Pre-clinical and Clinical Regulatory Overview Albert DeFelice, Ph.D. Supervisory Pharmacologist Division of Cardio-Renal Drug Products Office of Drug Evaluation I Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration Public Health Service Department of Health and Human Services Disclaimer: Views and opinions expressed are personal, and do not necessarily reflect those of the Food and Drug Administration or the Public Health Service

Outline II. FDA Model of Serial Evaluation: I. New Drug Review Process: First Principles II. FDA Model of Serial Evaluation: Investigational New Drug (IND) .... Pre-Clinical studies .... Clinical Trials Phases I  IV New Drug Application (NDA) Post-Marketing Surveillance III. Life Science Reviewers: Roles/Opportunities Pharmacology Physiology Toxicology Pathology Molecular Biology Chemistry Statistical Science Veterinary Medicine Biopharmaceutics (Pharm. D.)

Requirements for Drug Approval 1938 FDA Drug Law Amendment: - Requires drug safety prior to marketing 1962 Kefauver-Harris Drug Amendment: - Additional requirement of “adequate and well- controlled studies” CFR 201.56(a): - The labeling shall contain a summary of essential scientific information needed for safe and effective use of drug

FDA:First Principles …. Empiricism …. That subjects be exposed to least possible risk - Permissive/supportive animal safety testing - Qualified and Experienced Investigators - Oversight by Institution Review Board (IRB) - Informed consent: full disclosure of potential risks. …. Empiricism - Deliberate sequence of controlled clinical studies - Timely and sequential reliance on animal data for potential irreversible, not readily apparent toxicity (mutagenicity; carcinogenicity; reproductive toxicity) - Post-marketing surveillance; registries; epidemiology

Phases of Drug Development Discovery /Screening/Pre-Clinical IND: - Pre-Clinical studies - Clinical Studies - Phase One: Pharmacological Studies - Phase Two: Preliminary Clinical Efficacy - Phase Three: Extensive Clinical trials …...Adequate/Well-controlled NDA Review Post-Marketing

Discovery/Screening/Pre-Clinical Testing of promising compounds in animals - is the compound biologically active? Pharmacodynamics (in vitro; in vivo) - is the compound safe? Safety Pharmacology and Toxicity Studies - what is the dose-response for the activity and safety? Pharmacokinetic studies (ADME)

IND Submission to FDA Investigational New Drug Application (IND) Required for drug administration to humans in U.S. Contains results of animal testing, and identifies a safe dose for initial human exposure IND effective if FDA does not disapprove within 30 days

Clinical Trials:Phase I Purpose: …. Pharmacologic profiling …. Safe dose escalation to pharmacodynamic activity and/or toxicity Subjects: …. Normal volunteers (except potentially toxic drugs) …. Desireable / mandatory to use patients …. 20-100 subjects, generally Setting: …. No concomitant therapy unless mandatory …. 2-4 weeks washout of prior drugs …. Start dose based on animal NOAEL …. Prolonged placebo-controlled (4-6 weeks)

Phase I (Continued): Pharmacokinetics and Metabolism: …. early correlations of activity or safety with exposure to inform design of early Phase II trials in patients Additional Considerations: …. ECG important (non-cardiovascular drugs can affect ventricular repolarization) …. Special lab tests/monitoring: .. as alerted by animal target organs of toxicity .. as alerted by toxicity of structurally or pharmacologically- related drugs.

Clinical Trials Phase II: Preliminary Efficacy Purpose: …. Explore early efficacy and safety in patients - dose-selection/interval - use of surrogates …. Early ADME data to guide phase III trial design Subjects: …. Ordinarily only targeted disease/condition. …. Late phase II patients may have disease / therapy in addition to targeted …. Seldom more than 200 patient-subjects.

