1. 1 Nonclinical Perspective on Initiating Phase 1 Studies for Biological Oncology Products Martin D. Green, Ph.D. Supervisory Pharmacologist DBOP/OODP/CDER

2. 2 Outline and Purpose of Presentation Discuss the review of nonclinical safety data for an initial IND Present results from an internal review of initial INDs for nonclinical information and clinical hold decisions Currently developing new guidance for nonclinical standards for biological oncology –New molecular structures –New approaches to treatment of patients with cancer Presentation today –Assist in gaining comment on revisions to nonclinical recommendations for safety testing for biological oncology products and in particular on the question of the duration of nonclinical studies relative to clinical studies

3. 3 Sources for Information to Guide Reviewers and Assist Sponsors ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals –Relevant animal model –Typically relying on a single species ICH M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals –Timing and duration –Early stages should be 1 for 1 in terms of duration CBER Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use –Tissue cross-reactivity studies –In some exceptional cases this information may be the sole source of nonclinical safety data Pre-INDs –Outline of nonclinical toxicity studies or summary results often discussed and include comments on duration and frequency of dosing Provides a broad and flexible system

4. 4 Process of Evaluating Nonclinical Data for Scientific and Regulatory Decisions Consider selectivity and specificity of biological product –Molecular targeting (site and affinity of binding sites) –Non-specific effects (restricted or unrestricted access to tissue sites) Evaluate nonclinical data in terms of the proposed clinical study. Capability of addressing the safety concerns –Numbers of animals (often varies with species, e.g., non-human primates) –Quantitative and quality of aspects of endpoints (during dosing and recovery) –Range of doses (clinical relevant – safe dose vs. one that avoids toxicity) –Duration frequency of dosing (relative to proposed clinical study) –Unique aspects of the clinical situation relative to nonclinical testing Special conditions, e.g., wound healing model for anti-angiogenesis biologicals

5. 5 Process of Evaluating Nonclinical Data for Scientific and Regulatory Decisions Analysis and extrapolation –Was data adequate in terms of route of administration, dosing regimen and clinical population? –What concerns remained unaddressed? –What are the consequences of failing to obtain the additional data? Means of bridging the gap –Altering the starting dose –Modifying the dose escalation scheme –Increasing monitoring –Changing the inclusion and exclusion criteria Primary objective is to determine whether the clinical study can go forward safely with the available data

6. 6 Toxicology Study Primary means of assessing safety prior to clinical experience – Widely understood industrial standards –Comprehensive approach examining various levels of effect –Inter-relationship between frequency of dosing, dose (systemic exposure) and expression of toxicity –Monitoring –Reversibility Represents a resource issue for some development plans often in terms of time Limitations –Development of anti-product antibodies in test animals Neutralization, carrier formation, blocking Changes in pharmacokinetics and access to various organs –In rare instances human unique no available animal model –Differences in disposition based on receptor expression and extrapolation of pharmacokinetics (allometric principles)

7. 7 Factors Considered in Adequacy of Nonclinical Studies to Support Clinical Trials Dose –Sufficiently high to reveal potential adverse effect or –Provide sufficient multiples of the intended clinical dose Adequate number and timing of doses –Pharmacokinetics – long half-life, accumulation, steady-state, access to deep compartments Clinical dosing regimens are typically accumulative and require long periods of time to achieve steady-state conditions –Receptor modulation – up- or down-regulation, e.g. IL12 Adequate duration to express toxicities –Immediate acting (direct cell lysis or death, e.g. ricin conjugates) –Longer acting Effects on cellular pools with slow turnover (e.g. skin) or Physiological reserves (e.g. immune ablation and susceptibility to infection)

8. 8 IND Database Time period of July 2001 through Nov 2005 Continuous series of 51 INDs INDs were included if –NME –Proposed as anti-tumor agents INDs were excluded if –Single patient INDs, Emergency INDs –Radiolabeled therapeutic –Approved products –Diagnostic or supportive use only

9. 9 Mechanisms of Action Represented in the database –Blockade ligand binding –Complement dependent cytotoxicity –Antibody dependent cell-mediated cytotoxicity –Apoptosis induction –Disruption of signaling –Inhibition of angiogenesis –Toxin-mediated killing –Antagonist receptor activity –Agonist receptor activity Not used as a classification for the database –Multiple potential actions –Evolving understanding

10. 10 Sources of Data Analyzed in the data base Pharmacology and Medical Reviews Official correspondence –Divisional files –Biological Information Management System (BIMS) Original Submissions –As available at the time the original IND was submitted or within the 30 day period of review prior to a final decision

