1 / 11

Interim Analysis

DISCUSSION TOPIC #8 Should trials be continued if: The results for the primary endpoint are definitive, but there is uncertainty about key secondary outcomes ? Group 8. Interim Analysis.

saima
Download Presentation

Interim Analysis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. DISCUSSION TOPIC #8Should trials be continued if: The results for the primary endpoint are definitive, but there is uncertainty about key secondary outcomes?Group 8

  2. Interim Analysis An evaluation of the current data from an ongoing trial, which can potentially modify the conduct of the study Reasons to conduct interim analysis: Assess safety, identify important clinical findings, economic reasons Data Monitoring Committee (DMC): multi-disciplinary committee that meets at pre-specified intervals to carefully weigh the risks and benefits of treatment effects and determine if early termination is practical • Independent from investigators • Recommended to avoid/minimize bias

  3. Reasons for Early Termination • Safety Concerns - risk to participants • Substantially beneficial effects are observed • Unlikely to see a statistically significant difference between treatment groups (futility) • Data quality is compromised • Low accrual rate • Target question may no longer be important – already determined from other ongoing trials

  4. Dangers of Early Termination • Credibility of results • Bias in the assessment of the response variable(s) • Impact of missing data • For multi-site trial, internal consistency • Acceptability within clinical community • Potential adverse events and outcomes of secondary response variables after termination

  5. Primary and Secondary Endpoints Early termination relies on meeting either one or a combination of these endpoints: Primary Endpoint – A clinical endpoint that provides sufficient evidence to fully characterize the effect of treatment. Ex: Disease-related death Secondary Endpoint – A clinical endpoint that is of interest, but not primary interest. It can assess safety or help interpret a primary endpoint. Ex: MI, stroke

  6. Stopping Guidelines for Early Termination • Investigators and DMC agree upon stopping guidelines a priori • Set p-value thresholds for primary and secondary endpoints • P-value thresholds should be adjusted for multiple comparisons to maintain desired Type I Error (false positive) rate • For ethical reasons, p-value threshold for proof of harm often less stringent than for proof of benefit

  7. Primary versus Secondary Endpoints: “And”/“Or” Rules • “And” Rule: Study terminated only if primary and secondary endpoints show effect in the same direction (either benefit or harm) • P-value threshold for secondary endpoints may be less stringent (e.g. p=0.20), or left to discretion of DMC • “Or” Rule: Terminated if any endpoint shows benefit or harm to the pre-specified p-value

  8. Flexibility in Stopping Guidelines • According to the DHHS/FDA guidelines, DMC is not required to follow stopping guidelines; should exercise their judgment • Statistical stopping boundary is only one component in a complex decision • If primary outcome is significant but safety data is equivocal: a thorough benefit/risk assessment may not be possible at interim review • Adverse safety effects may be longer-term and/or may not be known yet • Treatment effect will be unstable at early stages of a trial

  9. Other Considerations in Decision to TerminateTrial • Clinical judgment plays a critical role • In a study with many endpoints, the most clinically relevant component may need to dominate the decision • Results from similar trials/earlier phases can provide further information on endpoints • If treatment is meant to be taken long-term, need long-term efficacy and safety data • FDA regulation requires rigorous evidence of both efficacy and safety

  10. Conclusions • Friedman et al: “Statistical methods are useful as guides but not adequate as rules” • Use combination of statistical guidelines and clinical judgment to weigh benefits/risks • Should trial be continued if primary endpoint is definitive, but there is uncertainty about safety endpoints? • Probably, but it is a case-by-case decision • Consider: p-values, clinical judgment of endpoints, # events that have occurred, and outside data

  11. References • Friedman L.M., Furberg C.D., DeMetsD.L.(2010). Fundamentals of Clinical Trials.293-310. • MontoriVM et al. (2005). Randomized Trials Stopped Early for Benefit. JAMA 294: 2203-2209. • Pocock SJ (2005). When (Not) to Stop a Clinical Trial for Benefit. JAMA 294: 2228-2230. • Schulz KF & Grimes AD (2005). Multiplicity in Randomised Trials II: Subgroup and Interim Analyses. The Lancet 365: 1657-1661. • U.S. DHHS & FDA (2006). Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. • Whitehead J, Todd S, Stallard N. (2001).Interim Analyses in Clinical Trials.51(5):393. • Zhao Y, Grambsch PM, & Neaton JD (2007). A Decision Rule for Sequential Monitoring of Clinical Trials with a Primary and Supportive Outcome. Clinical Trials 4: 140-152.

More Related