By Ray Tobey, Chief Medical Officer on Aug 10, 2017 10:04:00 AM
For safe and effective use of new drugs, clinicians need to determine the appropriate starting dose and the best way to adjust dosage to the needs of a particular patient. But where does one begin to find the appropriate starting dose? The answer is by designing an effective dose response study. Information from this type of study will allow you to determine the relationship among doses, drug effectiveness and acceptable undesirable effects. Here is a simple guideline to help you get started on developing this type of study for your new and innovative drug.
1. Start with reviewing preclinical work
Both in vitro and in vivo preclinical pharmacology studies will provide you with a starting point. From laboratory pharmacology studies, you will have data relating drug concentration and activity responses. These will provide a guide to produce desirable human blood concentration that will likely drive the desired effect. Also, the half-life of the drug determined from these in vitro studies, will provide an estimate of the appropriate dosing interval. From the human pharmacokinetic data, you will be able to determine the dose needed to produce the blood concentration that is necessary for the desired effect.
2. Follow the general guidelines on number of doses to be tested
In general, there should be 4-5 doses tested, with a minimum of 3, plus a placebo. The design ideally should include doses where you expect no difference from placebo, slight improvement, good improvement, and best improvement. Best improvement occurs where additional higher doses add very little in terms of efficacy (the plateau) or adverse experiences become unacceptable.
3. Consider the appropriate sample size
Determining the sample size number requires careful consideration. Cost and ethical considerations need to be addressed with your team to find the best solution for your needs. Moreover, you will need to evaluate the risk of enrolling too many participants versus not enough when trying to study the efficacy and safety of a new drug.
4. Review of the primary clinical response data
From the clinical response, you may discover the adverse experiences found at each of the doses and then determine the dose range for blood concentrations from minimal to maximum effect. In a dose response study, statistical validity is not required between the individual doses nor placebo if there is an adequate size difference compared to placebo. Statistical efficacy compared to placebo is required for the selected therapeutic doses in Phase III Safety and Efficacy trials. Data from these studies will provide data for a statistical power calculation for further development trials.
Here we’ve summarized a general guideline to develop a dose response study. For each individual novel drug there will be special characteristics to consider. Having an experienced team to work with you and develop a personalized guideline based on your needs will help secure a successful dose response study. What have you found most difficult when designing a dose response study and how did you resolve that difficulty?