DISCUSSION TOPIC #8
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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.

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Interim Analysis

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Interim analysis

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


Interim analysis

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


Reasons for early termination

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


Dangers of early termination

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


Primary and secondary endpoints

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


Stopping guidelines for early termination

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


Primary versus secondary endpoints and or rules

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


Flexibility in stopping guidelines

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


Other considerations in decision to terminate trial

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


Conclusions

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


References

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.


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