Dose setting for a Phase I Clinical Study x Dose setting for a Phase I Clinical Study Suzanne M. Sensabaugh, MS, MBA smsensabaugh@hw-fda.com 1

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

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

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

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 12.3 0.08 Hamster 7.4 0.13 Rat 6.2 0.16 Ferret 5.3 0.19 Guinea pig 4.6 0.22 Rabbit 3.1 0.32 Dog 1.8 0.54 Primates: Monkeys 3.1 0.32 Marmoset 6.2 0.16 Squirrel monkey 5.3 0.19 Baboon 1.8 0.54 Micro-pig 1.4 0.73 Mini-pig 1.1 0.95 5

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

Any questions? smsensabaugh@hw-fda.com 7