Clinical Trials Phase III Large controlled trials in patients with targeted disease Clinically - meaningful endpoints Trial design planned with FDA …. Adequate and Well-controlled Subjects: …. Typically two or more multi-center trials comprised of several thousand patient-subjects .. Rigorous exclusion/inclusion criteria .. Placebo and/or active drug-controlled design Considerations: …. Placebo - controlled design least ambiguous …. Ethics of placebo-controlled studies? …. Drug-Drug interactions

Adequate and Well -Controlled Trial (21CFR 314.126) Clear statement of objectives Summary of methods of analysis Precise description of study design - valid control - duration of treatment - sample size calculations - adequate inclusion/exclusion criteria - well-defined and appropriate efficacy, safety markers

(New Drug Application) Submission of NDA (New Drug Application) Contains all Information known about drug, chemical, pre-clinical, and clinical - typically 200-500 volumes of material Review by FDA takes 6 to 12 months - 6 months for ‘priority review’ - 10-12 months for ‘standard review’

NDA Review Team Medical Officer Chemistry Pharmacology/Toxicology - Assesses drug safety and efficacy Chemistry - Assesses drug purity, stability, sterility Pharmacology/Toxicology - Assesses pre-clinical pharmacologic, safety , and PK data Statistics - Assesses drug efficacy ( prospectively defined end-points) Biopharmaceutics - Assesses drug metabolism and drug-drug interactions Project Management - Coordination & industry liaison

Clinical Trials:Phase IV (Post marketing ) Purpose: …. Further elucidation of adverse events and/or pharmacology …. Large scale /long-term assessment of morbidity and mortality …. Further testing of drugs which - in interest of public health - were released prior to full assessment of safety …. Special population (pediatric; geriatric)

Pre-clinical Support for Phase I-III Clinical Trials1 Safety pharmacology (CNS; CV; Respiratory) Acute/Sub acute Toxicity Initial genotoxicity Initial reproductive toxicology Local tolerance Pharmacokinetic Phase II/III: Completed battery of Genotoxicity Completed battery Reproductive toxicity (male/female) Extended repeated dose toxicity Extended pharmacokinetic studies Phase III: Chronically used drugs: Chronic toxicity (rodent; non-rodent) Carcinogenicity Supplemental studies (special safety concerns, as alerted) 1 - M3 Guidance for Industry: Non-clinical Safety Studies for the Conduct of Human Clinical trials for Pharmaceuticals (July 1997 ICH)

Research serving new drug evaluation: Opportunities for Ph.D. Health Scientists at FDA: New drug evaluation: … Review and evaluation of animal pharmacology and toxicology data: risk assessment/projection … Group adjudication of critical animal safety issues … Writing guidances (design /interpretation of studies) … Professional development (continuing education ) Research serving new drug evaluation: … Prospective applied animal research … Retrospective regulatory research (animal and clinical) [FDA data archives are unique and extensive]

Published Guidances for FDA Pharmacologists/Industry # Biotechnology Impurities/Stereoisomers (5) Excipients Botanicals Phase I Trials/Starting Dose (3) Section 505(b-2) Efficacy Carcinogenicity (6) Timing of Studies (2) Pediatrics Special protocols Immunotoxicity Pharmacokinetics Reproductive Toxicity (5) Metabolism Photosafety (2) Electronic Submission Safety Pharmacology (2) Genotoxicity (2) Toxicokinetics Labeling Single/Repeat Dose Toxicity (3) # - Co-Authored by Pharm/Tox reviewers (FDA Working Groups & ICH) ( ) - There are multiple guidances for certain topics

Division of Cardio-Renal Drug Products: Director: Douglas C. Throckmorton, M.D. Professional Staff: M.D. (Medical Officers): 12 Ph.D.; Pharm.D; DVM: 31 Pathologists: 2 Physiologists: 2 Pharmacologist/Toxicologists: 11 Molecular Biologists: 2 Veterinarians: 3 Biopharmaceuticists: 7 Biostatisticians: 4 Chemists: 10 IT Specialist: 1 Consumer Safety Officers: 6