1. The Great Debate MTD: Is testing to the MTD unnecessary animal use or necessary to assure human safety? The Pro Position
Jack A. Reynolds
Annual Member Meeting and Social
SOT’s Regulatory and Safety Evaluation Specialty Section
Tuesday, March 18, 2008
Seattle, Washington

2. MTD Definition Classically defined from CA study design
Body weight gain decrements
Vague and subjective symptomatology based on stress & toxicity
Dose setting based on 3-month range-finding
Few measurements beyond clinical signs, body weight and clinical chemistry & hematology
Incomplete histology

3. MTD Definition Historically Current Debate definition
A retrospective judgment that required regulatory concurrence
Historically, often marked by numerous rounds of acrimony and vitriol
Current
Prospective review of range-finding and agreement on dose setting
Debate definition
Dose which elicits overt adverse effects and signs of toxicity assessed by clinical signs, clinical pathology or pathology

4. Purpose of MTD Establish relevant measure of biological perturbations
Appropriate for study design and specified objectives
May or may not be essential to meet the criteria of classic MTD, i.e., overt toxicity
Subjective & often irrelevant endpoints of MTD
Surrogates of toxicity

5. Objectives of in vivo Studies
Chemicals and environmental agents
NOEL’s & NOAEL’s
Exposure limits & safety multiples
Pharmaceuticals
Starting doses for clinical trials
Mechanistic insight into AE’s
Benefit/risk determinations

6. Objectives of in vivo Studies
What issues are we trying to ID and resolve
Chemicals
Low dose effects
Little focus on MOA or mechanism
Eliminate or minimize exposure
Pharmaceuticals
Low incidence effects (idiosyncratic)
Potent biological modifiers
Mechanistic insight
Mechanistic risk assessment
Informed decision making and risk management

7. Objectives of in vivo Studies
All of the study outcome criteria must be derived from studies that elicit some measurable adverse perturbation
Surrogates such as exposure levels, extrapolation from in vitro methods or biomarkers are not reliable nor in most cases, not validated
“MTD” or “Perturbation Dose” is essential