title: Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements?
abstract: Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs.
authors.affiliation: INSERM, Centre d'Investigation Clinique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Hôpital Jeanne d' Arc, 54200 Toul, Nancy, France. f.zannad@chu-nancy.fr
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.forename: Wendy Gattis
authors.initials: WG
authors.lastname: Stough
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Pocock
authors.forename: Peter
authors.initials: P
authors.lastname: Sleight
authors.forename: William C
authors.initials: WC
authors.lastname: Cushman
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Eva
authors.initials: E
authors.lastname: Lonn
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Geller
authors.forename: Hans
authors.initials: H
authors.lastname: Wedel
authors.forename: Eric
authors.initials: E
authors.lastname: Abadie
authors.forename: Angeles
authors.initials: A
authors.lastname: Alonso-Garcia
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
mesh_terms: D050197:Atherosclerosis / Q000517:prevention & control; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002986:Clinical Trials as Topic / Q000331:legislation & jurisprudence* / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007880:Legislation, Drug; D008297:Male; D015201:Meta-Analysis as Topic; D008833:Microcirculation / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000517:prevention & control
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents