Nonclinical Perspective on Initiating Phase 1 Studies for Small Molecular

Weight Compounds

John K. Leighton, PH.D., DABTSupervisory PharmacologistDivision of Drug Oncology ProductsOODP/CDER/FDA

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

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

Nonclinical Studies Conducted in Drug Development

Pharmacology/Pharmacodynamics Pharmacokinetics Safety Pharmacology Toxicology Genetic Toxicology Reproductive Toxicology Carcinogenicity

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.

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

Schedule of Nonclinical Studies Relative to Proposed Phase 1 Trial

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)

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

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

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

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

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

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.

Thank You