1. 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

2. 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.)

3. 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 (a):
- The labeling shall contain a summary of
essential scientific information needed for safe
and effective use of drug

4. 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

5. 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

6. 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)

7. 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

8. 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
… 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)

9. 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.

10. 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.

11. 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

12. Adequate and Well -Controlled Trial
(21CFR )
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

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

14. 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

15. 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)

16. 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)

17. 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]

18. 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

19. 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