • Is the endpoint objective (e.g., pregnancy, death) or subjective (e.g., pain score)?
   • Is the endpoint event-driven?
6. Have patient-reported outcomes (PROs) been considered as an endpoint? What are the risks and benefits of their use?

Conduct of key procedures, collection of critical data, and effective monitoring of trial participant safety depend on consistent conduct of study procedures. Resources should be focused on preventing opportunities for errors in critical study procedures supporting collection and reporting of critical data directly related to study endpoints and in study procedures necessary to ensure adequate monitoring of trial participant safety.

1. Can the investigational product technically do what you are aiming for clinically?
2. What procedures are critical to collecting reliable data for analysis of study endpoints? Which are non-critical?
3. How necessary is it for these procedures to be conducted absolutely consistently across sites or in a highly specific manner or window?
4. What procedures do not significantly impact data analysis or trial participant safety (i.e., where error or inconsistency in conduct can generally be tolerated)?

Appropriate controls must be in place to ensure equivalent consistency between IPs from manufacturing through administration. In addition, evaluation of both the efficacy and safety effects of an intervention requires confirmation that the assigned intervention was received as prescribed in the investigational plan.

1. Describe the IP, including any special considerations for its handling and use in this trial.
2. Evaluate any specific safety concerns associated with the use of the product and describe how these have been identified and managed in prior investigational or marketing experience.
3. What IP use data are integral to evaluating trial results? Why are these data critical?
4. For implantable devices, what information about the implant procedure is critical to trial analysis, results, and reporting?
5. For diagnostic trials, how will appropriate handling of specimens be verified?
6. If the protocol calls for dosage adjustments of IP or control product, are the directions and procedures for making dosage adjustment(s) clear and is the responsible entity (e.g., interactive voice response system directed, site staff) clearly defined?