Our data confirm the impression that in clinical practice the effects of anti‐TNF treatment are smaller than in published RCTs. In five of 11 comparisons there was a significant difference between the daily clinical practice data and the active drug group of the RCTs. Further, the data indicate that selection towards high disease activity in RCTs is a major explanation for the observed difference in efficacy. This can be concluded from the fact that the differences in response between the active drug groups and the eligible patients were smaller than the differences between the active drug groups and the ineligible patients. Furthermore, eligible patients had up to 44% higher response rates than ineligible patients.
With respect to dosing regime and co‐medication, a difference in the use of corticosteroids between daily clinical practice and RCTs was observed. In clinical practice, fewer patients used prednisone and many patients stopped prednisone after starting anti‐TNF therapy. This might be another explanation for the lower efficacy of anti‐TNF in clinical practice compared with the efficacy in RCTs.
Our results confirm the observation by Sokka and Pincus,21
who showed that most patients receiving routine care did not meet the inclusion criteria for the early RA trial of etanercept (ERA) and the ATTRACT study (42% and 5%, respectively, did meet the criteria). However DREAM patients fulfilled the inclusion criteria for disease activity more frequently, which is probably explained by the fact that their routine care cohorts consisted of all RA patients instead of RA patients who started anti‐TNF therapy. Zink and colleagues also showed that eligible patients had higher response rates than non‐eligible patients.22
Wolfe and Michaud concluded that the design of RCTs exaggerates the anti‐TNF treatment effect due to a wash‐out, patient selection and regression to the mean.23
This finding is confirmed by our result showing that daily clinical practice patients eligible for the RCTs have a larger response than patients ineligible for the RCTs. Wolfe and Michaud suggested that the efficacy of new drugs observed in RCTs should be corrected for the active comparators by subtracting the placebo response from the response in the RCT active drug group.23
This could be possible if the clinical effect of the placebo itself is zero. Is has been proven that this is not the case in subjective continuous outcomes, especially measures of pain.24
Five out of seven ACR core set measures are subjective outcome measures or consider pain. Therefore, the placebo response is a combination of the placebo effect itself and other effects, such as patients' preferences and regression to the mean. These placebo effects are different in every trial and observational setting, therefore it is not possible to develop an algorithm to correct the efficacy shown in RCTs for the expected effectiveness in daily clinical practice. Therefore, we illustrate the difference between clinical practice and RCTs by describing the possible confounding issues and their magnitude as observed.
This study has limitations. For our data collection we only counted 28 joints instead of 68 as in most RCTs. This might result in an overestimation of the baseline disease activity in the observational data because the 28 counted joints are likely to be the 28 joints most affected in RA.25
Next, patients in daily clinical practice are treated with the medication of preference. We consider it probable that this can result in a larger treatment effect than in RCTs.26,27
We were unable to calculate the exact ACR20 response criteria as was done in most selected papers. Instead, we had to compare the efficacy of anti‐TNF on an overestimation or underestimation of the ACR20 response, which makes interpretation more difficult.
RCTs are the appropriate design to evaluate efficacy of new interventions. However, observational phase IV studies have a complementary value to investigate long‐term side effects and efficacy, and may be useful to study effects in patients not typically included in phase III RCTs.26
This study confirms the impression that in clinical practice the effects of anti‐TNF are smaller than in published RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs. Responses were lower in patients ineligible for RCTs. Selection towards high disease activity and the continued use of co‐medication in RCTs are probable explanations for the difference in effects of anti‐TNF in clinical practice and in RCTs.