Michael Fralick1,2,3, Jerry Avorn4,5, Jessica M Franklin4,5, Abdurrahman Abdurrob5, Aaron S Kesselheim4,5. 1. Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Ste 3030, Boston, MA, 02120, USA. mif823@mail.harvard.edu. 2. Eliot Phillipson Clinician-Scientist Training Program, University of Toronto, Toronto, ON, Canada. mif823@mail.harvard.edu. 3. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA, USA. mif823@mail.harvard.edu. 4. Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Ste 3030, Boston, MA, 02120, USA. 5. Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA, USA.
Abstract
BACKGROUND: 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. OBJECTIVE: 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). CONCLUSION: 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.
BACKGROUND: 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. OBJECTIVE: 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). CONCLUSION: 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.
Entities:
Keywords:
clinical trial; lead-in; run-in; study design
Authors: Karen S L Lam; Chun Chung Chow; Kathryn C B Tan; Ronald C W Ma; Alice P S Kong; Peter C Y Tong; Man Wo Tsang; Tak Mao Chan; Sydney C W Tang; Ka Kui Lee; Wing Yee So; Brian Tomlinson Journal: Curr Med Res Opin Date: 2016-04-04 Impact factor: 2.580
Authors: R Peto; R Gray; R Collins; K Wheatley; C Hennekens; K Jamrozik; C Warlow; B Hafner; E Thompson; S Norton Journal: Br Med J (Clin Res Ed) Date: 1988-01-30
Authors: Michael Fralick; Jerry Avorn; Jessica M Franklin; Emily Bartsch; Abdurrahman Abdurrob; Aaron S Kesselheim Journal: J Gen Intern Med Date: 2018-06 Impact factor: 5.128