Background: Recently, biological agents (BIOs) with high cost and high therapeutic efficacy have become widely available for the treatment of rheumatoid arthritis (RA), and the prognosis of patients has improved dramatically. However, the rising cost of medical care has become a problem, and the use of biosimilars (BS), which are cheaper than the original BIOs, is being recommended in Japan. In the current treatment of RA, BIOs such as original infliximab (IFX) or BS of IFX (IFX‒BS) are administered in combination when the effect of methotrexate (MTX) alone is insufficient. Therefore, we compared the efficacy and safety of the IFX and IFX‒BS combination therapy with MTX for RA using meta-analysis.

Methods: We conducted a literature search using the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Ichushi web databases to compare the efficacy and safety of IFX and IFX‒BIO in MTX therapy for RA. After evaluating the quality of the articles obtained, we extracted the improvement in American College of Rheumatology (ACR) criteria as an index of efficacy and the number of cases of various adverse events (AEs) and discontinuations due to AEs as a safety index, and calculated the summary odds ratio (OR) and 95％ confidence interval (CI) by meta-analysis to compare the results.

Results: Using 6 clinical studies that met the final inclusion criteria for the meta-analysis, we compared the clinical equivalence of the efficacy (improvement in ACR criteria at 14 weeks, 30 weeks, 1 year, and 2 years after treatment) and safety. No significant difference was observed between 14 weeks and 1 year, but IFX‒BS was superior to original IFX at 2 years. In addition, there was no significant difference in the incidence of infection or discontinuation rate due to AEs. On the other hand, IFX‒BS tended to result in fewer infusion reactions.

Conclusions: Meta-analysis showed that there was no significant difference in efficacy and safety between the original IFX and IFX‒BS when MTX alone was ineffective in the treatment of RA, indicating clinical equivalence in efficacy and safety between IFX and IFX‒BS. However, due to the small number of trials examined in this study, further similar clinical trials need to be included in future analyses.

The authors attempted to manufacture an investigational drug using a manufacturing facility within the university without outsourcing it to a contract manufacturing organization (CMO). However, they experienced difficulty in purchasing an exclusive drug as a raw material for the process. The authors made inquiries to the Ministry of Health, Labor and Welfare (MHLW) about the interpretation of the Notice of the Director-General regarding Article 138 of the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices. The response was that the purchase of drugs dedicated to manufacture of investigational products for the purpose of administering them to humans may be possible, even if the manufacturing facilities are in a university that does not have the license for pharmaceutical manufacturing of drugs. Raw materials derived from manufacturing-specific drugs or (non-manufacturing) medical drugs, which are considered to be safer in humans than as research reagents, should consistently meets safety requirements for study subjects. Therefore, the regulatory authorities should consider revising the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices or the Notification by the Director-General to allow the purchase of drugs by research institutions for the purpose of manufacturing investigational drugs or test drugs to be used in clinical studies, and that investigational drugs or products be used for clinical research at research institutions, or that “the purpose of research should include clinical trials and clinical research.”