Estimating the Maximum SafeStarting Dose for First-in-Human
Clinical Trials
Beatrice Setnik, Ph.D.Research ScientistFebruary 12, 2007
Overview
Introduction
Selecting an appropriate dose for First-in-HumanTrials:
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
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 afirst-in-human clinical trial
Importance of selecting an appropriate and safestarting dose
Regulation
FDA Guidance, July 2005
Guidance for Industry: Estimating the Maximum SafeStarting Dose in Initial Clinical Trials for Therapeutics inAdult Healthy Volunteers
ICH and Health Canada do not have specific guidancedocument concerning this subject
Objectives
To determine:The maximum recommended starting dose (MRSD) for adult
healthy subjects when beginning a clinical investigation of anynew drug or biological therapeutic that has been studied inanimals
Not applicable to:Endogenous hormones and proteins (i.e. recombinant clotting
factors) used at physiological concentrations or prophylacticvaccines
Limitations:Applies to drug products for which systemic exposure is intended
Does not address dose escalation or maximum allowable doses inclinical trials
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 PKmodel
Aim of MSRD
Avoid toxicity at initial dose
Dose needs to be high enough to allow reasonably rapidattainment of phase I trial objectives (therapeutictolerability, pharmacodynamic (PD) and pharmacokinetic(PK) profile)
Data to be Considered
All relevant pre-clinical data
Pharmacologically active doses
Full toxicological profile
PK (absorption, distribution, metabolism and excretion[ADME])
The “Algorithm”
No observed adverse effectlevels (NOAEL)
Conversions of NOAEL tohuman equivalent dose (HED)
Determine MRSD based onHED
Step 1: NOAEL
No observed adverse effect level (NOAEL) = thehighest dose level that does not produce a significantincrease in adverse effects in comparison to the controlgroup; where AE are effects that are biologicalsignificant
NOAEL does not equal NOEL (refers to any effect)
Values identified for each species tested (at least threespecies, one of which in non-rodent)
Step 2: Human Equivalent Dose (HED)
HED is calculated by a conversion based on body surfacearea
Convert all NOAEL to HED
Based on mg/m2 and assumption that there is a 1:1 relationbetween species when body surface area is normalized
Table provided with conversion factor for different species
Step 3: Most Appropriate Species Selection
Selection of the most appropriate HED to use incalculation 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 predictiveof human toxicology
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 becauseVariability in extrapolating
Uncertainty about enhanced sensitivity in humans
Difficulties in detecting toxicity (e.g. headaches, mentaldisturbances)
Difference in receptor densities or affinities
Unexpected toxicities
Interspecies differences in ADME
Default safety factor is 10XIncreased/decreased under certain circumstances
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
Step 4: Application of Safety Factor
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 amoderate-to-shallow dose-response relationship with toxicitiesconsistent across tested species
NOAEL determined based on toxicity studies of a longer durationcompared to the proposed clinical schedule in healthy volunteers
Assumes that toxicities are cumulative, are not associated with acutepeaks in therapeutic concentrations and did not occur early in therepeated dose study
Step 5: Consideration of thePharmacologically Active Dose
Pharmacologically Active Dose (PAD)
MRSD compared to PAD
PAD estimation not described in guidance, but shouldbe considered in determining the initial startingdose in humans.
PAD may be lower than the MRSD and there may becases where this dose is used instead of thecalculated MRSD.
Additional Considerations
FDA has started an initiative to allow first in manstudies using microdosesLess than 1/100th of the dose calculated to yield a pharmacological
effect
Concerns with high potency agents
Additional Considerations
Expert Scientific Group on Phase One Clinical Trials; UK,30th Nov. 2006In 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
Summary
Dose selection
Key objective is safety
Conservative approach
5 steps to calculate MRSD
Other strategies (e.g. microdose, MABEL)
FDA guidelinesLimited to drugs, clinical trials involving health human
volunteers
Thank You.