Transcript THE DRUG APPROVAL PROCESS: The Role of Clinical

Regulatory Framework for Phase I &
Clinical Pharmacology Studies
Funmilayo O. Ajayi, PhD, FCP, FIST
Procter & Gamble
Cincinnati, Ohio
Talk Overview
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Background Information:
– history of drug approval regulation
– drug development paradigm
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Pre-clinical Studies & Required Data for IND
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IND Filing and Clinical Hold Issues
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Regulatory Importance of PK and PK/PD Data
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Sponsor-Agency Communication
Regulation of New Drug Development
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< 1906 - No effective regulation of human drugs
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1906 -
Drug removed from market only if adulterated or
misbranded
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1938 -
Requirement of evidence of safety of new drugs
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1962 -
Requirement of evidence of safety & effectiveness
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1997 -
FDA Modernization Act: enabled PDUFA
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2002 -
Medical Device User Fee & Modernization Act
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2007 -
FDA Amendments Act
Substantial Evidence of Effectiveness
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“....Evidence consisting of adequate and wellcontrolled investigations, including clinical
investigations, by qualified scientific experts, that
proves the drug will have the effect claimed in its
labeling....”
Section 505 (d)
Fed. Food, Drug & Cosmetic Act, 1962
The Drug & Cosmetic Act

Federal Food, Drug and Cosmetic Act:
– Defines what new drugs are
– States that a new drug must be the subject of an approved
new drug application (NDA)
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Food and Drug Administration (FDA):
– Interprets and enforces the laws provided in the Act
Regulations & Guidance Documents

Code of Federal Regulations (21 CFR):
– Written by the FDA to instruct and direct the public in
how this law is to be applied
– Outlines the general procedures and requirements that are
binding on the FDA
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Guidance Documents / Guidelines:
– Less than regulations but provide detailed guidance for
specific situations
Types of Preclinical Testing

Short Term Animal Studies (Acute):
– Determine pharmacological action and toxicity
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Long Term Animal Studies (Chronic):
– Look for potential side effects that may result from long
term use such as carcinogenicity
– Look for reproductive effects
Species Selection
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Data in two (2) Species is required
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Why 2 Species?
– Species differences in response
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Rodent – almost always rat
– Mouse has poorest clinical concordance
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Non-rodent – dog, non-human primate
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Considerations
– Compound supply
– Route of administration – e.g. mini-pig for dermal
Overview of Study Types

Safety Pharmacology
- functional assessment of major systems
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General Toxicology
- target organs, “chronicity of the toxicity”
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Developmental and Reproductive Toxicology
- fertility and reproductive performance (Seg I)
- embryo/fetal development (Seg II)
- neonatal development (Seg III)
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Genetic Toxicology
- potential for cancer and heritable mutations
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Carcinogenicity
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Specialty Toxicology
Why Preclinical Testing?
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Detect overt toxicity
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Identify, describe and characterize hazards
- reversible?
- clinically monitorable?
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Establish dose-response estimation of pharmacology &
toxic effects
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Assess drug distribution to organ systems
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Identify metabolic, kinetic and elimination pathways
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Assess carcinogenicity, reproductive toxicity and
teratogenic potential
General Toxicology Data – How Used
Dose Range
Provide data for dose
selection for definitive
study
Identify major target
organs
Lead selection
Species selection
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Definitive
Provide data for dose
selection for FIH
Establish NOEL and
MTD
Define toxicity over
duration of study
Provide TK data
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NOEL and NOAEL
Required Duration of Repeated Dose Toxicity
Studies to Support Phase I & II Trials
Duration of
Clinical Trials
Minimum Duration of Repeated Dose
Toxicity Studies
Rodents
Non-rodents
Single Dose
2 - 4 Weeks
2 Weeks
Up to 2 Weeks
2 - 4 Weeks
2 Weeks
Up to 1 Month
1 Month
1 Month
Up to 3 Month
3 Months
3 Months
Up to 6 Month
6 Months
6 Months
> 6 Months
6 Months
Chronic
What is an IND?

