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Pre-clinical and Clinical Regulatory Overview

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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

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