In December 2016, the FDA published an industry guidance related to the Biologics Price Competition and Innovation Act. This guidance offers suggestions to sponsors on the design and use of clinical pharmacology studies to support a claim of biosimilarity to a reference product. It provides specific instructions on developing clinical pharmacology data to support biosimilarity.

Critical considerations by the FDA include:

• Exposure and exposure-response
• Residual uncertainty remaining after evaluation of PK, PD and immunogenicity data
• The reliability and accuracy of the analytical assessment
• The accuracy, precision, specificity, sensitivity and reproducibility of the bioanalytic methods
• Safety and immunogenicity data

The guidance specifically states:

[t]hree key concepts—namely a PK and PD response assessment, an evaluation of residual uncertainty, and assumptions about analytical quality and similarity—are especially relevant to the stepwise development of proposed biosimilar products...

The guidance emphasizes the benefit of working with the FDA when developing a clinical pharmacology development plan. For critical consideration and inclusion in a development plan:

• The study design – of particular relevance are crossover designs and parallel study designs
• An adequate reference product
• The appropriate study population
• Dose selection
• Route of administration
• Pharmacokinetic measures
• Pharmacodynamics measures
• An appropriate pharmacodynamics time profile
• Statistical evaluation

Studies should use the same materials and equipment as will be used in the final manufacturing process. Studies on healthy subjects are preferred since they produce less PK and PD variability. It is also important to have a statistically meaningful demographic group. Dose selection should provide "clinically meaningful and interpretable data" and should be the most sensitive dose or the approved dose for the reference product.

The FDA suggests that PK measures be obtained for both the proposed biosimilar product and the reference product.

The sponsor should obtain measures of peak concentration (Cmax) and total area under the curve (AUC) in a relevant biological fluid. For single-dose studies, AUC should be calculated as the area under the biological product concentration-time curve from time zero to time infinity (AUC0-∞), where AUC0-∞ = AUC0-t + Ct/kel (or Ct (concentration at the last measurable timepoint) divided by kel (elimination rate constant)) is calculated based on an appropriate method. Cmax should be determined from the data without interpolation. For intravenous studies, AUC0-∞ will be considered the primary endpoint. For subcutaneous studies, Cmax and AUC will be considered coprimary study endpoints. For multiple dose studies, the measurement of total exposure should be the area under the concentration-time profile from time zero to the end of the dosing interval at steady-state (AUC0-tau), and is considered the primary endpoint. Both the concentration prior to the next dose during multiple dosing (Ctrough ss) and Cmax are considered secondary endpoints. Population PK data will not provide an adequate assessment for PK similarity.

The statistical evaluation should begin with a log-transformation of the exposure measures. Next, sponsors should:

use an average equivalence statistical approach to compare PK and PD parameters for both replicate and nonreplicate design studies. This average equivalence approach involves a calculation of a 90% confidence interval for the ratio between the geometric means of the parameters of the proposed biosimilar product and the reference product.

The new guidance also emphasizes the importance of modeling and simulation tools when available. These tools become more sophisticated and less expensive every year and can add great value to submissions