Transcript Toxicology in Drug Development

Toxicology in Drug Development
Lynnda Reid, Ph.D.
Pharmacology/Toxicology Reviewer
Center for Drug Evaluation and Research (CDER)
Rafael Ponce, Ph.D., DABT
Senior Scientist
ZymoGenetics, Inc.
Outline
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Regulatory Overview
 Drug/biologic development process
 Resources
 Questions (and answers?)
Parties involved in Drug Development
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FDA
Sponsor
Contract Labs
Clinical Sites
Manufacturing Sites
Consultants
Other…
Sponsors
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Pharmaceutical/Biotechnology Firms
Practicing Physicians and Dentists
Academic Institutions
NIH
Other
The FDA
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Center for Drug Evaluation and Research (CDER)
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Center for Biologic Evaluation and Research (CBER)
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Center for Devices and Radiological Health (CDRH)
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Center for Veterinary Medicine (CVM)
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Center for Food Safety and Applied Nutrition (CFSAN)
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National Center for Toxicological Research (NCTR)
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Office of Regulatory Affairs
Drug
Center for Drug Evaluation and Research (CDER)
– Conventional synthetic chemicals
– Antibiotics, natural and recombinant hormones
– Novel drugs such as antisense oligonucleotides
and synthetic peptides (< 40 AA)
Biologic
Center for Biologics Evaluation and Research (CBER)
– Blood and blood products
– Vaccines and allergenics
– Conventional biotechnology-derived products
– recombinant proteins, monoclonal antibodies, antigenic peptides
– Novel biotechnology-derived products
– cellular or gene therapies, tissue-engineered therapies
– DNA vaccines, xenotransplantation
Proteins
Small Molecules
Drug substance
Heterogenous mixture
Broad specs during development
Specs may change
Drug product
Usually IV or SC
Single entity; high chemical
purity
Exception: racemic mixtures
Specs well-defined early
Usually oral
Impurities
Difficult to standardize
Standards well established
Bridging
requirements
Significant for drug substance
Bioequivalence procedures
Biological activity
May mimic naturally occurring
molecules
Primary MOT
Predictive based on MOA
Variable significance
Less predictive
Chronic Toxicity
Lack of models; species specificity
and antigenicity
Models sometimes relevant
Impurities
Toxicity not a major issue, may
impact immunogenicity
May be significant
Purity standards well
established
Nonspecificity
Usually significant
Drug-drug interaction
FDA Organizational Chart (Partial)
FDA
Center for Devices and Radiological Health
Center for Biologics Evaluation and Research
Kathryn Zoon, PhD
Center for Drug Evaluations and Research
Office of Vaccines Research and Review
Karen Midthun, MD
Office of Therapeutics Research and Review
Jay Siegal, MD
Office of Blood Research and Review
Jay Epstein, MD
DIvision of Therapeutic Proteins
Amy Rosenburg, MD
Division of Monoclonal Antibodies
Katy Stein, PhD
Division of Clinical Trial Design and Analysis
Karen Weiss, MD
DIvision of Cell and Gene Therapy
Phillip Noguchi, MD
Division of Application Review and Processing
Glen Jones, PhD
CDER Review Divisions
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Anesthetic, Critical Care,
and Addiction
Anti-Viral
Anti-Infective
Anti-Inflammatory,
Analgesic, and Ophthalmic
Cardio-Renal
Dermatologic and Dental
Gastrointestinal and
Coagulation
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Metabolic and Endocrine
 Medical Imaging and
Radiopharmaceutical
 Neuropharmacological
 Oncology
 Over-the-Counter
 Pulmonary
 Reproductive and Urologic
 Special Pathogens and
Immunologic
What Types of Nonclinical
Studies Should Sponsors Conduct?
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ICH (International Conference on Harmonization) Guidelines
 Drug class specific guidance
Generaltoxicity?
Toxicology?
 FDA Consultations
General
Genotoxicity?
Genotoxicity?
Carcinogenicity?
Carcinogenicity?
Guidance, Guideline, or Regulation
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A guidance and a guideline are the same.
