A CASE STUDY ON DOSE RANGING:
FROM MADNESS TO METHOD
A Case Study on Dose Ranging: From MADness to Method
Clinical Research Associate, Clinical Research Strategies
Do you ever wonder where the labeling inside your medication comes from, or how your doctor knows how to prescribe it? Through a meticulous process that evaluates a drug’s pharmacological properties and intended therapeutic outcomes, researchers can identify dosages that prioritize patient safety. A critical factor in this process is a type of early-phase dose-ranging clinical study that involves testing different doses of a drug to determine its minimum and maximum effective doses for treatment. Once the appropriate dosage is determined, and further larger clinical trials provide additional safety and efficacy evidence of that dosage through a rigorous regulatory approval process, can doctors confidently prescribe medication to their patients, knowing that they are based on careful evaluation and testing?
Dose-ranging studies typically occur during Phase 1 or early Phase 2 clinical studies. Typically, Phase 1 studies aim to elucidate an initial assessment of a drug’s safety in healthy volunteers to minimize additional risks to the health and safety of affected or sick patients. This assessment includes looking at the safety profile of different dosages. Sometimes, Phase 1 studies include sick patients, such as in rare disease and cancer studies, since the potential benefit outweighs the risk. In general, Phase 2 studies aim to characterize the dose response in affected or sick patients, which is important for defining the therapeutic range of a drug. There are multiple study designs used to determine the safety and tolerance of a drug (see table below). The results of the clinical studies are then submitted to regulatory bodies, such as the FDA, in order to proceed to larger trials designed for broader safety and efficacy endpoints. After approval by regulatory bodies for a specific indication (e.g., fat reduction) and intended use (e.g., injection into the fat under the chin), doctors can prescribe the drug using those identified doses, or the drug can be sold over the counter to consumers.
These study designs can be combined for specific types of studies, such as SAD crossover and MAD crossover. Often, the outcome of a SAD study will be used to determine the starting range for a MAD study or the dose for a Phase 2 study with patients.
CRS Case Study of Phase 1 Experience in 18 Healthy Volunteers Undergoing Abdominoplasty
In a Phase 1 study, the Clinical Research Strategies (CRS) research team assisted a sponsor in the Asia-Pacific region with a dose ranging study that assessed the injection comfort, safety, and tolerability of an injectable drug. The purpose of the study was for a cosmetic application of chin fat reduction, but a suitable study type is widely known to be leveraged in a region of the body that will be removed with surgery, especially for safety purposes. In this case the sponsor was testing the drug in excess skin and tissue around the belly area for an abdominoplasty surgical procedure. The study closely followed the MAD dose ranging design, with some modifications and three different doses: Low, Medium, and High concentration, as well as three different subject groups called cohorts. In this study, each subject served as their own control as they also received a placebo injection and had an equivalent non-injection site for comparison.
RESULTS AND CONCLUSION
Determining the appropriate dosage range for a drug is a crucial step in drug development, as it ensures that the drug is both safe and effective for its intended use. The Phase 1 study discussed above, performed in healthy volunteers undergoing abdominoplasty, demonstrated promising comfort, safety, and tolerability outcomes with a satisfactory risk-benefit foundation, which is fundamental to continuing in larger clinical trials. The use of a dose-ranging study, such as this one, allows for the testing of various doses of a drug to determine the most effective and tolerable dosage range. Through the use of a MAD-based design, the CRS team was able to assist their client in completing this step in their pathway to larger clinical trials, which ultimately holds promise to meet the requirements for market approval. This study design allowed for the comparison of multiple doses, ultimately leading to the identification of a dosage range that was well-tolerated by the study participants. By implementing a well-designed study plan, which included defined dose escalation procedures, the CRS research team was able to successfully meet the needs of the sponsor and contribute to the development of a safe and effective drug.
1. Single Ascending Dose & Multiple Ascending Dose. (May 3, 2016) Amlan Kumar Pradhan, Portfolio Lead – Application Modernization in Cloud || Digital Transformation || IT Simplification || Parcels & Logistics, Healthcare, Lifesciences https://www.linkedin.com/pulse/single-ascending-dose-multiple-amlan-kumar-pradhan
2. 4 Types of Dose Finding Studies Used in Phase II Clinical Trials. (March 10, 2013) Rho, Inc. blog post. https://www.rhoworld.com/four-types-of-dose-finding-studies-used-in-phase-ii-clinical-trials
ABOUT THE AUTHOR
Clinical Research Associate
David is a graduate of Indiana University of Pennsylvania and a Clinical Research Associate at Clinical Research Strategies. During his time at Indiana University, he studied Biology and Anthropology with an interest in opioid research focusing on impoverished/minority populations. He also received special training and certification in mental health and naloxone administration. David continued his education in clinical research by completing the Barnetts CRA & CRC Beginner Program. His therapeutic indication experience is expansive, but he has recently worked on studies in oncology, substance abuse, respiratory diseases, pain treatments, and multiple medical devices. David conducts in-person monitoring visits and specializes in remote monitoring visits, managing the quality and integrity of data and sites by applying good clinical practices to his work.
Clinical Research Associate