Background
A sponsor developing a novel therapeutic faced a significant regulatory hurdle: evaluating the drug’s effect on cardiac repolarization (QT interval) as part of the NDA submission process. The traditional approach—a thorough QT (TQT) study—was not feasible. The drug could not be safely administered at clinically relevant or supratherapeutic doses to healthy volunteers, and the target patient population often used concomitant medications known to affect heart rate or QT interval. Additionally, the underlying disease itself could influence cardiac parameters, further complicating a standard TQT design.
Challenge
- Regulatory Requirement: FDA required a robust QT assessment for approval. For drug-induced QT prolongation, a change in QTc of 5 msec is the threshold of concern for further investigation.
- Study Constraints: Traditional TQT study was not possible due to safety concerns in healthy volunteers.
- Confounding Factors: High prevalence of concomitant medications and disease-related effects on ECG endpoints.
- Baseline Issues: Run-in dosing made it difficult to establish a clean baseline QT interval.
Solution
Allucent’s clinical pharmacology team designed and executed a concentration-QT (c-QT) analysis leveraging pooled ECG and pharmacokinetic data from multiple clinical studies across different phases:
- Rigorous Regulatory Alignment: Analysis performed according to regulatory standards and published white papers (e.g., Garnett et al.).
- Assumptions Verified: All necessary model assumptions were checked prior to analysis.
- Comprehensive Data Pooling: ECG and PK data were pooled from several studies, including various patient populations and study designs.
- Sophisticated Modeling: The relationship between drug (and metabolite) concentrations and QT interval was modeled to predict cardiac risk.
Results
- No QT Prolongation: The c-QT analysis demonstrated that neither the investigational drug nor its metabolites prolonged the QT interval. At peak plasma concentrations (~1,100 ng/mL), the predicted QTc prolongation was below the threshold of concern (<5 msec) (Figure)
- FDA Approval: The drug was approved without the need for an additional TQT study or further clinical data, saving significant time and cost for the sponsor1.
Broader Impact
Allucent has successfully applied this approach across multiple therapeutic areas, including neuroscience, oncology, and antiviral programs. In each case, Allucent:
- Developed a tailored analysis plan
- Executed a full c-QT analysis
- Delivered submission-ready reports that supported regulatory approval without a TQT study
Conclusion
By leveraging advanced concentration-QT modeling and regulatory expertise, Allucent enabled sponsors to meet cardiac safety requirements, avoid costly and time-consuming TQT studies, and accelerate time to market. This approach exemplifies Allucent’s commitment to delivering fewer detours and faster answers—backed by science.
About the Author
Lisa Benincosa, PhD, Senior Vice President Clinical Pharmacology Strategy at Allucent, is a seasoned leader in Clinical Pharmacology with over 25 years of experience spanning drug metabolism, pharmacokinetics, and translational medicine. As SVP of Clinical Pharmacology Strategy at Allucent, she leads a global team providing strategic scientific consultation to biopharma partners. Lisa holds a PhD in Pharmaceutical Sciences from the University at Buffalo and is recognized for her contributions to advancing innovative therapies through clinical and translational research.
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