Statistical methodology for highly variable compounds: A novel design approach for the ofatumumab Phase 2...

Area of Science:

• Pharmacokinetics and Drug Development
• Clinical Trial Design and Methodology
• Immunology and Neurology

Background:

• Testing pharmacokinetic equivalence of drug formulations is crucial for therapeutic success.
• Highly variable pharmacokinetics, common in subcutaneous injections, pose challenges for standard bioequivalence trials.
• Existing regulatory guidance for reference-Scaled Bioequivalence (RSABE) primarily applies to crossover designs, not parallel-group trials.

Purpose of the Study:

• To describe a novel mixed-scaling testing strategy combined with an adaptive parallel-groups bioequivalence trial.
• To evaluate the pharmacokinetic equivalence of two subcutaneous ofatumumab 20 mg formulations in relapsing multiple sclerosis patients.
• To address the challenges of high pharmacokinetic variability and the absence of specific regulatory guidance for RSABE in parallel-group designs.

Main Methods:

• A modified reference-Scaled Bioequivalence (RSABE) approach was applied to a parallel-groups design, utilizing between-subject variability of the reference drug.
• A two-stage adaptive trial design was implemented to adjust sample size based on interim pharmacokinetic variability estimates.
• Sample size re-estimation occurred at the end of the first stage, informed by simulations to ensure adequate statistical power.

Main Results:

• The novel adaptive parallel-groups bioequivalence trial successfully demonstrated pharmacokinetic equivalence between the autoinjector pen (test) and prefilled syringe (reference) ofatumumab formulations.
• The applied methodology effectively managed high coefficient of variation (>30%) in pharmacokinetic metrics (AUCtau and Cmax).
• The adaptive design allowed for precise sample size adjustments, ensuring the power of the RSABE test.

Conclusions:

• The described mixed-scaling testing strategy and adaptive parallel-groups design provide a robust framework for assessing bioequivalence of drugs with high pharmacokinetic variability.
• This methodology offers a viable solution for situations where crossover trials are not feasible and specific regulatory guidance for parallel-group RSABE is lacking.
• The study successfully established bioequivalence for subcutaneous ofatumumab, supporting its use in relapsing multiple sclerosis management.