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The Great Debate MTD: Is testing to the MTD unnecessary animal use or necessary to assure human safety? The Pro Position

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. MTD Definition.

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The Great Debate MTD: Is testing to the MTD unnecessary animal use or necessary to assure human safety? The Pro Position

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  1. The Great DebateMTD: 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 • 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

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