Table 2 Circumstances where interim result sharing may be warranted by the DSMB
Circumstance | With whom would the DSMB share? | What to share? | Risk or counter argument | Reference |
|---|---|---|---|---|
Theme 1) Current usual practice by DSMBs | ||||
Circumstance 1: When the DSMB recommends early termination and the recommendation needs to be evaluated by the SC and sponsor | Specified representative(s) of their trial’s SC and sponsor | Unmasked interim results | Risk: If the trial were to continue despite the recommendation to terminate, those few individuals privy to the interim data should not be a part of making future trial decisions. This will protect the trial’s integrity from potential biasing of results | [6] |
Circumstance 2: When the DSMB has concerns about the interim data or results given to them by the unblinded independent statistician or DAC for their interim review | Trial’s independent statistician or DAC | Anything needed | None made | |
Theme 2) Trial completion is threatened | ||||
Circumstance 3: When the trial may have to stop early because of poor accrual due to special circumstances, and it may be possible to improve accrual by sharing interim data or results, when all other efforts to improve accrual are exhausted | The public | Some type of unmasked interim result that will encourage accrual | Risk: Risk of biasing trial results even when special conditions are met as indicated by Stephens et al. [39]. Sharing interim results should be a judgement call that weights the benefits of sharing against the potential risk of biasing trial results | [39]* |
Circumstance 4: When there is a need to restore equipoise when one of two related trials finishes first and threatens the completion of the unfinished trial | The public | Sharing unmasked but limited comparative interim results that will help restore equipose | Counter argument: The unfinished trial(s) might not need to share interim information if it will contribute important information beyond what was reported by a similar trial that finished earlier. This sentiment should be expressed to all stakeholders to help restore confidence in trial completion | [1]* |
Theme 3) Concern about patient safety | ||||
Circumstance 5: When an uncertain severe safety issue appears at interim in a trial and there is another similar trial still underway | The DSMB of the similar trial | Safety: Unmasked interim safety result | Risk: Sharing may erode the independence of each trial in regards to the independent confirmation of results | [1]* |
Circumstance 6: When the DSMB assesses the risk of there being a serious adverse event at interim for enrolled patients in a particular treatment group, but continuing the trial may still be desirable because getting a definitive result on a patient primary endpoint is important to the public and medical community | Trial patients | Safety: Unmasked interim safety results | Risk: Unmasking of interim safety results with the trial patients may risk biasing the trial results, but in some cases it is ethically imperative to let the patients know of the severe safety risks to allow them to decide whether they want to continue in the trial and before allowing the trial itself to continue | [1]* |
Theme 4) Regulatory approval | ||||
Circumstance 7: When the regulator is currently assessing licensing approval for a new drug/treatment submitted with results from a completed trial and there is still a similar trial underway that will provide important new substantial information regarding results | The regulators | Relevant unmasked interim results that will help with assessing the status that should be given for a licensing application | Risk: Interim review of the second ongoing trial could jeopardise its own integrity and introduce bias, as the public could prognosticate the results of that trial based on the regulator’s subsequent decision to either approve or delay a manufacturer’s licensing application | [1]* |
Circumstance 8: When a regulatory wants to assess a drug for conditional or accelerated/expedited approval for a manufacturer to be able to market a drug early | The regulators | Unmasking interim results | Risk: Bias could also be introduced to the trial with knowledge of regulatory decisions made based on interim results and known threshold criteria for approval, even if exact interim endpoints are not shared publically | |
Other special circumstances | ||||
Circumstance 9: When adaptive confirmatory trials base interim trial adaptive changes on the trial’s interim results | Authorised qualified persons at the sponsor (1 or 2 people) who are not participating in the trial but can assist with trial adaptations | Whatever is agreed upon a priori | Risk: Unmasking of interim data or results can introduce bias and risk trial integrity | |
Circumstance 10: When patients outside of the trial are facing important treatment decisions and may benefit from some interim results from non-inferiority or superiority trials with a long follow-up | The public and patients and physicians facing important treatment decisions | Relevant unmasked interim results that will help with treatment decision | Risk: Knowledge of an interim endpoint result could influence a clinical decision to have a new treatment before safety of that treatment is determined more definitively in ongoing trial | |
Circumstance 11: When sponsors, investigators or regulators are planning for future studies, new products or allocating resources for future use | Sponsors, investigators or regulators | Unmasked yet non-comparative interim information. This could be: • Control group event rates OR • Control group adverse event rates OR • Pooled event rate | Risk: Bias can be introduced to the unfinished trial if new plans are to be published and can be interpreted by a wider audience. Planning errors could result from using uncertain interim results | |