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.