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  • Refer to Chapter 4, Drug Literature Evaluation I: Controlled Clinical Trial Evaluation



  • Is the reference drug’s efficacy established using adequate historical data and/or addition of a placebo arm?

  • Are the participants and outcome measures for the noninferiority similar compared to previous studies that confirmed the efficacy of the reference drug (e.g., constancy assumption)?

  • Is the method used to determine the noninferiority (NI) margin predetermined before the study, both clinically and statistically sound, and the reasoning clearly stated in the article?

  • Was a per-protocol analysis used? If so, did they also perform an intention-to-treat analysis?

  • Was the sample size modified as the study progressed? If so, was a clear explanation of how the blinded information was handled and by what method these modifications were determined also provided?

  • Was this study an attempt to rescue a failed superiority trial?


  • Was assignment of active and control treatment to study periods randomized?

  • Was the study blinded?

  • Were multiple observation periods used?

  • Were study endpoints clearly defined?

  • Was the washout period between study periods adequate?


  • Are the methodologies used to make adaptive changes in the trial adequately described?

  • What logistical issues exist and have they been adequately addressed?

  • Are the adaptive changes based on evidence and good clinical judgment?

  • Did extensive adaptation to the protocol occur during the study?

  • To what extent is intrusion of bias noted?

  • Who has access to the information created from interim analyses?

  • If the study was stopped early, is the totality of evidence adequate?


  • Were study methodologies and test conditions clearly defined?

  • Were validated assays used?

  • Were assays validated using time-zero measurements and an adequate number of test samples taken?


  • Did the protocol define the characteristics of the subjects?

  • Were confounding factors (e.g., smoking, alcohol use) identified and controlled?

  • Was a crossover design used?

  • Was the study randomized and blinded?


  • Were one of two options used for subject comparison: (1) comparison of subjects to those not using the program or service, (2) comparison of subjects before or after initiation of the program or service?

  • Was the program or service clearly defined?

  • Did the authors specify from whose perspective (e.g., patient, provider, physician, third-party payer) the study was undertaken?

  • If costs were analyzed, were all costs associated with provision of the program or service included in the analysis, including personnel, inflationary changes, and cost savings had the intervention not occurred?

  • Were clinically important outcome parameters used to assess effectiveness of the program or service?



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