Transcript Drug Development - Welcome to Toxipedia

Drug Development
Lynnda Reid, Ph.D.
Pharmacology/Toxicology Reviewer
Center for Drug Evaluation and Research (CDER)
Rafael Ponce, Ph.D., DABT
Scientific Director
Amgen
Outline
• Regulatory Overview
• Drug/biologic development process
• Resources
• Questions (and answers?)
Parties involved in Drug Development
• FDA
• Sponsor
• Contract Labs
• Clinical Sites
• Manufacturing Sites
• Consultants
• Other…
Sponsors
• Pharmaceutical/Biotechnology Firms
• Practicing Physicians and Dentists
• Academic Institutions
• NIH
• Other
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
Center for Drug Evaluation and Research (CDER)
Office of New Drugs
•
Cardiovascular and renal
•
Neurology
•
Anti-infectives and ophthalmology
•
Psychiatry
•
Anti-viral
•
Anesthesia, Analgesia,
Rheumatology
•
Special pathogens and transplant
products
•
Metabolism and endocrinology
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Drug oncology
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Pulmonary and allergy
•
Biological oncology
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Gastroenterology
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Medical imaging and hematology
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Dermatology and dental
•
Nonprescription
•
Urology
Driving issues for nonclinical assessment
Discovery
Nonclinical
development
Clinical
development
1. What is a safe starting dose? How shall I dose
escalate?
2. What are the primary toxicological consequences
of treatment? Are they reversible?
3. Can I monitor for these adverse effects (i.e., are
there useful premonitory indicators)?
Is there an ideal toxicological model?
Yes
In the absence of the ideal, what next?
Informative alternative species
1. What is a safe starting dose? How shall I dose
escalate?
2. What are the primary toxicological consequences
of treatment? Are they reversible?
3. 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?
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
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
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
Development Process
Development
Discovery
PRELEAD
IND
NDA/BLA
Pharmacology, Lead ID
Process Development
Pharmacokinetics
Nonclinical safety
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

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

Nonclinical Information Flow
In vitro/Animal Models
Application
Trial
• Hypothesis testing
• Potential for effect
• Mechanism of action
• Toxicity profile
• Safety assessment
• Dose/regimen
• Develop surrogate
markers
• Route of administration
• ADME/PK
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
Types of Nonclinical Studies Reviewed by FDA
• Basic pharmacology
• primary and secondary mechanisms of action
• nonclinical efficacy studies
• Safety pharmacology
• Pharmacokinetics
• Toxicology
• Genotoxicology
• Carcinogenicity
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
What Does FDA Expect from Nonclinical Studies?
• Pharmacokinetics
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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?
• 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
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
Timing of Nonclinical Studies - Phase 1
• Prior to “First Time in Humans”
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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
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
Timing of Nonclinical Studies - Phase 3
• Phase 3 Clinical Trials
• repeat dose toxicity studies of appropriate length
• male and female fertility
• post-natal development
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?
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?
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
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
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.
Nonclinical support for FIH dosing
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)
Drug action at target
site
(PD, Tox)
MABEL/PAD vs NOAEL
Pharmacological
effect
%
Response
Adverse effect
X
Excess
proportion
X
MABEL
X
X
XX
X
Controls 1
and 2
X
X
X
X
BMD NOAEL
Scaled human equivalent dose
Decision
Threshold
Backup slides
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
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

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