Table 1.
Extension of content guidance for statistical analysis plans (SAP) from early phase clinical trials
| Section/item | Original SAP content guidance | Recommended early phase clinical trials extension guidance | |||
|---|---|---|---|---|---|
| Item No | Description | Item No | Description | ||
| Section 1: Administrative information | |||||
| Title and trial registration | 1a | Descriptive title that matches the protocol, with SAP either as a forerunner or subtitle, and trial acronym (if applicable) | |||
| 1b | Trial registration number | ||||
| SAP version | 2 | SAP version number with dates | |||
| Protocol version | 3 | Reference to version of protocol being used | |||
| SAP revisions | 4a | SAP revision history | |||
| 4b | Justification for each SAP revision | ||||
| 4c | Timing of SAP revisions in relation to interim analyses, etc | ||||
| Roles and responsibility | 5 | Names, affiliations, and roles of SAP contributors | |||
| Signatures of: | 6a | Person writing the SAP | |||
| 6b | Senior statistician responsible | ||||
| 6c | Chief investigator or clinical lead | ||||
| Section 2: Introduction | |||||
| Background and rationale | 7 | Synopsis of trial background and rationale including a brief description of research question and brief justification for undertaking the trial | |||
| Objectives | 8 | Description of specific objectives or hypotheses | 8 | Description of specific question, objectives, or hypotheses. It should be made clear what the key objectives are (eg, primary and secondary objectives that encompasses toxicity, efficacy, pharmacokinetics, pharmacodynamics, or some combination) | |
| Section 3: Study methods | |||||
| Trial design | 9 | Brief description of trial design including type of trial (eg, parallel group, multiarm, crossover, factorial) and allocation ratio and might include brief description of interventions | 9a | Brief description of trial design, including the trial phase and the design method (dose escalation (eg, CRM); or single arm phase II (eg, Simon’s two stage)). If the trial has a randomised element to it, summary information regarding the randomisation, including the allocation ratio, should be specified | |
| 9b | Treatment information, including the dose levels of intervention(s). Where appropriate, and if multiple doses are used, the following should also be reported: the ordering and combination (in the instance of multiple agents under investigation) of dose levels, and the dose level to start at | ||||
| 9c | Details regarding the statistical methodology underpinning the trial, including the choice of the number of parameters in the model if applicable, its empirical form and all formulas. Ensure that all model parameters are given, including the weights of the model, where appropriate | ||||
| 9d | Rules of the trial design and model: information on the target objective (toxicity, response, pharmacodynamics, pharmacokinetics, either singularly or in combination), classification of overdosing, and any stopping boundaries should be given. This information can include the desired certainty in these estimates. Moreover, for dose decisions (eg, escalation, de-escalation, remain at current dose or stop early), details regarding dose transitions and dose skipping should be given | ||||
| 9e | Experimental details and design specifics: for dose escalation trials, information regarding cohort size, including whether this is fixed or flexible should be given. Indication of the stopping rules for interim and final evaluations: for model based and model assisted designs, details of the prior including full skeleton (if applicable) and its elicitation should be given; for single arm phase II trials, the target sample size and, where appropriate, the timing of any interim analyses should be given | ||||
| Randomisation | 10 | Include randomisation details (eg, whether any minimisation or stratification occurred (including stratifying factors used or the location of that information if it is not held within the SAP)) | 10 | Where appropriate, include randomisation details (eg, whether any minimisation or stratification occurred (including stratifying factors used or the location of that information if it is not held within the SAP)) and, where applicable, details on blinding. | |
| Sample size | 11 | Full sample size calculation or reference to sample size calculation in protocol (instead of replication in SAP) | 11 | Full sample size determination or justification or reference to relevant section in protocol (instead of replication in SAP) | |
| Framework | 12 | Superiority, equivalence, or non-inferiority hypothesis testing framework, including which comparisons will be presented on this basis | 12 | If applicable, specify whether trial is to be performed under hypothesis testing or bayesian framework | |
| Statistical interim analyses and stopping guidance | 13a | Information on interim analyses specifying what interim analyses will be carried out and listing of time points | 13a | Information pertaining to interim dose decisions (eg, escalation, de-escalation, remain at current dose or stop early) | |
| 13b | Any planned adjustment of the significance level due to interim analysis | 13b | Information on other interim analyses specifying what and when interim analyses will be conducted. | ||
| 13c | Details of guidelines for stopping the trial early | 13c | Any planned adjustment of the significance level due to interim analysis | ||
| 13d | Details of guidelines for stopping the trial early | ||||
| Timing of final analysis | 14 | Timing of final analysis (eg, all outcomes analysed collectively or timing stratified by planned length of follow-up) | |||
| Timing of outcome assessments | 15 | Time points at which the outcomes are measured, including visit periods | |||
| Section 4: Statistical principles | |||||
| Indications of uncertainty† | 16 | Level of statistical significance | 16* | Level of statistical significance | |
| 17 | Description and rationale for any adjustment for multiplicity and, if so, detailing how the type 1 error is to be controlled | 17 | Description of any planned adjustment for multiplicity, and if so, including how the type 1 error is to be controlled | ||
| 18 | Confidence intervals to be reported | 18 | Either confidence or credible intervals to be reported (appropriately picked dependent on the trial methodology) | ||
| Adherence and protocol deviations | 19a | Definition of adherence to the intervention and how this is assessed including extent of exposure | |||
| 19b | Description of how adherence to the intervention will be presented | ||||
| 19c | Definition of protocol deviations for the trial | ||||
| 19d | Description of which protocol deviations will be summarised | ||||
