Case Studies

Successfully Waived a Thorough QT/QTc Study

Project Background and Strategic Question
The client was developing a small molecule drug for treatment of multiple different types of seizures. Phase 3 registration trials were ongoing, but the need for a thorough QT/QTc (TQT) study, as listed in the Food and Drug Administration (FDA) guidance for industry (, was not known. Because a TQT study is expensive and time-consuming, the question was whether the study could be waived based on the available phases 1 and 2 clinical data.

Determination of Dose Range for the First-in-Human Study

Project Background and Strategic Question
The client was developing a molecule for the potential treatment of a pancreatic cancer and solid tumors with multiple mutations. A series of nonclinical studies were conducted to support an Investigational New Drug Application (IND). For the IND application, the client needed an investigational plan for a first-in-human study (FIH). However, the selection of starting dose and dose range in the FIH study was a challenge: choosing a narrow dose range might not identify a recommended phase-2 dose (RP2D), whereas selecting a wider dose range would be an expensive and time-consuming addition to the study objectives for the RP2D.

Assessment of Drug-Drug Interaction Potential

Project Background and Strategic Question
The client planned to conduct two phase-3 studies to evaluate a small molecule drug being developed as adjunctive therapy for the treatment of patients with genetic defects caused epilepsies. It was essential to evaluate potential drug-drug interactions (DDIs) between the investigational drug and other commonly used anti-epilepsy drug (AEDs) in this patient population.

The sponsor conducted both cytochrome P450 (CYP)-mediated and transporter-mediated drug-drug interaction (DDI) studies in vitro. Additional in vitro DDI studies were also conducted for uridine diphosphate glucuronosyltransferase (UGT). There was an urgent need for speedy interpretation of the in vitro study results to determine the potential for clinical DDIs with commonly used AEDs.

PK Exposure-Response Analyses for New Drug Application

Project Background and Strategic Question
Patisiran (ONPATTRO®) is a member of a new class of drugs known as small interfering ribonucleic acid (siRNA) treatment. Patisiran is comprised of a novel siRNA, formulated in a lipid nanoparticle (LNP), and developed for treating hereditary transthyretin-mediated (hATTR) amyloidosis. The patisiran dose in the phase-3 APOLLO trial (patients with hereditary transthyretin amyloidosis) was 0.3 mg/kg, given intravenously every 3 weeks. For the new drug application (NDA), it was necessary to justify the dose per recommendations in the FDA publication, Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications (

Modeling and Simulation for Subcutaneous Dose Selection

Project Background and Strategic Question
Tocilizumab is a humanized monoclonal antibody that inhibits interleukin-6 (IL-6) from binding to soluble interleukin-6 (sIL-6R) and membrane-expressed forms of its receptor, thus inhibiting the IL-6–mediated signaling cascade that brings about the proinflammatory activity of the cytokine. Tocilizumab was approved in many countries for the treatment of patients with moderate to severe active rheumatoid arthritis (RA) as an intravenous infusion (IV dose of 8 mg/kg every 4 weeks). However, this dosing schedule necessitates monthly visits to the infusion clinic. A subcutaneous (SC) formulation of tocilizumab for self-administration was important for patients. The challenge was to find 2 SC doses comparable to the 2 approved IV doses, in order that SC dosing options could be available in the approved tocilizumab label, along with the IV doses.