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The determination of practically useful doses of new drugs: some methodological considerations
Abstract:
An important aim of Phase 2 clinical trials is the firm determination of the doses and the dose regimes to be used both in later clinical trials and in clinical practice. Comparisons of findings made during clinical development and recommendations contained in the package leaflets of marketed preparations indicate that this objective is rarely achieved. The possible reasons for this difficulty are investigated by reviewing the methodology used in the so-called dose-finding trials performed during drug development. Since the terminology used in this context is frequently misleading, definitions are given and alternative approaches, referring to the direct and indirect methods of bioassay, are suggested. The practical use of these models depends on a number of medical and ethical considerations, on the indications for treatment and on the characteristics of the drug under investigation. Some examples are given, indicating that dose-response relationships can be determined more easily for efficacy, where endpoints more reliably fit commoner distributions, than for tolerability, where the responses frequently follow irregular patterns. This area deserves further investigation to improve the criteria for assessment and to develop adequate statistical methods.
Insights
Determining optimal drug doses in Phase 2 clinical trials is challenging, often not achieved as intended. This review examines dose-finding trial methodologies and suggests alternative bioassay approaches for better dose-response determination.
Area of Science:
- Clinical pharmacology
- Drug development
- Biostatistics
Background:
- Phase 2 clinical trials aim to establish definitive drug doses and regimens for subsequent studies and clinical practice.
- Current drug development practices frequently fail to meet this objective, as evidenced by discrepancies between clinical findings and product labeling.
Purpose of the Study:
- To investigate the reasons behind the difficulties in achieving precise dose determination during drug development.
- To review and critique the methodologies employed in dose-finding trials.
- To propose alternative approaches for more effective dose-response assessment.
Main Methods:
- Review of methodologies used in dose-finding trials.
- Analysis of terminology and definitions in dose-finding contexts.
- Exploration of direct and indirect bioassay methods as alternatives.
- Consideration of medical, ethical, and drug-specific factors influencing model application.
Main Results:
- The objective of firm dose determination in Phase 2 trials is rarely achieved.
- Methodological limitations and misleading terminology in dose-finding trials contribute to this challenge.
- Dose-response relationships for efficacy are generally easier to determine than for tolerability due to endpoint distribution differences.
Conclusions:
- There is a need to improve the assessment criteria and statistical methods for dose-finding studies.
- Alternative bioassay models offer potential improvements but require careful consideration of practical factors.
- Further research is warranted to enhance the reliability of dose determination in drug development.