Calculating l Safe Start t Doses from Toxicology Studies

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<strong>Safe</strong>ty Factor, continued Default of 10, may be decreased if: • Drug is a member of a well-characterized class, is being given according to an established clinical dosing regimen, and has similar PK/ADME and toxicity it profiles across species, including human. • Toxicities are easily predicted, monitored, and are reversible. • Dose-response for toxicity is not steep. • The NOAEL upon which the HED is based was determined in longer-term nonclinical studies; this assumes that toxicities are cumulative and were not observed early in the longer-term studies. Food and Drug Administration
Changes in start t dose ‣ It is always acceptable (<strong>from</strong> a safety perspective) to use a clinical start dose lower than the MRSD. ‣ Use of pharmacologically active dose (PAD) May use if lower than MRSD May be used to justify lowering the MRSD, e.g., in cases in which toxicity is due to exaggerated pharmacologic effects. Food and Drug Administration
Page 1 and 2: Calculating l Safe Start t Doses fr
Page 3 and 4: CDER guidance on “start dose”
Page 5: Safety Factor ‣ Application of sa
Page 9 and 10: Food and Drug Administration
Page 11 and 12: Events in clinical trial ‣ TeGene
Page 13 and 14: CD28 Monoclonal Trial in UK ‣ No
Page 15 and 16: Could this toxicity have been predi
Page 17 and 18: Other clues ‣ OKT3, murine monocl
Page 19 and 20: Reaction to Tegenero Incident ‣ E
Page 21 and 22: MABEL Approach ‣ “Minimal Antic
Page 23 and 24: EMEA Guidance ‣ On its face, this

Calculating l Safe Start t Doses from Toxicology Studies

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