 Provide direction and a course(s) of action
 Not legally binding
 Public comments are considered, but responses are optional
Regulation
 A rule or a law by which conduct is governed
 Legally binding
 Published through notice and rulemaking, e.g., CRF, FR
 Substantive public comments MUST be responded to in the
preamble of the final rule
The ICH Process
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Established in 1990 to improve efficiency of the new drug
approval process in Europe, Japan, and the United States
 Regulators and industry representatives from all three
regions participated
 The harmonized topics are safety, quality, and efficacy
ICH Nonclinical Guidance Topics
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Reproductive toxicology (3)
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Genotoxicity (2)
Timing of nonclinical safety
studies
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Carcinogenicity (4)
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Phase 1 studies (2)
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Pharmacokinetics
Duration of chronic toxicity
testing
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Safety Pharmacology
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Biotechnology products
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Acute and Repeat dose toxicity
studies (3)
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Impurities & Stereorisomers (4)
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Toxicokinetics
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Nonclinical safety studies for
pharmaceuticals
FDA Nonclinical Guidance Topics
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Published Guidance Documents:
– Content and Format of INDs for Phase 1 Studies
– Single Dose Acute Toxicity Testing for Pharmaceuticals
– Product Specific guidance
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anti-virals
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vaginal contraceptives and STD preventatives
– Special Protocol Assessment
– Submission in Electronic Format (2)
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Published Draft Guidances:
– Carcinogenicity study protocols
– Immunotoxicology
– Photosafety testing
– Statistical evaluation of carcinogenicity studies
Types of Toxicology Studies Recommended
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General Toxicology
– acute and repeat dose toxicology studies
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Special Toxicology Studies
– local irritation studies, e.g., site specific, ocular
– hypersensitivity studies for inhalation and dermal drug products
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Reproductive and Developmental Toxicology Studies
– male and female fertility
– embryonic and fetal development
– post-natal reproductive and developmental effects
Impact of Nonclinical Studies on Drug
Development
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Setting Initial Doses in Humans
Identification of Possible Adverse Effects
Identification of Reversible vs Irreversible Effects
Identification of Useful Biomarkers for Monitoring Toxicity
during Clinical Trials
Drug Labeling
Drug Development Process
PRELEAD
IND
Investigational New Drug
NDA
New Drug Application
Research
“Discovery”
Development
Toxicology Testing Process
PRELEAD
IND
NDA/BLA
Discovery
Development
Nonclinical tox studies in animals
P1
P2
P3
Clinical trials
What are Phase 1, 2, and 3 Trials?
Phase 1:
Safety and pharmacokinetics
 Generally 20 to 80 subjects
 Closely controlled
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Phase 2:
Efficacy and safety
 Usually no more than
several hundred subjects
 Closely controlled
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Phase 3:
Efficacy and safety
 Several hundred to several
thousand subjects
 Controlled and uncontrolled
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Nonclinical Information Flow
In vitro/Animal Models
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Hypothesis testing
 Mechanism of
action
 Safety assessment
 Develop surrogate
markers
 ADME/PK
Application
Trial
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Potential for effect
 Toxicity profile
 Dose/regimen
 Route of administration
J. Lipani, 1998
Contract Research Organizations
• Formulation/Manufacture/Fill and Finish
• Metabolism/distribution (ADME/PK)
• In vitro
– Activity/high throughput screening
– Toxicity (non-GLP and GLP)
• In vivo
– Research
– Model development
– Proof of concept/efficacy
– Development
– GLP toxicology testing for regulatory submission
Good Laboratory Practice (GLP) for Nonclinical
Laboratory Studies
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21 CFR Part 58
Regulatory guidelines for conduct of toxicology (safety)
studies in support of regulatory submission
Guidelines “intended to assure the quality and integrity of
the safety data…”
GLP Overview
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Cover food additives, human and animal drugs, biologics,
devices, and electronics
Define terms
Define responsibility of facility management, study
director, quality assurance unit
Describe facility requirements
– Animal care, test/control articles, lab operations,
specimen and data storage, equipment, SOPs, records,
etc.
Toxicology CRO
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Independent research facility
Specialized facility designed to meet
– Animal care requirements (Dept. of Agriculture)
– Quarantine requirements (CDC)
– Facility/study GLP requirements (US FDA)
– Safety and health regulations (OSHA, state, region)
Provide general or specialized testing
– Discovery
– Development (GLP toxicology testing for regulatory
submission)
Study Director
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Responsible to Sponsor, Facility, FDA
 Single point of control
 Responsible for overall technical conduct of study
 Interprets, analyzes, documents, and reports results
SD does not necessarily conduct all aspects of these activities,
but has ultimate responsibility
Study Director
• Often, but not always, a toxicologist
• Often, but not always, MS or PhD (depends on
experience)
• DABT or equivalent a plus – marketable
Types of Nonclinical Studies Reviewed by FDA
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Basic pharmacology
– primary and secondary mechanisms of action
– nonclinical efficacy studies
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Safety pharmacology
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Pharmacokinetics
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Toxicology
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Genotoxicology
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Carcinogenicity
What Does FDA Expect from Nonclinical Studies?
