Toxicology in Drug Development Lynnda Reid, Ph.D

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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.

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Outline

• Regulatory Overview
• Drug/biologic development process
• Resources
• Questions (and answers?)

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Parties involved in Drug Development

• FDA
• Sponsor
• Contract Labs
• Clinical Sites
• Manufacturing Sites
• Consultants
• Other

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Sponsors

• Pharmaceutical/Biotechnology Firms
• Practicing Physicians and Dentists
• Academic Institutions
• NIH
• Other

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The FDA

• Center for Drug Evaluation and Research (CDER)
• Center for Biologic Evaluation and Research
  (CBER)
• Center for Devices and Radiological Health (CDRH)
• Center for Veterinary Medicine (CVM)
• Center for Food Safety and Applied Nutrition
  (CFSAN)
• National Center for Toxicological Research (NCTR)
• Office of Regulatory Affairs

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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 (lt 40 AA)

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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

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Proteins Small Molecules
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CDER Review Divisions

• Metabolic and Endocrine
• Medical Imaging and Radiopharmaceutical
• Neuropharmacological
• Oncology
• Over-the-Counter
• Pulmonary
• Reproductive and Urologic
• Special Pathogens and Immunologic

• 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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What Types of Nonclinical Studies Should
Sponsors Conduct?

• ICH (International Conference on Harmonization)
  Guidelines
• Drug class specific guidance
• FDA Consultations

General toxicity? Genotoxicity?
Carcinogenicity?
General Toxicology? Genotoxicity? Carcinogenicity
?
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Guidance, Guideline, or Regulation

• 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

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The ICH Process

• 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

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ICH Nonclinical Guidance Topics

• Reproductive toxicology (3)
• Genotoxicity (2)
• Carcinogenicity (4)
• Duration of chronic toxicity testing
• Biotechnology products
• Impurities Stereorisomers (4)

• Nonclinical safety studies for pharmaceuticals
• Timing of nonclinical safety studies
• Phase 1 studies (2)
• Pharmacokinetics
• Safety Pharmacology
• Acute and Repeat dose toxicity studies (3)
• Toxicokinetics

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FDA Nonclinical Guidance Topics

• Published Guidance Documents
• Content and Format of INDs for Phase 1 Studies
• Single Dose Acute Toxicity Testing for
  Pharmaceuticals
• Product Specific guidance
• anti-virals
• vaginal contraceptives and STD preventatives
• Special Protocol Assessment
• Submission in Electronic Format (2)
• Published Draft Guidances
• Carcinogenicity study protocols
• Immunotoxicology
• Photosafety testing
• Statistical evaluation of carcinogenicity studies

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Types of Toxicology Studies Recommended

• General Toxicology
• acute and repeat dose toxicology studies
• Special Toxicology Studies
• local irritation studies, e.g., site specific,
  ocular
• hypersensitivity studies for inhalation and
  dermal drug products
• Reproductive and Developmental Toxicology Studies
• male and female fertility
• embryonic and fetal development
• post-natal reproductive and developmental effects

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Impact of Nonclinical Studies on Drug Development

• 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

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Drug Development Process
PRELEAD IND NDA
Investigational New Drug New Drug
Application
Research
Discovery
Development
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Toxicology Testing Process
PRELEAD IND NDA/BLA

Discovery
Development
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What are Phase 1, 2, and 3 Trials?

• Phase 1
• Safety and pharmacokinetics
• Generally 20 to 80 subjects
• Closely controlled

• Phase 2
• Efficacy and safety
• Usually no more than
• several hundred subjects
  
• Closely controlled

• 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 Application Trial

• Hypothesis testing
• Mechanism of action
• Safety assessment
• Develop surrogate markers
• ADME/PK

• Potential for effect
• Toxicity profile
• Dose/regimen
• Route of administration

J. Lipani, 1998
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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

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Good Laboratory Practice (GLP) for Nonclinical
Laboratory Studies

• 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

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GLP Overview

• 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.

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Toxicology CRO

• 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)

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Study Director

• 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

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Study Director

• Often, but not always, a toxicologist
• Often, but not always, MS or PhD (depends on
  experience)
• DABT or equivalent a plus marketable

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Types of Nonclinical Studies Reviewed by FDA

• Basic pharmacology
• primary and secondary mechanisms of action
• nonclinical efficacy studies
• Safety pharmacology
• Pharmacokinetics
• Toxicology
• Genotoxicology
• Carcinogenicity

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What Does FDA Expect from Nonclinical Studies?

• 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

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What Does FDA Expect from Nonclinical Studies?

• 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

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What Does FDA Expect in General Toxicology
Studies?

• Acute and repeat toxicology studies in two
  species
• Duration of repeat dose nonclinical studies
  should be at least equal or greater than the
  duration of the proposed clinical study
• A control and at least 3 drug concentrations
• identification of the NOAEL and MTD
• identify shape of the dose-response curve
• Doses/systemic exposure should exceed clinical
  dose/exposure

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What Does FDA Expect in General Toxicology
Studies?

• Formulation should be the same as the clinical
  formulation
• Route of exposure
• should be the same as clinical route
• additional routes of exposure may be needed to
  achieve systemic toxicity
• Histopathology examination of all animals and
  standard tissues
• Lymphoproliferative tissues should be assessed
  for unintended effects on the immune system
• Toxicokinetic information

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Timing of Nonclinical Studies - Phase 1

• 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 and a nonrodent
• local tolerance
• in vitro evaluation of mutations and chromosomal
  damage
• hypersensitivity for inhaled and dermal drugs
• teratogenicity studies

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Timing of Nonclinical Studies - Phase 1/2

• Phase 1-2 Clinical Trials
• repeat dose toxicity studies of appropriate
  length
• Phase 2 Clinical Trials
• complete genotoxicity assessment (in vivo and in
  vitro)
• repeat dose toxicity studies of appropriate length

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Timing of Nonclinical Studies - Phase 3

• Phase 3 Clinical Trials
• repeat dose toxicity studies of appropriate
  length
• male and female fertility
• post-natal development

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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

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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)

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Questions Asked by Review Pharmacologist/Toxicolo
gist

• 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?

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More Questions

• 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?

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Career Opportunities for FDA Toxicologist

• Pre-IND Consulting
• Review nonclinical protocols
• Serve on intra- and inter-agency expert working
  committees
• Generate guidance and policy documents
• Professional development

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For Online Information on FDA

• http//www.fda.gov/
• CDER News
• Guidelines
• ICH Documents
• Employment Opportunities