Drug Development - Toxipedia

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5 Δεκ 2012 (πριν από 4 χρόνια και 10 μήνες)

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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