Dose Range Finding

Safety and efficacy at different dose levels

Dose range-finding studies, often referred to as dose range-finding or dose selection studies, are preclinical investigations conducted during the development of a new drug, specifically in the context of an Investigational New Drug (IND) application. These studies aim to identify the appropriate dose levels for subsequent pivotal preclinical and clinical trials.

The primary objectives of dose range-finding studies include:

1. Determine Dose-Response Relationship:

  • Assess how the drug's efficacy and toxicity vary with different dose levels.
  • Identify the dose range that provides optimal efficacy with an acceptable safety margin.


2. Establish Starting Doses for Clinical Trials:

  • Determine the initial doses to be tested in early-phase clinical trials (Phase I and Phase II).
  • Provide a foundation for selecting doses that are both safe and likely to demonstrate therapeutic effects.
     

3. Evaluate Pharmacokinetics (PK) and Pharmacodynamics (PD):

  • Investigate how the drug is absorbed, distributed, metabolized, and eliminated (ADME).
  • Assess the drug's effects on the body and its relationship to dose levels.
     

4. Assess Tolerability and Safety:

  • Identify the dose levels at which adverse effects may occur.
  • Determine the No Observed Adverse Effect Level (NOAEL) and the Lowest Observed Adverse Effect Level (LOAEL).
     

5. Inform Study Design for Pivotal Preclinical Studies:

  • Guide the design of subsequent pivotal preclinical studies, such as longer-term toxicity studies and efficacy assessments.
  • Ensure that the selected doses align with the intended clinical use and are supported by a robust preclinical safety profile.
     

6. Optimize Study Design for Efficacy Assessments:

  • Explore different dose levels to understand the drug's potential therapeutic range.
  • Inform the design of later-stage efficacy studies by identifying doses likely to produce meaningful clinical outcomes.
     

7. Contribute to Regulatory Submissions:

  • Provide critical data for inclusion in regulatory submissions, such as the IND application.
  • Demonstrate a clear understanding of the drug's dose-response characteristics and safety profile.


Dose range-finding studies are typically conducted in animal models to extrapolate findings to humans. They involve the administration of the investigational drug at various dose levels, often including both low and high doses, to evaluate its effects on safety, efficacy, and other relevant parameters. The results of these studies inform the design and implementation of subsequent preclinical and clinical trials, laying the foundation for a systematic and well-informed drug development process.

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DRF - Objective and Outcome Measures for each test

A comprehensive package of Investigational New Drug (IND) application dose range-finding studies for regulatory purposes involves a series of preclinical investigations to identify appropriate dose levels for subsequent pivotal studies and clinical trials. The package should be designed in accordance with regulatory guidelines and address the safety, tolerability, and preliminary efficacy of the investigational drug.

Below is an outline of key dose range-finding studies, their objectives, and outcome measures:


1. Single Dose Escalation Studies:
Objective: Evaluate the safety, tolerability, and pharmacokinetics of a single administration at various dose levels.
Outcome Measures:

  • Acute toxicity assessment.
  • Pharmacokinetic parameters (Cmax, Tmax, AUC).
  • Preliminary efficacy indicators, if applicable.


2. Short-Term Repeated Dose Studies:
Objective: Assess safety and tolerability with multiple doses over a short duration (e.g., 7 to 14 days).
Outcome Measures:

  • Subacute toxicity evaluation.
  • Pharmacokinetics if applicable.
  • Preliminary efficacy assessments.


3. Pharmacokinetic Studies:
Objective: Understand the drug's absorption, distribution, metabolism, and excretion (ADME) properties.
Outcome Measures:

  • Comprehensive pharmacokinetic profile.
  • Dose-dependent changes in drug exposure.


4. Preliminary Efficacy Studies:
Objective: Explore potential therapeutic effects at different dose levels.
Outcome Measures:

  • Biomarkers or indicators of efficacy.
  • Preliminary evidence of therapeutic activity.


5. Local Tolerance Studies:
Objective: Evaluate tolerance at the site of administration.
Outcome Measures:

  • Local reactions, irritation, or damage.
  • Observations at the injection or application site.


6. Preliminary Biomarker Assessments:
Objective: Identify potential biomarkers associated with drug activity or toxicity.
Outcome Measures:

  • Changes in relevant biomarkers in response to different dose levels.


7. Pilot Toxicity Studies:
Objective: Obtain initial insights into potential adverse effects.
Outcome Measures:

  • Identification of NOAEL and LOAEL.
  • Preliminary safety profile.


8. Dose-Response Relationship Studies:
Objective: Establish a dose-response relationship for safety and efficacy.
Outcome Measures:

  • Efficacy and toxicity assessments across a range of doses.
  • Refinement of the therapeutic index.
     

9. Safety Pharmacology Assessments:
Objective: Assess potential effects on physiological functions.
Outcome Measures:

  • Cardiovascular, respiratory, and central nervous system function assessments.
  • Identification of potential safety concerns.


10. Exploratory Toxicology Studies:
Objective: Provide initial insights into organ toxicity and systemic effects.
Outcome Measures:

  • Identification of target organs for toxicity.
  • Overall safety profile.


11. Integrative Summary Report:
Compilation of Results: Summarize findings from all dose range-finding studies.
Conclusions: Provide conclusions and recommendations for dose levels to be further evaluated in pivotal toxicology studies and clinical trials.


12. Regulatory Documentation:
Dose Selection Rationale: Clearly articulate the rationale for selecting specific dose levels for subsequent studies.
Data Analysis: Present comprehensive data analysis, including dose-response relationships and safety margins.
Safety and Efficacy Predictions: Outline predictions for safety and efficacy based on dose range-finding results.

This comprehensive package aims to provide regulatory agencies with a thorough understanding of the drug's safety and efficacy at different dose levels, supporting the rationale for selecting doses for subsequent phases of development. It is essential to align the package with regulatory guidelines and consult with regulatory experts to ensure that the studies are designed and conducted in compliance with regulatory expectations.