Preclinical and Clinical Regulatory Overview

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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

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Outline 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.)
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• 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

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FDAFirst Principles . That subjects be
exposed to least possible risk - Permissive/suppo
rtive 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
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• 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

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• 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)

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• 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

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Clinical TrialsPhase 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)
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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.
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Clinical Trials Phase II Preliminary
Efficacy Purpose . Explore early efficacy
and safety in patients - dose-selection/interv
al - 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.
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• 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

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• 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
  

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• 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

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• NDA Review Team
• Medical Officer
• - 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

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Clinical TrialsPhase 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)
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Pre-clinical Support for Phase I-III Clinical
Trials1 Phase I Safety pharmacology (CNS
CV Respiratory) Acute/Sub acute
Toxicity Initial genotoxicity Initial
reproductive toxicology Local tolerance Pharmaco
kinetic 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)
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Opportunities for Ph.D. Health Scientists at
FDA New drug evaluation Review and
evaluation of animal pharmacology and
toxicology data risk assessment/projection Gr
oup 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
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Published Guidances for FDA Pharmacologists/Indus
try 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 Reprodu
ctive Toxicity (5) Metabolism Photosafety
(2) Electronic Submission Safety Pharmacology
(2) Genotoxicity (2) Toxicokinetics Labeling Sin
gle/Repeat Dose Toxicity (3) - Co-Authored by
Pharm/Tox reviewers (FDA Working Groups ICH) (
) - There are multiple guidances for certain
topics
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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 Pharma
cologist/Toxicologists 11 Molecular
Biologists 2 Veterinarians 3 Biopharmaceuticis
ts 7 Biostatisticians 4 Chemists 10 IT
Specialist 1 Consumer Safety Officers 6