1. Dose setting for a Phase I Clinical Studyx
Dose setting for a Phase I Clinical Study
Suzanne M. Sensabaugh, MS, MBA 1

2. Suzanne Sensabaugh, MS, MBA
Former FDA: Reviewer of hundreds of industry submissions.
Committee member who drafted FDA Guidelines: Received numerous awards.
Former industry: Drafted submissions for FDA review. Since
2009, assisted in the development of over 120 drugs. 2

3. Dose setting for Phase I
Based on No Observed Adverse Effect Level (NOAEL) or Minimal Anticipated Biological Effect Level (MABEL)
FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in healthy adult volunteers, July 2005 3

4. An algorithmic manner to compute the Maximal Recommended Starting Dose
Toxicity should be avoided, but need dose high enough to meet trial objectives
NOAEL: the highest dose level that does not produce a significant increase in adverse effects in comparison to the control group
Select the most relevant species, conversion of NOAEL to Human Equivalent Dose (HED), and apply a safety factor of at least 10
For biologics, relevant species selected based on in vitro binding and functional assays
The use of the safety factor is based on the possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than predicted by the animal models, bioavailability may vary across species, and that the models tested do not evaluate all possible human toxicities
Although many NOAELs will be determined, only one should be used in the calculation 4

5. Conversion of Animal Doses to HED Based on Body Surface Area
To Convert Animal Dose in mg/kg to HED in mg/kg,
Divide animal dose by Multiply Animal Dose By
Human
Child (20 kg)
Mouse
Hamster
Rat
Ferret
Guinea pig
Rabbit
Dog
Primates:
Monkeys
Marmoset
Squirrel monkey
Baboon
Micro-pig
Mini-pig 5

6. MABEL
Determine No Observed Effect Level (NOEL) and lowest dose where pharmacological response was seen
Then apply a safety factor
A calculation based on microdosing is frequently used
Determine No Observed Effect Level (NOEL) and lowest dose where pharmacological response was seen
NOEL is a determination of any effect, not just an adverse effect
May be the same as the NOAEL
Then apply a safety factor
A calculation based on microdosing is frequently used
Less than 1/100th the dose calculated to yield a pharmacologic effect 6

7. Any questions? smsensabaugh@hw-fda.com7