Recommended dosage in clinical trials
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Recommended Dosage Determination in Clinical Trials
Phase I Clinical Trials and Dose-Finding Strategies
In early-phase (Phase I) clinical trials, the main goal is to determine the recommended dose and safety profile of a new drug or drug combination. Traditionally, the maximum tolerated dose (MTD) has been used as the primary endpoint, especially for cytotoxic agents, with dose escalation guided by observed toxicities to avoid exposing patients to unsafe or subtherapeutic doses Cook2015Tourneau2009Zacks2020. However, for newer therapies such as molecularly targeted agents (MTAs) and immunotherapies, toxicities may not be dose-dependent, and chronic or unpredictable side effects can occur. This has led to the consideration of alternative endpoints, such as pharmacokinetic and pharmacodynamic outcomes, to better define the recommended dose Cook2015Tourneau2009.
Modern Approaches: Optimal Biological Dose and Dose Ranges
Recent research suggests that defining a single recommended dose based solely on toxicity may not always yield the most effective or best-tolerated dose. Instead, defining a recommended dose range for further testing in later-phase trials is encouraged, especially for oncology drugs. This approach allows for flexibility and adaptation to different patient populations and drug mechanisms Araújo2022Tourneau2009. The concept of the optimal biological dose (OBD), which focuses on achieving the best biological effect rather than just avoiding toxicity, has shown promise. When OBDs are used as the recommended phase II dose, they are more likely to align with final approved doses compared to MTD-based recommendations .
Patient-Centered and Adaptive Trial Designs
There is a growing interest in patient-centered dose-finding methods. Incorporating patient-reported outcomes (PROs) alongside clinician assessments can help ensure that recommended doses are both effective and tolerable from the patient’s perspective. New trial designs, such as the Utility-PRO-Continual Reassessment Method (U-PRO-CRM), use both clinician and patient data to optimize dose recommendations, potentially improving the accuracy and relevance of dose selection . Additionally, adaptive and model-based designs, including those that allow for intrapatient dose escalation and real-world eligibility criteria, are being recommended to enhance safety and optimize dosing Araújo2022Mozgunov2021.
Predictive and Computational Methods
Advances in computational methods, such as machine learning models, are being used to predict the maximum recommended daily dose for new compounds. These models integrate multiple features, including molecular properties and human research data, to improve the accuracy and reliability of initial dose selection, especially for first-in-human trials .
Special Considerations for Specific Drugs and Therapies
For some drugs, such as risperidone, clinical experience and post-marketing studies have led to updated dosage recommendations that are lower and titrated more slowly than those used in initial trials, particularly for vulnerable populations like the elderly or first-episode patients . In radiation therapy clinical trials, consistency in dose calculation and reporting is also emphasized, with a preference for reporting dose to medium in medium (Dm,m) to maximize comparability across studies .
Conclusion
The determination of recommended dosage in clinical trials is evolving beyond traditional toxicity-based endpoints. Modern strategies incorporate biological activity, patient-reported outcomes, adaptive trial designs, and computational predictions to optimize dosing for safety, efficacy, and patient tolerability. These approaches are improving the accuracy and relevance of dose recommendations, ultimately enhancing patient outcomes in clinical research Cook2015Araújo2022Li2023+4 MORE.
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Most relevant research papers on this topic
Oncology Phase I Trial Design and Conduct: Time for a Change MDICT Guidelines 2022.
The MDICT Guidelines 2022 recommend flexible, adaptive trial designs, expert teams, and clear endpoint definitions to optimize dosage selection in early oncology trials, leading to better patient outcomes.
Dose Escalation Methods in Phase I Cancer Clinical Trials
Phase I clinical trials use various dose escalation methods to establish optimal doses for new anticancer agents, preserving safety and ensuring rapid accrual.
Report dose-to-medium in clinical trials where available; a consensus from the global Harmonisation group to maximize consistency.
The Global Harmonization Group recommends preferring dose to medium in medium (Dm,m) for radiation dose calculation and reporting in clinical trials, even if only water in water (Dw,w) is available.
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