Should non-inferiority drug trials be banned altogether?

Non-inferiority (NI) trials can be used in a situation when a new drug is expected to have a similar efficacy to its comparator but can offer other advantages over the existing drug, such as a more convenient method of administration or fewer side effects. Here, we discuss the advantages and disadvantages of NI trials from an ethical, methodological and regulatory perspective. We suggest that such trials should be designed to address simultaneously the objective of showing NI with regard to drug efficacy and the objective of establishing superiority of the additional advantages of a drug over its active comparator.

[1]  A. Hoes,et al.  Interpretation and Inference in Noninferiority Randomized Controlled Trials in Drug Research , 2010, Clinical pharmacology and therapeutics.

[2]  C. White,et al.  Comparative Effectiveness of Low‐Molecular‐Weight Heparins versus Other Anticoagulants in Major Orthopedic Surgery: A Systematic Review and Meta‐analysis , 2012, Pharmacotherapy.

[3]  A. Shimony,et al.  Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. , 2012, The American journal of cardiology.

[4]  A. Hoes,et al.  The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants , 2013, Canadian Medical Association Journal.

[5]  S. Gillespie,et al.  The ethics of non-inferiority trials , 2008, The Lancet.

[6]  Arno W. Hoes,et al.  Room for Improvement in Conducting and Reporting Non-Inferiority Randomized Controlled Trials on Drugs: A Systematic Review , 2010, PloS one.

[7]  S. Sullivan,et al.  Australian managed entry scheme: a new manageable process for the reimbursement of new medicines? , 2012, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[8]  C. Chuang-Stein,et al.  The ethics of non-inferiority trials , 2008, The Lancet.

[9]  S. Garattini,et al.  Non-inferiority trials are unethical because they disregard patients' interests , 2007, The Lancet.

[10]  Scott S Emerson,et al.  Bio‐creep in non‐inferiority clinical trials , 2010, Statistics in medicine.

[11]  Thomas R Fleming,et al.  Current issues in non‐inferiority trials , 2008, Statistics in medicine.

[12]  Malcolm Man-Son-Hing,et al.  Determination of the clinical importance of study results , 2002, Journal of General Internal Medicine.

[13]  T. Perneger,et al.  What differences are detected by superiority trials or ruled out by noninferiority trials? A cross-sectional study on a random sample of two-hundred two-arms parallel group randomized clinical trials , 2010, BMC medical research methodology.

[14]  S. Pocock,et al.  Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. , 2006, JAMA.

[15]  A. Gandjour.  The ethics of non-inferiority trials , 2008, The Lancet.

[16]  R. D'Agostino,et al.  Non‐inferiority trials: design concepts and issues – the encounters of academic consultants in statistics , 2002, Statistics in medicine.

[17]  T. Campbell.  An Introduction to Clinical Significance: An Alternative Index of Intervention Effect for Group Experimental Designs , 2005 .