The challenge of indication extrapolation for infliximab biosimilars

Abstract

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support "indication extrapolation" to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

“…Variation in infliximab CL across patient populations could be due to a number of different factors. Elevated inflammatory status in UC could contribute to higher CL due to a higher whole body turnover rate and increased nonspecific proteolytic degradation rate 2 , 29 . In addition, CL of infliximab has also been shown to be affected by concomitant medication, as well as immunogenicity 29 .…”

“…Elevated inflammatory status in UC could contribute to higher CL due to a higher whole body turnover rate and increased nonspecific proteolytic degradation rate 2 , 29 . In addition, CL of infliximab has also been shown to be affected by concomitant medication, as well as immunogenicity 29 . In the analysis by Dirks and Meibohm, the population CL value for therapeutic mAbs ranged between 0.2–0.5 L/day (0.12– 0.3 mL/h/kg assuming a 70 kg individual).…”

El papel de los biosimilares en la enfermedad inflamatoria intestinal: una realidad en nuestro país

“…Además, se escogió la enfermedad menos sensible como modelo clínico para detectar una diferencia potencial en eficacia entre el biosimilar y el originador, que en otras circunstancias si sería evidente. En otras palabras, la efectividad en similitud demostrada por el CT-P13 y el Remicade ® para la AR no excluye la posibilidad de una diferencia clínicamente significativa en efectividad entre ambas moléculas si se aplican en un modelo mucho más sensible, tal como la EII (29). medicamento de referencia y el biosimilar.…”

Biosimilar Drugs and Pharmacovigilance

“…Extrapolation of indications should be also considered in terms of safety and efficacy. Further specific clinical trial needs should be assessed on the biosimilar basis [6].…”