1. Drug Development Lynnda Reid, Ph.D. Pharmacology/Toxicology Reviewer
Center for Drug Evaluation and Research (CDER)
Rafael Ponce, Ph.D., DABT
Scientific Director
Amgen

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. Center for Drug Evaluation and Research (CDER) Office of New Drugs
Cardiovascular and renal
Neurology
Psychiatry
Anesthesia, Analgesia, Rheumatology
Metabolism and endocrinology
Pulmonary and allergy
Gastroenterology
Dermatology and dental
Urology
Anti-infectives and ophthalmology
Anti-viral
Special pathogens and transplant products
Drug oncology
Biological oncology
Medical imaging and hematology
Nonprescription

7. Driving issues for nonclinical assessment
Nonclinical development
Clinical
development
Discovery
What is a safe starting dose? How shall I dose escalate?
What are the primary toxicological consequences of treatment? Are they reversible?
Can I monitor for these adverse effects (i.e., are there useful premonitory indicators)?

8. Is there an ideal toxicological model?
Yes

9. In the absence of the ideal, what next?
Informative alternative species
What is a safe starting dose? How shall I dose escalate?
What are the primary toxicological consequences of treatment? Are they reversible?
Can I monitor for these adverse effects (i.e., are there useful premonitory indicators)?
Is my animal model a reliable biological model for human response?
What limitations does my species have as a surrogate for humans?

10. Proteins Small Molecules

11. 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

12. 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

13. Development Process Discovery Development PRELEAD IND NDA/BLA
Pharmacology, Lead ID
Process Development
Pharmacokinetics
Nonclinical safety
Clinical trials
P1 P2 P3

14. 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

15. 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

16. 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

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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)

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

25. 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?

26. 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?

27. Why does species selection matter?
Use of an unsuitable species may lead to false conclusions
False positive
There is an observed toxicity in a nonclinical species that will not develop in humans
Consequence: Resource wasting
Increased clinical monitoring, evaluation/investigation
Decision to slow or terminate program
Management: Investigative tox, clinical confirmation
False negative
Toxicity that will develop in humans is not predicted by nonclinical species
Consequence: Increased (unknown) risk to humans
Development of an unexpected toxicity
Not easily managed

28. Our collective interest
Minimize the risk of a false negative
Identify toxicological liabilities of a candidate therapeutic as early as possible
Kill unsuitable candidates early
Distribute resources to best candidates
Informed risk-benefit assessment
Appropriate monitoring
Efficient dose escalation and candidate progression

29. Nonclinical support for FIH dosing
Drug exposure and distribution to the target site (PK): First step in animal to human extrapolation
Nonclinical study mimics dose route
Appropriate allometry to scale dose from nonclinical species to humans
Adjustment for known differences in protein binding, metabolism, clearance, etc.

30. Nonclinical support for FIH dosing
Drug action at target site
(PD, Tox)
Second step in animal to human extrapolation
Similar underlying physiology for target/pathway
Presence of biological target at site of action in nonclinical species
Similar drug-target interaction (e.g., KD)
Similar pharmacological potency of drug (e.g., Emax, ED50)

31. MABEL/PAD vs NOAEL

32. Backup slides

33. 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

34. 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)

35. 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