Application and impact of run-in studies

  • Michael Fralick
  • Jerry Avorn
  • Jessica M. Franklin
  • Abdurrahman Abdurrob
  • Aaron S. Kesselheim
Review Paper



A run-in phase is often employed prior to randomization in a clinical trial to exclude non-adherent patients, placebo responders, active drug non-responders, or patients who do not tolerate the active drug. This may impact the generalizability of trial results.


To determine if clinical outcomes differed between randomized controlled trials with run-in phases compared with randomized controlled trials of the same medication without run-in phases.

Design, participants

From 2006 to 2014, the Food and Drug Administration approved 258 new medications. Sitaglitpin, saxagliptin, linagliptin, and alogliptin were among the only drugs with a common mechanism of action that each had multiple clinical trials, some of which had run-in phases and some of which did not. We identified all published randomized controlled trials for these four medications from MEDLINE and EMBASE as well as prior systematic reviews.

Main measures

We extracted key measures of medication efficacy (reduction in hemoglobin A1C) and safety (serious adverse events) from qualifying trials. Study results were pooled for each medication using random effects meta-analysis.

Key results

We identified 106 qualifying trials for DPP4 inhibitors, of which 88 had run-in phases and 18 did not. The average run-in phase duration was 4.0 weeks (range 1–21), and 73% of run-in phases administered placebo rather than active drug. The reduction in hemoglobin A1C compared to baseline was similar for trials with and without run-in phases (0.70%, 95% confidence interval [CI] 0.65–0.75 vs 0.76%, 95% CI 0.69–0.84, p = 0.27). The proportion of patients with serious adverse events was also similar for trials with and without run-in phases (4%, 95% CI: 3–5% vs 3%, 95% CI: 1–4%, p = 0.35).


Trials with run-in phases provided similar estimates for medication efficacy and safety compared to trials without run-in phases. Because run-in phases are costly and time-consuming, these results call their utility into question for clinical trials of short duration.


run-in lead-in clinical trial study design 



We thank Dr. Donald Redelmeier, Dr. Chana Sacks, Dr. Nicola Goldberg, and Kristina Stefanini for providing comments on earlier versions of our manuscript (none received any compensation for their work).

Authors’ contributions

Study concept and design: Fralick M, Kesselheim A, and Avorn J.

Acquisition of data: Fralick M and Abdurrob A.

Analysis/interpretation of data: Fralick M, Kesselheim A, Franklin J, and Avorn J.

Drafting of the manuscript: Fralick M.

Critical revision of the manuscript: Kesselheim A, Franklin J, Avorn J, and Abdurrob A.

Statistical analysis: Fralick M and Franklin J

Compliance with ethical standards

Conflict of interest

Dr. Franklin is the principal investigator on a grant from Merck. All other authors declare no conflicts of interest.


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Copyright information

© Society of General Internal Medicine 2018

Authors and Affiliations

  • Michael Fralick
    • 1
    • 2
    • 3
  • Jerry Avorn
    • 1
    • 3
  • Jessica M. Franklin
    • 1
    • 3
  • Abdurrahman Abdurrob
    • 3
  • Aaron S. Kesselheim
    • 1
    • 3
  1. 1.Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine Brigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Eliot Phillipson Clinician-Scientist Training ProgramUniversity of TorontoTorontoCanada
  3. 3.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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