Nonclinical Perspective on Initiating Phase 1 Studies for Small Molecular Weight Compounds

1. Nonclinical Perspective on Initiating Phase 1 Studies for Small Molecular Weight Compounds John K. Leighton, PH.D., DABT Supervisory Pharmacologist Division of Drug Oncology Products OODP/CDER/FDA

2. Overview • Nonclinical studies conducted for drug development • Historical perspective • Current recommendations for nonclinical studies for drug oncology products to initiate a first in human study • General toxicology • Schedule, duration, design, test species, GLP • Combinations of drugs • Pharmacology studies • preIND meetings • Deficiencies in nonclinical data potentially leading to a clinical hold

3. Nonclinical Development of Anticancer Drugs for Patients with Advanced Disease • Drugs/biologics are often used to treat life-threatening malignancies. • Side effects of chemotherapy are often less threatening to a patient than their underlying disease. • Nonclinical testing of oncology drugs for patients with life-threatening disease therefore differs from non-oncology drugs. • Follow ICH M3 for others

4. Nonclinical Studies Conducted in Drug Development • Pharmacology/Pharmacodynamics • Pharmacokinetics • Safety Pharmacology • Toxicology • Genetic Toxicology • Reproductive Toxicology • Carcinogenicity

5. Historical Perspective- 1980s nonclinical Studies for Cytotoxic Oncology Drugs • ODAC Subcommittee meetings in July and Oct, 1979 • Recommendations presented by FDA to ODAC May, 1982 • Mice: • LD10 on Dx1 and Dx5 schedules • Include 28 day recovery period • Dogs: • Assess safety of 1/10th LD10 on Dx1 and Dx5 schedules • Second dose should produce overt toxicity • include 60 day observation period • Histopathology recommended but not required; submit before phase 2 • Requirement for additional testing prior to phase 1 as necessary.

7. Purpose of Nonclinical IND Safety Studies • Safety of First in Human assessed by studies of pharmacodynamics, pharmacokinetics, toxicity and their relationships • Conduct toxicology studies in 2 species • Goal • Identify starting dose • Identify organ toxicities and reversibility • Guide dosing regimens and escalation schemes • Design • Follow standard protocols • Use clinical schedule, route, and formulation • Conduct according to GLP

8. Schedule of Nonclinical Studies Relative to Proposed Phase 1 Trial

9. 21 CFR Part 58 • Conduct pivotal studies according to Good Laboratory Practices (GLPs) • a set of organizational requirements to assure generation of high quality, reliable safety data • E.g., analysis of test article, testing of dosing solutions, qualifications of study personnel, record keeping, etc. • If not conducted according to GLP, need to explain study deviations from GLP and discuss their impact on study outcome • Draft, unaudited studies are acceptable for initiation of IND, but final, QA’ed study reports should be available within 120 days of initiation of IND (stamp date)

11. Duration of Nonclinical Studies Relative to Proposed Phase 1 Trial In the absence of documented disease progression and acceptable toxicity: • Drugs administered on an intermittent schedule • Multiple cycles acceptable • Therapeutics administered continuously • Continuous dosing for 28 days in rodents and nonrodents is generally sufficient to support trials continuing past 28 days • Rationale • Longer duration studies may lead to unacceptable start dose • Shorter duration studies do not adequately predict potential toxicities • Plasma half-life indicates little accumulation for most drugs or that steady state is reached quickly • Approach depends upon a clinical assessment of safety at the appropriate interval to support continued dosing in the individual patient beyond duration of toxicological support

12. Combination of Drugs • FDA Draft Guidance: Nonclinical Safety Evaluation of Drug Combinations • Oncology perspective • Toxicology studies of the combination may not be necessary for patients with advanced disease, if: • No pharmacokinetic, metabolic, or pharmacodynamic synergy is expected. • Drugs are not packaged as a combination. • All components of the combination are well studied individually. • Information from pharmacology studies may be useful to assess whether an additional toxicology study is necessary

13. Pharmacology Studies • Pharmacological activity assessed by models of disease are generally of low relevance to safety (IND) and efficacy (NDA) decisions • Efficacy in vitro and in vivo from nonclinical studies may not dependably predict clinical efficacy • Heterogeneity of disease • Interspecies differences in ADME • Role of immune system, etc. • Pharmacology studies are useful for: • Assessing an appropriate schedule (daily, weekly, q 3 weeks) • Justification of drug combination • Understanding effect at molecular target • Examine receptor specificity • Identifying and evaluating biomarkers

14. Pre IND Meetings • Highly recommended, particularly for unique products/questions • Purpose is to get feedback from the Division as to the appropriateness of the initial development plan • Not a full data review • Generally study synopsis submitted, or studies are still in planning • No protocol concurrence, including start dose – this is a review issue when the IND is submitted

15. Deficiencies in Nonclinical Data Leading to Clinical Holds • Factors (usually more than one) involved in clinical holds • Inadequate study design • Standard protocols not followed • Appropriate endpoints not adequately assessed • Inadequate number of animals to assess STD10 • Study reports not organized in a manner for review or were not provided • Data provided in a single test species • Non GLP studies and deviations not discussed • No data to support the intended route of administration • Studies of inadequate duration to support clinical trial • Commercial and investigator-initiated INDs involved • Alternative to avoid clinical hold is the usual approach

16. Summary • Conduct two pivotal toxicology studies using the same schedule, formulation, and route as the proposed clinical trial • Conduct a rodent study that identifies life-threatening doses. • Conduct a non-rodent study that confirms non-life threatening doses have been identified. • Studies of 28 days should be provided for continuous administration • Studies of one or several administrations, depending upon the schedule for intermittent schedules • Provide full histopathology in one of those studies. • Conduct other studies as needed • Multiple cycles/continuous treatment generally acceptable, assuming acceptable safety profile in the clinical setting • PreIND meetings with sponsors are encouraged to discuss problem areas and provide alternative pathways to initiating the phase 1 trial. • Most potential clinical holds resolved through discussions with sponsor.

17. Thank You