Control treatments in biologics trials of rheumatoid arthritis were often not deemed acceptable in the context of care.
OBJECTIVE
Control treatments in randomized controlled trials (RCTs) should not deliberately disadvantage patients. The objectives of the study were to compare (1) willingness to include vs. (2) willingness to prescribe control treatment among physicians randomized to assess, respectively, either (1) enrollment in a trial or (2) appropriateness of control treatment in a care context for the same fictional patient.


METHODS
Physicians were authors of articles about rheumatoid arthritis (RA), involved in RA patient care, and used to enrolling patients in trials. The outcomes were willingness to give control treatment: trial enrollment or control-treatment appropriateness in care context. We derived three case vignettes of fictional standard eligible patients for each of 30 RCTs assessing biologics in RA. Physicians were randomly allocated to the "trial" or "care" arm. For each of the 90 fictional patients, physicians assigned to the trial arm were asked if they would enroll the patient in the RCT the patient was derived from. For the same 90 fictional patients, physicians assigned to the care arm were asked if the control treatment of the RCT was appropriate in a context of usual care.


RESULTS
Of the 1,779 physicians invited to participate, 151 were randomized. Half of the fictional patients {41/90; 45% [95% confidence interval (CI): 37%, 53%]} would be enrolled in the RCT although the control-arm treatment of the RCT was not considered appropriate for them in the context of care. This rate differed by type of comparator [55% for non-head-to-head RCTs vs. 6% for head-to-head RCTs; adjusted odds ratio (aOR), 23.9 (95% CI: 5.5, 92.7)] and duration of trial control treatment [56% for ≤24 weeks and 15% for >24 weeks; aOR, 10.7 (95% CI: 2.8, 63.9)] but not patient RA activity [aOR, 2.5 (95% CI: 1.0, 6.6)]. The limitation of this study was that physicians gave their opinion on fictional patients with only RA.


CONCLUSIONS
Control treatments in RCTs of biologics in RA are often deemed not acceptable in the context of usual care, especially those for non-head-to-head RCTs. These findings raise ethical concerns and challenge the choice of the comparator in RCTs.
AP-HP, Hôpitaux Universitaire Paris Nord Val de Seine, Hôpital Bichat, Département d'Epidémiologie et Recherche Clinique, 46 rue Henri Huchard, 75877 Paris, France; INSERM, U738, 16 rue Henri Huchard, 75877 Paris, France; Centre d'Investigation Clinique-Epidémiologie Clinique CIC EC 1425, INSERM, 46 rue Henri Huchard, 75877 Paris, France. Electronic address: candice.estellat@bch.aphp.fr.
Candice
C
Estellat
AP-HP, Hôpitaux Universitaire Paris Nord Val de Seine, Hôpital Bichat, Département d'Epidémiologie et Recherche Clinique, 46 rue Henri Huchard, 75877 Paris, France; INSERM, U738, 16 rue Henri Huchard, 75877 Paris, France; Centre d'Investigation Clinique-Epidémiologie Clinique CIC EC 1425, INSERM, 46 rue Henri Huchard, 75877 Paris, France; PRES Sorbonne Paris Cité, Université Paris Diderot, 5 rue Thomas Mann, 75013 Paris, France.
Florence
F
Tubach
Department of Rheumatology, Hôpital Bicêtre, AP-HP, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
Raphaèle
R
Seror
Centre d'Investigation Clinique-Epidémiologie Clinique CIC EC 1425, INSERM, 46 rue Henri Huchard, 75877 Paris, France.
Toni
T
Alfaiate
INSERM, U738, 16 rue Henri Huchard, 75877 Paris, France; Centre d'Investigation Clinique-Epidémiologie Clinique CIC EC 1425, INSERM, 46 rue Henri Huchard, 75877 Paris, France; Département d'Epidémiologie et Recherche Clinique, Hôpital Louis Mourier, Hôpitaux Universitaire Paris Nord Val de Seine, AP-HP, 178 rue des Renouillers, 92700 Colombes, France.
David
D
Hajage
AP-HP, Hôpitaux Universitaire Paris Nord Val de Seine, Hôpital Bichat, Département d'Epidémiologie et Recherche Clinique, 46 rue Henri Huchard, 75877 Paris, France; Centre d'Investigation Clinique-Epidémiologie Clinique CIC EC 1425, INSERM, 46 rue Henri Huchard, 75877 Paris, France.
Yann
Y
De Rycke
INSERM, U738, 16 rue Henri Huchard, 75877 Paris, France; Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, AP-HP, 1, place du Parvis Notre Dame, 75004 Paris, France; PRES Sorbonne Paris Cité, Université Paris Descartes, 12 rue de l'école de médecine, 75006 Paris, France; Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY 10032, USA.
Philippe
P
Ravaud
D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001688:Biological Products / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000941:ethics* / Q000592:standards*; D057212:Therapeutic Equipoise
D001688:Biological Products
Antirheumatic agents; Control groups; Ethics; Ethics Committees; Placebo; Rheumatoid arthritis; Therapeutic equipoise