11. 11 NMEs 51 NME products Products comprising the data base –Monoclonal antibodies, N = 37 (73%) –Fusion proteins, N = 8 (16%) –Cytokines, N = 2 (4%) –Other, N = 4 (8%) Data elements –Nonclinical study duration (estimate of exposure) –Frequency of nonclinical dosing (most often to match clinical dosing regimen but in some few cases to make-up for duration) –Issues related to clinical holds Safety concerns based on pharmacology and toxicology data Proposed and actual clinical holds

12. 12 Nonclinical Toxicology Studies by Study Duration Submitted in Initial INDs Nonclinical studies of 1 week to 4 weeks –41% of initial INDs –Most commonly performed nonclinical study Nonclinical studies >4 weeks to 3 months –27% of initial INDs Nonclinical studies <1 week –25% of initial INDs Nonclinical studies >3 months –4% of initial INDs No toxicity studies performed –4% of initial INDs

13. 13 Duration Nonclinical -Toxicology Study vs. Clinical Study Duration ratio –Defined as the days of the nonclinical dosing divided by the proposed days of clinical dosing –Calendar days –Does not consider number of doses administered in the period to time Mean 4.5 –95% Confidence Interval of 8.64 - 0.42 Average initial INDs contained 4 to 5 times more nonclinical days of exposure to biological product compared to proposed clinical dosing Wide range often reflects intended duration of clinical study

14. 14 Number of Doses - Nonclinical Toxicology Study vs. Clinical Study Number of doses ratio –Defined as the number of nonclinical doses divided by number of proposed clinical doses –Nonclinical dosing regimen tended to match proposed clinical dosing regimen Mean of 1.6 Range 0.27 to 7 Nonclinical studies on averaged closely approximated the frequency of dosing in the proposed clinical study Higher dosing ratio’s were not problematic Lower dosing ratio’s were often regarded as under dosed relative to the clinical dosing regimen –Animals often have increased rates of clearance –Production of anti-product antibodies was not a confounding variable in this series –Formulations in nonclinical studies were similar to those proposed clinically

15. 15 Clinical Hold Decisions A majority of potential hold concerns involved chemistry (CMC), clinical and/or pharmacology/toxicology were resolved prior to 30 day date –Additional information provided by sponsor –Modification of clinical protocol Increased monitoring Staggering of dose cohorts Inclusion and exclusion criteria Dose escalation scheme

16. 16 Continuation of Clinical Dosing Beyond Nonclinical Testing Continuation allowed based on –Acceptability of toxicities Reversible Degree of potential harm clinically manageable –Ability to monitor Occurred in approximately 90% of IND when requested

17. 17 Proposed Clinical Holds and Pharmacology and Toxicology Concerns Involved 9 INDs –Less than half of the holds were resolved in discussions and modifications with the sponsor during review cycle –Four involved adequacy of duration –Often pharmacology and toxicology concerns accompanied concerns of other disciplines, e.g. clinical aspects of study or issues related to chemistry (CMC)

18. 18 Examples of Safety Concerns Related to Pharmacology and Toxicology in Proposed Clinical Holds Lack of stability of investigational biological product used in the toxicity study Failure to demonstrate anticipated binding pattern in the human tissue cross-reactivity study Potential clinical risk revealed by animal findings and inability to provide adequate monitoring and provide emergency care in the clinical study Preclinical data suggesting tumor stimulation

19. 19 Actual Divisional Holds Of 13 of the actual clinical holds, 6 involved pharmacology and toxicology issues Four were primarily based on concerns related to pharmacology and toxicology Three of these involved duration –Their average duration ratio was 0.3 –These INDs used frequency of dosing in the nonclinical studies approximated the proposed clinical dosing –Involved clinical proposals for continuous dosing

20. 20 Examples of Safety Concerns Related to Pharmacology and Toxicology - Actual Clinical Holds Example A – 3 month toxicology study –Failure to use a relevant animal species Toxicity study considered invalid –Human tissue cross-reactivity study – failed to demonstrate anticipated binding pattern Technically unacceptable Example B – 2 month; concern based on member of class exhibiting toxicity at times >2 mo; product contamination issue Concerns based on the relationship of toxicity and duration are subject of the subsequent presentation

21. 21 Conclusion and Summary Assessing clinical risk from nonclinical studies –Evolving over time –Increasingly complex Current approach to assessing of safety from nonclinical studies –Flexible and broad standards –Based on general guidances for biotechnology products In the future there will be a nonclinical guidance on biological oncology products

22. 22 Conclusion and Summary Review of recently submitted biologic INDs –Regarding clinical holds for initial INDs, toxicity testing was a component in approximately 50% of the holds and a major component in approximately 30% of the holds –In approximately 90% of clinical studies allowing continuous dosing was contingent on Clinical population Actual and perceived risks Acquisition of additional nonclinical data concurrent with the clinical study