DOSE RANGE-FINDING STUDIES

In preclinical research, a dose range finding study determines the ideal dosage range to be used to conduct the definitive GLP IND-enabling studies, and further safety and efficacy tests of a novel therapy.

The following are the main results of a dose range finding study: 

1. Determining the Minimum Effective Dose (MED)―the lowest dosage required to achieve the intended therapeutic outcome. 
2. Finding the Maximum Tolerated Dose (MTD)―the maximum dosage that can be given without having a significant negative impact or causing toxicity. 
3.  Identifying the Dose-Response Relationship―determining a therapeutic window by comprehending how various dosages impact the biological response. 
4. Providing a Safety Profile―preliminary information about possible toxicities or adverse effects at different dosage levels. 
5. Guiding Future Research―information to aid in planning upcoming clinical, pharmacokinetic, and pharmacodynamic investigations.

The following procedures are commonly involved in the conduct of a dose range finding study:

1. Study design and dose selection to find safe and effective doses by examining a wide range. 
2. Dosage administration through the appropriate routes of administration (oral, intravenous, subcutaneous, dermal, inhalation, etc.) 
3. Toxicity and efficacy monitoring to identify side effects and therapeutic reactions. 
4. Pharmacokinetic (PK) and pharmacodynamic (PD) evaluations to assess the ADME of the drug substance as well as its impact on biological processes, linking dosage levels to therapeutic outcomes. 
5. Data analysis to ascertain dose-response relationship, maximum tolerated dosage (MTD), and minimal effective dose (MED). This aids in defining the range of safe and efficient dosages for further research. 
6.  A report summarizing the results includes suggestions for the optimal dose range to apply in further investigations, such as clinical safety and efficacy trials.

Key regulatory considerations for preclinical dose range finding studies include:

• Choosing an appropriate study design, route of administration, and setting clear objectives; 
• Adhering to the International Council for Harmonization (ICH) regulatory guidelines, ICH M3(R2) and ICH S6, which recommend the design, duration, and reporting of nonclinical safety studies. These studies must be conducted in compliance with GLP guidelines to ensure data integrity, reproducibility, and scientific rigor;
• Choosing an animal model based on the drug’s pharmacokinetic, pharmacodynamic, and toxicity profile. The animal species should have a metabolic profile that closely reflects human metabolism for reliable dose predictions; 
• Scientists must ensure compliance with animal welfare regulations and ethical guidelines; 
• Studies must include low, mid, and high doses to identify the dose-response relationship. The dosing range should be based on prior information, such as pharmacology, in vitro data, and data from similar compounds (e.g., in the same therapeutic class); 
• Full documentation of the study design, methods, results, and analyses must be provided and submitted as part of the Investigational New Drug (IND) application to the FDA or the Clinical Trial Application (CTA) to other regulatory authorities.

Both non-GLP and GLP DRF studies help determine safe and effective doses, but with varying levels of detail and regulatory significance. 

Non-GLP studies use simpler designs and smaller animal groups to provide an initial estimate of a drug’s dose range. While useful for early-stage decisions, these studies are not suitable for regulatory approval.

GLP DRF studies, on the other hand, adhere to rigorous protocols and involve larger animal groups, providing precise and reliable data needed for regulatory submissions. This high-quality data paves the way for further drug development and is essential for advancing to later stages. 

The choice between non-GLP and GLP studies depends on the stage of your research.