Blinded Safety Signal Monitoring for the FDA IND Reporting Final Rule

We introduce a safety monitoring procedure for two-arm blinded clinical trials. This procedure incorporates a Bayesian hierarchical model for using prior information and pooled event rates to make inferences on the rate of adverse events of special interest in the test treatment arm. We describe a collaborative process for specifying the prior and calibrating the operating characteristics.

[1]  G. Ball,et al.  Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 2: Statistical considerations. , 2011, Contemporary clinical trials.

[2]  E. S. Pearson,et al.  ON THE USE AND INTERPRETATION OF CERTAIN TEST CRITERIA FOR PURPOSES OF STATISTICAL INFERENCE PART I , 1928 .

[3]  P. Thall,et al.  Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes. , 1995, Statistics in medicine.

[4]  D J Spiegelhalter,et al.  The what, why and how of Bayesian clinical trials monitoring. , 1994, Statistics in medicine.

[5]  Donald A. Berry,et al.  Group sequential clinical trials: a classical evaluation of Bayesian decision-theoretic designs , 1994 .

[6]  A. Wald.  Sequential Tests of Statistical Hypotheses , 1945 .

[7]  N Stallard,et al.  Sample size determination for phase II clinical trials based on Bayesian decision theory. , 1998, Biometrics.

[8]  D J Spiegelhalter,et al.  Comparison of Bayesian with group sequential methods for monitoring clinical trials. , 1989, Controlled clinical trials.

[9]  G. Guyatt,et al.  Randomized Trials Stopped Early for Harm in HIV/AIDS: A Systematic Survey , 2006, HIV clinical trials.

[10]  Claire Gilbert Foster,et al.  International ethical guidelines for biomedical research involving human subjects , 1994 .

[11]  S. Goodman.  Toward Evidence-Based Medical Statistics. 1: The P Value Fallacy , 1999, Annals of Internal Medicine.

[12]  Scott M Berry,et al.  Accounting for Multiplicities in Assessing Drug Safety: A Three‐Level Hierarchical Mixture Model , 2004, Biometrics.

[13]  A I Goldman,et al.  Optimal continuous sequential boundaries for monitoring toxicity in clinical trials: a restricted search algorithm. , 2001, Statistics in medicine.

[14]  D. Heitjan,et al.  Bayesian interim analysis of phase II cancer clinical trials. , 1997, Statistics in medicine.

[15]  S J Pocock,et al.  Interim analyses for randomized clinical trials: the group sequential approach. , 1982, Biometrics.

[16]  H Amy Xia,et al.  Planning and core analyses for periodic aggregate safety data reviews , 2011, Clinical trials.

[17]  Bin Yao,et al.  Safety Monitoring in Clinical Trials , 2013, Pharmaceutics.

[18]  Christy Chuang-Stein,et al.  The Practice of Pre-Marketing Safety Assessment in Drug Development , 2013, Journal of biopharmaceutical statistics.

[19]  J. Cornfield.  Recent methodological contributions to clinical trials. , 1976, American journal of epidemiology.

[20]  R. Tiwari,et al.  A Review of Statistical Methods for Safety Surveillance , 2014, Therapeutic innovation & regulatory science.

[21]  Wolzt,et al.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , 2003, The Journal of the American College of Dentists.

[22]  J. Cornfield.  Sequential Trials, Sequential Analysis and the Likelihood Principle , 1966 .

[23]  J. Herson,et al.  Predictive probability early termination plans for phase II clinical trials. , 1979, Biometrics.

[24]  K. K. Lan,et al.  Discrete sequential boundaries for clinical trials , 1983 .

[25]  Bradley P. Carlin,et al.  Bayesian Hierarchical Modeling for Detecting Safety Signals in Clinical Trials , 2011, Journal of biopharmaceutical statistics.

[26]  S. Pocock.  Group sequential methods in the design and analysis of clinical trials , 1977 .

[27]  F. J. Anscombe.  Sequential Medical Trials , 1963 .

[28]  Robert T O'Neill.  Regulatory perspectives on data monitoring. , 2002, Statistics in medicine.

[29]  P F Thall,et al.  Practical Bayesian guidelines for phase IIB clinical trials. , 1994, Biometrics.

[30]  P. O'Brien,et al.  A multiple testing procedure for clinical trials. , 1979, Biometrics.

[31]  A. Goldman.  Issues in designing sequential stopping rules for monitoring side effects in clinical trials. , 1987, Controlled clinical trials.

[32]  Jesse A Berlin,et al.  Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team , 2009, Clinical trials.