RSESS SOT 2008 Great Debate MTD Is testing

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

MTD – Maximally Tolerated Dose Context for this Debate – Is NOT Rodent Carcinogenicity Studies l 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) l Alternative Viewpoints of what the MTD (and study goal) should be: l – 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

MTD – Maximally Tolerated Dose l 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…

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

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

Opposing Forces & Challenges Both Product Developers and Regulatory Authorities want target organs of toxicity defined to maximize patient safety monitoring. l BUT, often different viewpoints on the severity of toxicity that should be induced l 3 R’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. l 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. l

All 1) 2) 3) 4) 5) 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?

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

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

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

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

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

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

Jack Reynolds l Is testing to the MTD unnecessary animal use or always necessary to assure human safety ? l Can a margin of 10 X, 25 X, 50 X, 1000 X 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?

All 1) 2) 3) 4) 5) l 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?