A submission through which a drug sponsor alerts
the FDA of its intention to conduct clinical trials
with an investigational drug

Application seeking permission to do clinical trials
in humans

A request for exemption from the Federal laws that
prohibits unapproved drugs from being shipped in
interstate commerce
Types of INDs
IND Regulations/Guidances
21 Code of Federal Regulations, Section 312
 1987 IND Rewrite
 1995 Content and Format of Investigational New
Drug Applications for Phase I Studies, Including
Well-Characterized, Therapeutic, BiotechnologyDerived Products
 1997 ICH M3 Non-clinical Safety Studies for the
Conduct of Human Clinical Trials for
Pharmaceuticals
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When to File an IND
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An IND is filed prior to initiation of clinical
trials in humans if it is to evaluate a:
-
New chemical entity
New indication for marketed agent
New route of administration
New dosage level
Common Reasons for Clinical Holds
The IND does not contain sufficient information for
the FDA to assess risks to subjects
 Additional toxicology data is required - unexpected
animal death or toxicity, or positive geno-toxicity
 Maximum human dose planned is not supported by
toxicology data - e.g. low margin of safety
 CMC data is not sufficient or convincing
 Investigator is not qualified or ineligible
 Clinical Investigator’s Brochure is misleading,
erroneous, or incomplete
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Second Stage in New Drug Development
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Involves three phases of clinical trials of the
drug in humans:
– Phase I, II & III
Clinical Trial - Phase I
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Initial testing in humans
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Normal volunteers or patients with or at risk for the
target disease
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Open-label, dose escalating, safety and tolerance PK
studies
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Healthy volunteers and patients
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Intense level of monitoring
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Flexibility in making dosage adjustments
Phase I & Clinical Pharmacology Studies
R&D cost 800M -1.5B/drug
Discovery
Preclinical
Phase I
Approval
Phase II
In the 21st Century
•Microsomes
•CACO2
•Permeability
•Solubility
Phase III
•Human Volunteer PK Profiles
•Patient PK Profiles
•PK/PD Models and Simulation
•PopPK Studies
•Drug Interactions
•IVIVC Models
•Disease States
•Special Pops
•BE Studies
Market
Regulations & A Few Guidance Documents
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21 CFR 320
ICH Guidance Documents (15+)
EMEA Guidance Documents (30+)
General BA/BE Guidance
Population PK Guidance
Exposure/Response Guidance
USDA (Animal Welfare Act)
Good Laboratory Practices
BCS Guidance
IVIVC Guidance
SUPAC Guidance documents (IR, MR and SS)
http://www.fda.gov/cder/guidance
General BA/BE Guidance
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Intended to provide recommendations to sponsors planning
to include BA and BE information for orally administered
drug products in INDs, NDAs, ANDAs and supplements.
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Also generally applicable to non-orally administered drug
products when one relies on systemic exposure measures for
BA/BE.
* FDA Guidance: Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products — General Considerations
PK/PD: Implication in New Formulations
and/or New Doses of Approved Drugs*
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Where blood levels ... are not very different, it may be
possible to conclude ... is effective on the basis of
pharmacokinetic data alone.
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Even if blood levels are quite different, if there is a wellunderstood relationship between blood concentration
and response (PK/PD), ..., it may be possible to conclude ...
is effective on the basis of pharmacokinetic data without
an additional clinical efficacy trial.
*Guidance for Industry “Providing Clinical Evidence of Effectiveness for Human Drugs
and Biological Products”, May 1998
Regulatory Support for Pharmacokinetics /
Pharmacodynamic Data
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FDAMA Sec. 115. Clinical investigations:
– Support of one adequate and well-controlled clinical
investigation by “confirmatory evidence” comprising
PK or PK/PD
PK/PD - Why Bother?
FDAMA, Sec. 115 Clinical Investigations
CONGRESSIONAL COMMITTEE REPORTS*
“confirmatory evidence” = “scientifically sound data from any
investigation in the NDA that provides substantiation as to
the safety and effectiveness of the new drug”
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Confirmatory evidence =“consisting of earlier clinical trials,
pharmacokinetic data, or other appropriate scientific
studies”
*House Commerce Committee, 10/7/97, and Committee on Disagreeing votes of
the two Houses, 11/9/97
Regulatory Support for Pharmacokinetics
FDA Modernization Act of 1997 (“FDAMA)”
 Sec. 111. Pediatric studies of drugs
– PK bridging studies to support use in pediatric population
Pharmacokinetics - Why Bother?
Pediatric Labeling Regulations
(21 CFR 201.56)
“FDA may approve a drug for pediatric use based on
…studies in adults, with other information
supporting pediatric use …. Additional information
supporting pediatric use must ordinarily include data
on the pharmacokinetics of the drug in the pediatric
population ….Other information, such as data on
pharmacodynamic studies …..”
Attrition On The R&D
Process