| Analysis populations | 20 | Definition of analysis populations (eg, intention to treat, per protocol, complete case, safety) | 20 | Clear definition of the trial or dose cohort(s) including how cohorts will be referred to, how patients enter cohorts, the minimum number of patients needed to be in a cohort (and how long they have been in) before dose escalation decisions can be made. Trial level definitions of patient populations (eg, per protocol, intention to treat, safety) should be given. Details regarding evaluable patients and specify what happens to unevaluable patients should also be made. These definitions should also be provided for any interim analysis populations | |
| Section 5: Trial populations | |||||
| Screening data | 21 | Reporting of screening data (if collected) to describe representativeness of trial sample | |||
| Eligibility | 22 | Summary of eligibility criteria | |||
| Recruitment | 23 | Information to be included in the CONSORT flow diagram | |||
| Withdrawal/follow-up | 24a | Level of withdrawal (eg, from intervention or from follow-up) | |||
| 24b | Timing of withdrawal/lost to follow-up data | ||||
| 24c | Reasons and details of how withdrawal/lost to follow-up data will be presented | ||||
| Baseline patient characteristics | 25a | List of baseline characteristics to be summarised | 25a* | List of baseline characteristics to be summarised | |
| 25b | Details of how baseline characteristics will be descriptively summarised | ||||
| Section 6: Analysis | |||||
| Estimand definition (list and describe each primary and secondary outcome including details of each item)‡ | 26a | Specification of outcomes and timings. If applicable include the order of importance of primary or key secondary end points (eg, order in which they will be tested) | 26a | Details of the treatment (including treatment combinations), and any alternative treatments to which comparisons will be made (where appropriate). For dose finding trials, information on whether analysis will be performed per cohort, per dose received, pooled across all dose levels, or in some combination of these | |
| 26b | Specific measurement and units (eg, glucose control, HbA1c (mmol/mol or %)) | 26b | The trial population, defined with reference to item 20, pertinent to each estimand | ||
| 26c | Any calculation or transformation used to derive the outcome (eg, change from baseline, quality-of-life score, time to event, logarithm) | 26c | The variable of interest to be obtained for each patient that is required to answer the scientific question. For outcomes recorded at multiple time points, distinction as to which of these time points are required for the estimand | ||
| 26d | Intercurrent events and their handling strategy, including adjustment to analysis | ||||
| 26e | Detail the population level summary measure for each estimand | ||||
| Analysis methods | 27a | What analysis method will be used and how the treatment effects will be presented | 27a | What estimator and analysis method will be used and how the results will be presented | |
| 27b | Any adjustment for covariates | 27b* | Any adjustments for covariates | ||
| 27c | Methods used for assumptions to be checked for statistical methods | 27c* | Methods used to check assumptions of the underlying statistical methods and goodness of fit for the model | ||
| 27d | Details of alternative methods to be used if distributional assumptions do not hold (eg, normality, proportional hazards) | 27d* | Details of alternative methods to be used if distributional assumptions do not hold | ||
| 27e | Any planned sensitivity analyses for each outcome where applicable | 27e | Any planned sensitivity analyses for each estimand where applicable | ||
| 27f | Any planned subgroup analyses for each outcome including how subgroups are defined | 27f | Any planned subgroup analyses for each estimand including how subgroups are defined | ||
| Missing data | 28 | Reporting and assumptions or statistical methods to handle missing data (eg, multiple imputation) | 28* | Reporting and assumptions or statistical methods to handle missing data (eg, multiple imputation) | |
| Additional analyses | 29 | Details of any additional statistical analyses required (eg, complier-average causal effect analysis) | |||
| Harms | 30 | Sufficient detail on summarising safety data (eg, information on severity, expectedness, and causality); details of how adverse events are coded or categorised; how adverse event data will be analysed (that is, grade 3/4 only, incidence case analysis, intervention emergent analysis) | 30 | Sufficient detail on summarising safety data outside of those used for dose escalation (eg, non-DLT safety data), such as information on severity, expectedness, and causality; details of how adverse events are coded or categorised; how adverse event data will be analysed (that is, by grade, incidence case analysis, intervention emergent analysis) | |
| Statistical software | 31 | Details of statistical packages to be used to carry out analyses | 31 | Details of statistical packages to be used to carry out design, simulation, and analyses | |
| References | 32a | References to be provided for non-standard statistical methods | |||
| 32b | Reference to data management plan | ||||
| 32c | Reference to the trial master file and statistical master file | ||||
| 32d | Reference to other standard operating procedures or documents to be adhered to | ||||
| Section 7: Suggested SAP appendices | |||||
| Simulation report | 33 | Operating characteristics of the trial design to assess the probability of trial success under different plausible scenarios | |||
| Dose transition pathways | 34 | For dose escalation trials, indication of the dose transition pathways (either using tables or trees/graphs) under different DLT scenarios | |||
| Code | 35 | Full model specification and programming code used for evaluation of dose escalation decisions | |||
| Reports template | 36 | Optional section detailing example tables, graphs, and report templates | |||
Supplementary checklist 1 provides a printable version of the checklist. CONSORT=consolidated standards of reporting trial; CRM=continual reassessment method; DLT=dose limiting toxicity; HbA1c=glycated haemoglobin. Blank table cells in the right hand column indicate that the original item (in the left hand column) is appropriate and covers the necessary content for early phase trials, with examples for all items given in appendix 5.
*
Items for which the table description has remained the same, but the explanation, as detailed in appendix 5, has been amended.
†
This item was originally labelled as “Confidence intervals and P values” in the Gamble et al paper.1 It has been changed to “Indications of uncertainty” to reflect that many early phase trials designs are underpinned by bayesian methodology.
‡
This item was originally labelled as “Outcome definitions” in the Gamble et al paper.1 It has been changed to “Estimand definition” following the wider adoption of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use’s E9 guidelines (ICH E9 R1; addendum on estimands and sensitivity analyses).