1. 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.

2. Outline Regulatory Overview Drug/biologic development process
Resources
Questions (and answers?)

3. Parties involved in Drug Development
FDA
Sponsor
Contract Labs
Clinical Sites
Manufacturing Sites
Consultants
Other…

4. Sponsors Pharmaceutical/Biotechnology Firms
Practicing Physicians and Dentists
Academic Institutions
NIH
Other

5. 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

6. 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)

7. 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

8. Proteins Small Molecules

10. CDER Review Divisions Anesthetic, Critical Care, and Addiction
Anti-Viral
Anti-Infective
Anti-Inflammatory, Analgesic, and Ophthalmic
Cardio-Renal
Dermatologic and Dental
Gastrointestinal and Coagulation
Metabolic and Endocrine
Medical Imaging and Radiopharmaceutical
Neuropharmacological
Oncology
Over-the-Counter
Pulmonary
Reproductive and Urologic
Special Pathogens and Immunologic

11. 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?

12. 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

13. 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

14. ICH Nonclinical Guidance Topics
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
Reproductive toxicology (3)
Genotoxicity (2)
Carcinogenicity (4)
Duration of chronic toxicity testing
Biotechnology products
Impurities & Stereorisomers (4)

15. 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

16. 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

17. 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

18. Drug Development Process
PRELEAD IND NDA
Investigational New Drug New Drug Application
Research
“Discovery”
Development

19. Toxicology Testing Process
PRELEAD IND NDA/BLA
Discovery
Development
Nonclinical tox studies in animals
Clinical trials
P1 P2 P3

20. What are Phase 1, 2, and 3 Trials?
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

21. 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

22. 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

23. 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…”

24. 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.

25. 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)

26. 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

27. Study Director Often, but not always, a toxicologist
Often, but not always, MS or PhD (depends on experience)
DABT or equivalent a plus – marketable

28. Types of Nonclinical Studies Reviewed by FDA
Basic pharmacology
primary and secondary mechanisms of action
nonclinical efficacy studies
Safety pharmacology
Pharmacokinetics
Toxicology
Genotoxicology
Carcinogenicity

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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)

35. Timing of Nonclinical Studies - Phase 3
Phase 3 Clinical Trials
repeat dose toxicity studies of appropriate length
male and female fertility
post-natal development

36. 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

37. 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)

38. Questions Asked by Review Pharmacologist/Toxicologist
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?

39. 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?

40. 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

41. For Online Information on FDA
CDER News
Guidelines
ICH Documents
Employment Opportunities