Estimating the Maximum Safe Starting Dose for First-in-Human Clinical Trials


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Part of the MaRS BioEntrepreneurship series session: Clinical Trials Strategy
Speaker: Beatrice Setnik

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Estimating the Maximum Safe Starting Dose for First-in-Human Clinical Trials

  1. 1. Estimating the Maximum Safe Starting Dose for First-in-Human Clinical Trials Beatrice Setnik, Ph.D. Research Scientist February 12, 2007
  2. 2. Overview Introduction Selecting an appropriate dose for First-in-Human Trials: Determining the No Observed Adverse Effect Level (NOAEL) Calculating the Human Equivalent Dose (HED) Selecting the most appropriate species Applying the Safety Factor Considering the Pharmacologically Active Dose (PAD) Other Considerations Summary
  3. 3. Safety in Preliminary Clinical Trials Assessing variability: Species-species and species-human differences Drug absorption, distribution, metabolism, excretion Physiology/ adverse effect profiles e.g. Thalidomide Teratogenic in humans and not in rats e.g. TGN412 (monoclonal antibody) March 2006- severe toxicity in six healthy male volunteers in a first-in-human clinical trial Importance of selecting an appropriate and safe starting dose
  4. 4. Regulation FDA Guidance, July 2005 Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers ICH and Health Canada do not have specific guidance document concerning this subject
  5. 5. Objectives To determine: The maximum recommended starting dose (MRSD) for adult healthy subjects when beginning a clinical investigation of any new drug or biological therapeutic that has been studied in animals Not applicable to: Endogenous hormones and proteins (i.e. recombinant clotting factors) used at physiological concentrations or prophylactic vaccines Limitations: Applies to drug products for which systemic exposure is intended Does not address dose escalation or maximum allowable doses in clinical trials
  6. 6. Estimating the MRSD Calculations based on: 1. Administered doses 2. Observed toxicities 3. Algorithmic calculation Alternatively: Animal pharmacokinetic and modeling may be used Often insufficient data to construct a scientifically valid PK model
  7. 7. Aim of MSRD Avoid toxicity at initial dose Dose needs to be high enough to allow reasonably rapid attainment of phase I trial objectives (therapeutic tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profile)
  8. 8. Data to be Considered All relevant pre-clinical data Pharmacologically active doses Full toxicological profile PK (absorption, distribution, metabolism and excretion [ADME])
  9. 9. The “Algorithm” No observed adverse effect levels (NOAEL) Conversions of NOAEL to human equivalent dose (HED) Determine MRSD based on HED
  10. 10. Step 1: NOAEL No observed adverse effect level (NOAEL) = the highest dose level that does not produce a significant increase in adverse effects in comparison to the control group; where AE are effects that are biological significant NOAEL does not equal NOEL (refers to any effect) Values identified for each species tested (at least three species, one of which in non-rodent)
  11. 11. Step 2: Human Equivalent Dose (HED) HED is calculated by a conversion based on body surface area Convert all NOAEL to HED Based on mg/m2 and assumption that there is a 1:1 relation between species when body surface area is normalized Table provided with conversion factor for different species
  12. 12. Step 3: Most Appropriate Species Selection Selection of the most appropriate HED to use in calculation of MRSD If most appropriate species cannot be determined, then most sensitive species should be selected (i.e. with the lowest HED) Most appropriate species based on: ADME Class experience that indicates a species is more predictive of human toxicology
  13. 13. Step 4: Application of Safety Factor Once HED from NOAEL of the most appropriate (sensitive) species is determined a safety factor should be applied Safety factor applied because Variability in extrapolating Uncertainty about enhanced sensitivity in humans Difficulties in detecting toxicity (e.g. headaches, mental disturbances) Difference in receptor densities or affinities Unexpected toxicities Interspecies differences in ADME Default safety factor is 10X Increased/decreased under certain circumstances
  14. 14. Step 4: Application of Safety Factor Increasing the Safety Factor (> 10) Steep dose response curve Severe toxicities Nonmonitorable toxicity Toxicities without premonitory signs Variable bioavailability Irreversible toxicity Unexplained mortality Large variability in doses of plasma drug levels eliciting effects Nonlinear pharmacokinetics Inadequate dose-response data Novel therapeutic targets Animal models with limited utility
  15. 15. Step 4: Application of Safety Factor Decreasing the Safety Factor (< 10) Usually for therapeutics of a well characterized class Administered by same route schedule and duration Similar metabolic profile and bioavailability Similar toxicity profiles across all the species tested including humans Toxicity is easily monitored, reversible, predictable and exhibits a moderate-to-shallow dose-response relationship with toxicities consistent across tested species NOAEL determined based on toxicity studies of a longer duration compared to the proposed clinical schedule in healthy volunteers Assumes that toxicities are cumulative, are not associated with acute peaks in therapeutic concentrations and did not occur early in the repeated dose study
  16. 16. Step 5: Consideration of the Pharmacologically Active Dose Pharmacologically Active Dose (PAD) MRSD compared to PAD PAD estimation not described in guidance, but should be considered in determining the initial starting dose in humans. PAD may be lower than the MRSD and there may be cases where this dose is used instead of the calculated MRSD.
  17. 17. Additional Considerations FDA has started an initiative to allow first in man studies using microdoses Less than 1/100th of the dose calculated to yield a pharmacological effect Concerns with high potency agents
  18. 18. Additional Considerations Expert Scientific Group on Phase One Clinical Trials; UK, 30th Nov. 2006 In general, the more species-specific an agent is, the less reliable will be the information from animal studies as a guide to selecting the starting dose in humans If different methods give different estimates of the MRSD, the lowest value should be used Minimum Anticipated Biological Effect Level (MABEL) recommended as a useful approach to calculate safe starting dose More conservative estimate
  19. 19. Summary Dose selection Key objective is safety Conservative approach 5 steps to calculate MRSD Other strategies (e.g. microdose, MABEL) FDA guidelines Limited to drugs, clinical trials involving health human volunteers
  20. 20. Thank You.