~100 Discovery Approaches
7,000,000
Compounds Screened
Preclinical
Pharmacology
Preclinical Safety
1-2
Products
Clinical Pharmacology
& Safety
Discovery
Exploratory Development
Phase I
0
Idea
Full Development
Phase II
Phase III
10
5
11 - 15 Years
15
Drug
CHANGING THE INDUSTRY/FDA
INTERPHASE:
A CRITICAL PATH OPPORTUNITY
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Target Validation
Molecular Sciences
Screening
And Technologies
Lead Development
Pre-Lead
Pharmacology
Lead
First in Human-FDA dialogue
Proof of Concept-FDA dialogue Experimental
Medicine
Full Development-FDA dialogue
Clinical
Development
Expanded
Scope:
•Exploratory IND
•Microdosing
•PK/PD
•Biomarkers
•Desired Human Exposure
•Proof of Non-viability
•Proof of Concept
Critical Path Agenda and Opportunities
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Need for a paradigm shift to improve the efficiency of
clinical drug development
Model-based drug development approaches are powerful
tools to improve clinical drug development, regulatory
guidance and the quality of NDA submissions
Model-based drug development such as:
– drug and disease modeling
– exposure-response modeling
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Importance of FDA and academia to lead the widespread
adoption of the tools and concepts in the pharmaceutical
industry
Drug/Disease Modeling and Clinical Trial
Simulation: A Well-Established Strategy
Drug
Model
– Drug
– Disease
– Patients
Trial Design Strategies
Structure
Schedule
Endpoints
Results
Graphics
Replications
Subject Selection
Compliance
Dropout
Statistical
Analysis
Interface to
SAS, Etc.
Modify Trial Design
Modify Drug Model
Population Pharmacokinetic & Dynamic Modeling:
A Fundamental Tool to Characterize E-R Relationships
Sparse PK
0.0
0.0
Drug Concentration
0.05 0.10 0.15 0.20
Drug Concentration
0.02
0.04
0.06
Extensive PK
4
6
Time (h)
8
10
12
0
Mixed Effects Modeling
0
20
0
2
4
Exposure
2
6
8
3
Time (h)
4
5
6
8
10
Safety
0.0
Effect(%)
40 60 80 100
Efficacy
0
1
1
2
3
Time (h)
4
Choice
of Dosage Regimen
5
6
probality(DLT)
0.0 0.2 0.4 0.6 0.8 1.0
2
Drug Concentration
0.05 0.10 0.15 0.20
0
0
2
4
6
Exposure
12
Advanced Quantitative Modeling: Implication in Drug
Development & Approval Process
Exposure vs. response (efficacy & safety)
relationship in dose selection
 Computer-assisted simulation of clinical trials to
address study design and data analysis issues
 Population PK/PD data analysis to understand
variability and to provide evidence for label claims
 Dose adjustment in special populations (hepatic,
renal, gender, age and drug interactions)
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– based on inter-subject variability and risk assessment
Sponsor-Regulatory Agency
Communication
Communication brings added value or benefits to the drug
development process
The goal has always been to find ways to achieve more frequent
and more direct communication with reviewers.
Also to understand the….
1. What?
2. When?
3. How?
4. Why?
Communication: On What?
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Questions during the drafting of study protocols
– more likely to arise earlier than later in clinical development when
input can be of high value (e.g., specific study)
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Review of finalized, individual study protocols or reports
– often occurs right before or after next study begins
– it is important to know when this will add value during IND phase
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Comments on overall clinical development program
– could be of value & provide context for role of study in overall
program
Communication: When?
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Pre-IND
– enables discussion of issues related to specific study design
before protocol is finalized – e.g. dosing strategy, proposed
clinical pharmacology program
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EoP2A
– focus on questions or issues related to key E/R parameters of
interest, data analysis, dose-ranging and proposed study
designs for phase 2B and 3
– discuss special more complex issues in overall clinical
development strategy (e.g., QT studies, pharmacogenetic
studies, drug interactions with transporters)
Communication: How?
Formal meetings:
desired feedback may be more urgent
given the time to set up meetings
Communication: How?

Informal Meetings – e.g. teleconferences
– policies regarding direct communication between
reviewers and sponsors varies with medical division
– most medical divisions want sponsor to go through
project managers for specific review questions
– rationale is that medical divisions are better able to
keep track of decisions made - especially those that
impact or influence efficacy/safety or CMC issues
Communication: Why?

Open, timely, exchange of ideas between Sponsor
and regulatory agencies
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Obtain Agency’s views on questions / issues
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Opportunity for specific questions to be addressed e.g., # of special population or interaction studies
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Minimize regulatory decision surprises
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Facilitates good review management principles
Effective Communication Strategy
Submit IND protocols for review at least 90 days
before anticipated start of study
 State in cover letter that review of protocol &/or
study report is requested
 Provide adequate information / data

– facilitates review & response to Questions

Describe role of study in overall development
program and/or potential regulatory outcomes
(e.g., label claim)
Questions?