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Pharmacology
– proposed mechanism of action
– identification of secondary pharmacologic effects
– Proof of Concept studies for serious indications
 Safety Pharmacology
– effects on neurological, cardiovascular, pulmonary,
renal, and gastrointestinal systems
– abuse liability
What Does FDA Expect from Nonclinical Studies?
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Pharmacokinetics
– comparison of ADME in species used for toxicology
studies
– identification of bioaccumulation potential
– identification of potential differences in gender
– generation of PK parameters, e.g., Cmax, Tmax,
AUC(o-inf.), half life
What Does FDA Expect
in General Toxicology Studies?
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Acute and repeat toxicology studies in two species
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Duration of repeat dose nonclinical studies should be at least
equal or greater than the duration of the proposed clinical study
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A control and at least 3 drug concentrations
– identification of the NOAEL and MTD
– identify shape of the dose-response curve
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Doses/systemic exposure should exceed clinical dose/exposure
What Does FDA Expect
in General Toxicology Studies?
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Formulation should be the same as the clinical formulation
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Route of exposure:
– should be the same as clinical route
– additional routes of exposure may be needed to achieve systemic toxicity
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Histopathology examination of all animals and standard tissues
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Lymphoproliferative tissues should be assessed for unintended effects on the
immune system
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Toxicokinetic information
Timing of Nonclinical Studies - Phase 1
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Prior to “First Time in Humans”
– safety pharmacology
– pharmacokinetics/toxicokinetics (exposure data)
– single dose toxicity studies in 2 mammalian species
– expanded acute or repeat dose toxicity studies in a rodent
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and a nonrodent
local tolerance
in vitro evaluation of mutations and chromosomal damage
hypersensitivity for inhaled and dermal drugs
teratogenicity studies
Timing of Nonclinical Studies - Phase 1/2
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Phase 1-2 Clinical Trials
– repeat dose toxicity studies of appropriate length
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Phase 2 Clinical Trials
– complete genotoxicity assessment (in vivo and in vitro)
– repeat dose toxicity studies of appropriate length
Timing of Nonclinical Studies - Phase 3
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Phase 3 Clinical Trials
– repeat dose toxicity studies of appropriate length
– male and female fertility
– post-natal development
Acute dose range finding in rats
• 10 rats (5M/5F)
• Control + 4 Dose groups
• Single exposure, IV
• Monitor clinical observations, food consumption, serum chemistry,
hematology, coagulation over 7 days (+ baseline)
• Serum PK
• Gross observations, histopathology on major organs and tissues
Chronic GLP Tox in Cynos
• 32 cynomolgus nonhuman primates (16M/16F)
• Control (5M/5F), Low (3M/3F), Med (3M/3F), High (5M/5F)
• Repeated exposure over 4 weeks, Sac 3M/3F, 4 week recovery
• Monitor clinical observations, food consumption, serum chemistry,
hematology, coagulation over 56 days (+ baseline)
• Monitor PK, antibody formation
• Gross observations, histopathology on major organs and tissues
• Include other clinical endpoints as appropriate (EKG, ophthalmology, BP)
• Perform specialty testing on tissues/blood (immunohistochemistry, FACS)
Questions Asked by
Review Pharmacologist/Toxicologist
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Validity of study design:
– Was the appropriate animal model used?
– Were dose(s) and duration sufficient to
support the proposed clinical study or
labeling?
– Were adequate systemic exposures
achieved?
– Was the route of administration
relevant to clinical used?
More Questions:
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Did the test system exhibit any effects?
Were the effects treatment-related?
Are the effects biologically significant?
Are the effects reversible?
Are the effects clinically relevant?
Can the effects be monitored clinically?
Career Opportunities for FDA
Toxicologist
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Pre-IND Consulting
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Review nonclinical protocols
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Serve on intra- and inter-agency expert working
committees
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Generate guidance and policy documents
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Professional development
For Online Information on FDA
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http://www.fda.gov/
– CDER News
– Guidelines
– ICH Documents
– Employment Opportunities