RSESS SOT 2008 “Great Debate”

1. RSESS SOT 2008 “Great Debate” “MTD: Is testing to the MTD unnecessary animal use or always necessary to assure human safety ?” Speakers: Dr. Jack Reynolds – President, JAReynold Associates; former Global Head of Safety Sciences, Pfizer; 30+ years pharmaceutical industry experience (PRO – MTD Position) Dr. Bob Osterberg - Aclairo Consulting; former Supervisory Pharmacologist, FDA; 34+ years regulatory agency experience (PRO – Safety Margin Based Approach Position) Moderated by RSESS VP, Dr. Frank Sistare , Merck

2. MTD – Maximally Tolerated Dose • Context for this Debate – Is NOT Rodent Carcinogenicity Studies • Context for this Debate - Is the series of Pre-Chronic to Chronic Rodent and Non-Rodent Toxicology Studies used to support the safe conduct of clinical trials and drug registrations (2 wk, 4 wk, 3 mo, 6/9/12 mo IND and NDA enabling studies) • Alternative Viewpoints of what the MTD (and study goal) should be: • Highest dose that does NOT induce overt toxicity and is NOT expected to shorten the life span of the animal • …Or, highest dose that induces overtly severe toxicity but not death within the timespan of a given study

3. MTD – Maximally Tolerated Dose • Signs of only “minimal” toxicity • Weight gain (<10% inhibition) • Gross and Microscopic Pathology (expert evaluation of adverse vs. adaptive) • Clinical Chemistry (expert evaluation of magnitude and combination of alterations) • Physiologic Intolerability – BP, EKG, Consciousness… • Behavioral – Morbidity, Food Intake…

4. MTD – Maximally Tolerated Dose Death within the Study Duration MTD Exceeded & Target Organ Toxicities Defined MTD Animal Toxicity Response NOAEL NOEL Exposure

5. MTD – Maximally Tolerated Dose Death within the Study Duration MTD Exceeded & Target Organ Toxicities Defined MTD ??? MTD Animal Toxicity Response NOAEL NOEL Exposure

6. Opposing Forces & Challenges • Both Product Developers and Regulatory Authorities - want target organs of toxicity defined to maximize patient safety monitoring. • BUT, often different viewpoints on the severity of toxicity that should be induced • 3R’s and USDA Animal Research Legislation – seek to eliminate ALL harmful and inhumane animal treatment. Animals should be either euthanized, receive treatment mitigation, stop dosing when duress is noted. • Challenge in initial and all subsequent longer duration studies is to: 1) NOT exceed the MTD in quest to reach the MTD, 2) and define all relevant target organ toxicities, while 3) ensuring full survival at study end without morbidity.

7. All • SHOULD testing to the MTD and establishing target organ toxicities be a desired goal of IND enabling and product registration studies? • Is testing to the MTD ALWAYS necessary in EVERY study to assure human safety? • SHOULD we EVER dose our animals past the MTD to induce overtly severe toxicities? • SHOULD we ALWAYS dose our animals past the MTD to induce overtly severe toxicities? • Does a safety margin based approach, in the absence of demonstrating a MTD, EVER make sense?

8. Jack Reynolds • Is testing to the MTD unnecessary animal use or always necessary to assure human safety ?

9. Jack Reynolds • Is testing to the MTD unnecessary animal use or always necessary to assure human safety ? • Should we always/ever dose our animals past the MTD to induce overtly severe toxicities?

10. Jack Reynolds • Is testing to the MTD unnecessary animal use or always necessary to assure human safety ? • Should we always/ever dose our animals past the MTD to induce overtly severe toxicities? • If the MTD and target organ toxicities are defined in early studies is it reasonable to require that the MTD and target organ toxicities be re-established at the end of EVERY subsequent (e.g., 13 wk, 26 wk, etc.) rodent and non-rodent tox study?

11. Bob Osterberg • Is testing to the MTD unnecessary animal use or always necessary to assure human safety?

12. Bob Osterberg • Is testing to the MTD unnecessary animal use or always necessary to assure human safety? • When we take an exposure-based safety margin approach what margin is sufficiently high to ensure patients will not be at risk for a non-monitorable toxicity (and conclude it to be unpredicted)?

13. Bob Osterberg • Is testing to the MTD unnecessary animal use or always necessary to assure human safety? • When we take an exposure-based safety margin approach what margin is sufficiently high to ensure patients will not be at risk for a non-monitorable toxicity (and conclude it to be unpredicted)? • When we do, the devil is in the details - how do you propose the details be addressed (e.g., parent/metabolite; AUC/Cmax; total/free, expanded clinical monitoring endpoints, etc)?

14. Jack Reynolds • Is testing to the MTD unnecessary animal use or always necessary to assure human safety ? • Can a margin of 10X, 25X, 50X, 100X, 1000X obviate the need to dose to an MTD; i.e., if we can accept a “limit dose” why not a “limit exposure”? Are there ever reasonable circumstances/ practical resource constraints that justify this approach?

15. All • SHOULD testing to the MTD and establishing target organ toxicities be a desired goal of IND enabling and product registration studies? • Is testing to the MTD ALWAYS necessary to assure human safety? • SHOULD we EVER dose our animals past the MTD to induce more severe toxicities? • SHOULD we ALWAYS dose our animals past the MTD to induce more severe toxicities? • Does a safety margin based approach, in the absence of demonstrating a MTD, EVER make sense? • WHAT SHOULD THE NEXT STEPS BE?