Primary Outcome in Clinical Trials and Clinical Significance

Pocock SJ, Stone GW.
The Changing Face of Clinical Trials: The Primary Outcome Is Positive — Is That Good Enough? N Engl J Med 2016;375:971-979.

The following are key points to remember from this review about findings of a clinical trial when the primary outcome is positive:

  1. The achievement of statistical significance for the primary outcome is typically a necessary prerequisite for the adoption of a new therapy, but it is not sufficient.
  2. The totality of trial results will be scrutinized by numerous stakeholders, including regulators, payers, journal editors and reviewers, clinical experts, guidelines committees, physicians, patients, and critics.
  3. The determination of whether the findings provide evidence that is sufficient to modify medical practice requires in-depth interpretation of the trial data and the results of earlier, related trials.
  4. Answering the key questions listed below may help to identify which “positive” trials provide evidence that is sufficient to advance clinical practice.
    • Does a p value of <0.05 provide strong enough evidence?
    • What is the magnitude of the treatment benefit?
    • Is the primary outcome clinically important (and internally consistent)?
    • Are secondary outcomes supportive?
    • Are the principal findings consistent across important subgroups?
    • Is the trial large enough to be convincing?
    • Was the trial stopped early?
    • Do concerns about safety counterbalance positive efficacy?
    • Is the efficacy–safety balance patient-specific?
    • Are there flaws in trial design and conduct?
    • Do the findings apply to my patients?
  5. If the efficacy and safety outcomes of the trial are convincingly met, the next step is to evaluate its overall quality and internal validity.
  6. It must also be determined whether the findings translate into treatment effectiveness (and net clinical benefit) in real-world patients.
  7. Gauging the cost-effectiveness of treatments across different types of health care systems will determine the level of reimbursement (which in turn will affect the adoption of a new therapy).
  8. Determining whether the evidence justifies the announcement of a major advance in medical care or a more cautionary note that further studies are warranted requires a comprehensive approach to all available evidence by various stakeholders.
  9. Societal guideline committees play an important role in synthesizing the knowledge base and classifying the strength of evidence for new treatments; their endorsements strongly affect practice.
  10. Ultimately, however, physicians at the point of care bear the final responsibility for accurately interpreting clinical trial results and for integrating regulatory and guideline recommendations in order to make the best treatment decisions for each patient in their care.

Clinical Topics: Prevention

Keywords: Clinical Trial, Clinical Trials as Topic, Cost-Benefit Analysis, Myocardial Ischemia, Outcome Assessment (Health Care), Patient Safety, Point-of-Care Systems, Primary Prevention, Quality Control, Treatment Outcome

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