Part of the MaRS BioEntrepreneurship series session: Clinical Trials Strategy Speaker: Beatrice Setnik This is available as an audio presentation: http://www.marsdd.com/bioent/feb12 Also view the event blog and summary: http://blog.marsdd.com/2007/02/14/bioentrepreneurship-clinical-trial-strategies-its-never-too-soon/

1. Estimating the Maximum Safe
Starting Dose for First-in-Human
Clinical Trials
Beatrice Setnik, Ph.D.
Research Scientist
February 12, 2007

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. 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. 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. 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. 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. 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. Data to be Considered
All relevant pre-clinical data
Pharmacologically active doses
Full toxicological profile
PK (absorption, distribution, metabolism and excretion
[ADME])

9. The “Algorithm”
No observed adverse effect
levels (NOAEL)
Conversions of NOAEL to
human equivalent dose (HED)
Determine MRSD based on
HED

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. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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

19. 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

20. 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

21. Thank You.