Background Randomized controlled trials (RCT) are designed to answer specific questions using a certain number of patients, determined by sample size calculation. If the calculation is not done properly, more than the needed number of patients may be enrolled, leading to unnecessary exposure for those patients to potentially harmful drugs. In an ideal world, assumptions that go into the calculation of the sample size would be more certain. However in the real world it is not always possible to have ideal calculations and it would be expected that under and over enrolling would be seen in roguishly similar number of RCTs.
Objectives To determine the actual numbers of patients needed to be enrolled in RA biologic RCT.
Methods A Pubmed search was conducted, for RCT of abatacept, adalimumab, etanercept, infliximab, rituximab and tocilizumab, in rheumatoid arthritis (RA) patients (n=291). Only original initial studies where the primary outcome was efficacy were analyzed (n=42). Using the final results of the primary outcome, back calculation of the actually needed patients for the trials were calculated and compared to the actual enrollment numbers.
Results 42 studies were analyzed (infliximab 10, etanercept 7, adalimumab 8, abatacept 7, tocilizumab 5, rituximab 5). Primer efficacy outcome was ACR 20 in 29 studies. ACR 50 in 3 studies, ACR N in 2 studies, DAS-28 in 5 studies, Paulus 20 in 2 studies and reduction of number of swollen/tender joints in 1 study.
The mean number of patients enrolled in the treatment arms were 153 and the control arms were 114. After back calculation, the actual needed numbers for the treatment arm was 79 and control arm was 79.
According to the recalculated sample size results, there were more patient than required to show differences between groups in 35 studies (83%) and less patients than required in 7 studies. In the 35 studies were more than necessary patients were enrolled had a median of 103 extra patients.
Conclusions Over 80% of RCT of biologic agents in the treatment of RA had on average 103 patients unnecessarily enrolled. This was a trend seen regardless of agent or how many previous RCT had been done with the same agent. It is an ethical obligation to conduct a RCT with only the necessary number of patients to answer the scientific question that is being asked. Our data suggests that most RCT fall short of this standard.
Disclosure of Interest S. Celik: None Declared, Y. Yazici Grant/Research support from: Abbott, BMS, Celgene, Genentech, Consultant for: Abbott, BMS, Centocor, Celgene, Pfizer, genentech, UCB, Takeda