Drug Development - 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

•

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

Driving issues for nonclinical assessment

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)?

Discovery

Nonclinical
development

Clinical

development

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

Single entity; high chemical
purity

Exception: racemic mixtures

Specs well
-
defined early

Drug product

Usually IV or SC

Usually oral

Impurities

Difficult to standardize

St
andards well established

Bridging
requirements

Significant for drug substance

Bioequivalence procedures

Biological activity

May mimic naturally occurring
molecules

Primary MOT

Predictive based on MOA

Less predictive

Nonspecificity

Variable significance

Usually significant

Drug
-
drug interaction

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
establishe
d



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

PRELEAD



IND



NDA/BLA

Discovery

Development





Clinical trials

P1

P2

P3

Pharmacology, Lead ID

Process Development

Pharmacokinetics

Nonclinical safety

What are Phase 1, 2, and 3 Trials?




Phase 1:



Safety and pharmacokinetics



Generally 20 to 80 subjects



Closely controlled






Phase 3:



Efficacy and safety



Several hundred to several


thousand subjects



Controlled and uncontrolled





Phase 2:




Efficacy and safety



Usually no more than


several hundred subjects



Closely controlled


Nonclinical Information Flow

In vitro/Animal Models

Application


Trial





J. Lipani, 1998

•
Hypothesis testing

•
Mechanism of action

•
Safety assessment

•
Develop surrogate
markers

•
ADME/PK

•
Potential for effect

•
Toxicity profile

•
Dose/regimen

•
Route of administration

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

•
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”


•
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

Drug exposure and distribution to the target site (PK):
First
step in animal to human extrapolation

Nonclinical support for FIH dosing

•
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.

Drug action at target
site

(PD, Tox)

Nonclinical support for FIH dosing

•
Similar underlying physiology for target/pathway

•
Presence of biological target at site of action in
nonclinical species

•
Similar drug
-
target interaction (e.g., K
D
)

•
Similar pharmacological potency of drug (e.g.,
Emax, ED
50
)

Second step in animal to human
extrapolation


X
X
X
X
X
X
X
X
Pharmacological
effect
Decision
Threshold
Scaled human equivalent dose
%
Response
Excess
proportion
X
X
X
Controls 1
and 2
Adverse effect
BMD
MABEL
NOAEL
MABEL/PAD vs NOAEL

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


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)


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