x Dose setting for a Phase I Clinical

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

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

Suzanne Sensabaugh, MS, MBA Former FDA: Reviewer of hundreds of industry submissions. Committee member

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. www. hw-fda. com 2

Dose setting for Phase I • Based on No Observed Adverse Effect Level (NOAEL)

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 www. hw-fda. com 3

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Conversion of Animal Doses to HED Based on Body Surface Area To Convert Animal

Conversion of Animal Doses to HED Based on Body Surface Area To Convert Animal Dose in mg/kg to HED in mg/kg, Human Child (20 kg) Mouse Hamster Rat Ferret Guinea pig Rabbit Dog Primates: Monkeys Marmoset Squirrel monkey Baboon Micro-pig Mini-pig Divide animal dose by ----12. 3 7. 4 6. 2 5. 3 4. 6 3. 1 1. 8 Multiply Animal Dose By 3. 1 6. 2 5. 3 1. 8 1. 4 1. 1 ----0. 08 0. 13 0. 16 0. 19 0. 22 0. 32 0. 54 0. 32 0. 16 0. 19 0. 54 0. 73 0. 95 www. hw-fda. com 5

MABEL • Determine No Observed Effect Level (NOEL) and lowest dose where pharmacological response

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 www. hw-fda. com 6

Any questions? smsensabaugh@hw-fda. com www. hw-fda. com 7

Any questions? smsensabaugh@hw-fda. com www. hw-fda. com 7