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Regulatory Framework for Phase I & Regulatory Framework for Phase I & Clinical Pharmacology StudiesClinical Pharmacology Studies
Funmilayo O. Ajayi, PhD, FCP, FISTFunmilayo O. Ajayi, PhD, FCP, FISTProcter & GambleProcter & GambleCincinnati, OhioCincinnati, Ohio
Talk OverviewTalk Overview
Background Information:Background Information:– history of drug approval regulationhistory of drug approval regulation– drug development paradigmdrug development paradigm
Pre-clinical Studies & Required Data for IND Pre-clinical Studies & Required Data for IND
IND Filing and Clinical Hold IssuesIND Filing and Clinical Hold Issues
Regulatory Importance of PK and PK/PD DataRegulatory Importance of PK and PK/PD Data
Sponsor-Agency CommunicationSponsor-Agency Communication
Regulation of New Drug DevelopmentRegulation of New Drug Development
< 1906 - No effective regulation of human drugs 1906 - Drug removed from market only if adulterated or
misbranded 1938 - Requirement of evidence of safety of new drugs 1962 - Requirement of evidence of safety & effectiveness 1997 - FDA Modernization Act: enabled PDUFA
2002 - Medical Device User Fee & Modernization Act 2007 - FDA Amendments Act
Substantial Evidence of EffectivenessSubstantial Evidence of Effectiveness
“....Evidence consisting of adequate and well-controlled 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 ActThe 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)
Food and Drug Administration (FDA):– Interprets and enforces the laws provided in the Act
Regulations & Guidance DocumentsRegulations & 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
Guidance Documents / Guidelines:– Less than regulations but provide detailed guidance for
specific situations
Types of Preclinical TestingTypes of Preclinical Testing
Short Term Animal Studies (Acute):Short Term Animal Studies (Acute):– Determine pharmacological action and toxicityDetermine pharmacological action and toxicity
Long Term Animal Studies (Chronic):Long Term Animal Studies (Chronic):– Look for potential side effects that may result from long Look for potential side effects that may result from long
term use such as carcinogenicityterm use such as carcinogenicity
– Look for reproductive effectsLook for reproductive effects
Species SelectionSpecies Selection Data in two (2) Species is requiredData in two (2) Species is required
Why 2 Species?Why 2 Species?– Species differences in responseSpecies differences in response
Rodent – almost always ratRodent – almost always rat– Mouse has poorest clinical concordanceMouse has poorest clinical concordance
Non-rodent – dog, non-human primateNon-rodent – dog, non-human primate
ConsiderationsConsiderations– Compound supplyCompound supply– Route of administration – e.g. mini-pig for dermalRoute of administration – e.g. mini-pig for dermal
Overview of Study TypesOverview of Study Types Safety Pharmacology
- functional assessment of major systems
General Toxicology - target organs, “chronicity of the toxicity”
Developmental and Reproductive Toxicology- fertility and reproductive performance (Seg I)- embryo/fetal development (Seg II)- neonatal development (Seg III)
Genetic Toxicology- potential for cancer and heritable mutations
Carcinogenicity Specialty Toxicology
Why Preclinical Testing?Why Preclinical Testing?
Detect overt toxicityDetect overt toxicity Identify, describe and characterize hazards Identify, describe and characterize hazards
- reversible? - reversible? - clinically monitorable?- clinically monitorable?
Establish dose-response estimation of pharmacology & Establish dose-response estimation of pharmacology & toxic effectstoxic effects
Assess drug distribution to organ systemsAssess drug distribution to organ systems Identify metabolic, kinetic and elimination pathwaysIdentify metabolic, kinetic and elimination pathways Assess carcinogenicity, reproductive toxicity and Assess carcinogenicity, reproductive toxicity and
teratogenic potentialteratogenic potential
General Toxicology Data – How Used General Toxicology Data – How Used
Dose Range Provide data for dose
selection for definitive study
Identify major target organs
Lead selection Species selection
Definitive Provide data for dose
selection for FIH Establish NOEL and
MTD Define toxicity over
duration of study Provide TK data
NOEL and NOAELNOEL and NOAEL
Required Duration of Repeated Dose Toxicity Required Duration of Repeated Dose Toxicity Studies to Support Phase I & II TrialsStudies to Support Phase I & II Trials
Duration of Duration of Clinical TrialsClinical Trials
Minimum Duration of Repeated Dose Minimum Duration of Repeated Dose Toxicity Studies Toxicity Studies
RodentsRodents Non-rodentsNon-rodentsSingle DoseSingle Dose 2 - 4 Weeks2 - 4 Weeks 2 Weeks2 Weeks
Up to 2 WeeksUp to 2 Weeks 2 - 4 Weeks2 - 4 Weeks 2 Weeks2 Weeks
Up to 1 MonthUp to 1 Month 1 Month1 Month 1 Month1 Month
Up to 3 MonthUp to 3 Month 3 Months3 Months 3 Months3 Months
Up to 6 MonthUp to 6 Month 6 Months6 Months 6 Months6 Months
> 6 Months> 6 Months 6 Months6 Months ChronicChronic
What is an IND?What is an IND?
A submission through which a drug sponsor alerts A submission through which a drug sponsor alerts the FDA of its intention to conduct clinical trials the FDA of its intention to conduct clinical trials with an investigational drugwith an investigational drug
Application seeking permission to do clinical trials Application seeking permission to do clinical trials in humansin humans
A request for exemption from the Federal laws that A request for exemption from the Federal laws that prohibits unapproved drugs from being shipped in prohibits unapproved drugs from being shipped in interstate commerceinterstate commerce
Types of INDsTypes of INDs
IND Regulations/GuidancesIND Regulations/Guidances
21 Code of Federal Regulations, Section 31221 Code of Federal Regulations, Section 312 1987 IND Rewrite1987 IND Rewrite 1995 Content and Format of Investigational New 1995 Content and Format of Investigational New
Drug Applications for Phase I Studies, Including Drug Applications for Phase I Studies, Including Well-Characterized, Therapeutic, Biotechnology-Well-Characterized, Therapeutic, Biotechnology-Derived ProductsDerived Products
1997 ICH M3 Non-clinical Safety Studies for the 1997 ICH M3 Non-clinical Safety Studies for the Conduct of Human Clinical Trials for Conduct of Human Clinical Trials for PharmaceuticalsPharmaceuticals
When to File an IND When to File an IND
An IND is filed prior to initiation of clinical trials in humans if it is to evaluate a:
- New chemical entityNew chemical entity- New indication for marketed agentNew indication for marketed agent- New route of administrationNew route of administration- New dosage levelNew dosage level
Common Reasons for Clinical HoldsCommon Reasons for Clinical Holds The IND does not contain sufficient information for The IND does not contain sufficient information for
the FDA to assess risks to subjectsthe FDA to assess risks to subjects Additional toxicology data is required - unexpected Additional toxicology data is required - unexpected
animal death or toxicity, or positive geno-toxicityanimal death or toxicity, or positive geno-toxicity Maximum human dose planned is not supported by Maximum human dose planned is not supported by
toxicology data - e.g. low margin of safetytoxicology data - e.g. low margin of safety CMC data is not sufficient or convincingCMC data is not sufficient or convincing Investigator is not qualified or ineligibleInvestigator is not qualified or ineligible Clinical Investigator’s Brochure is misleading, Clinical Investigator’s Brochure is misleading,
erroneous, or incompleteerroneous, or incomplete
Second Stage in New Drug DevelopmentSecond Stage in New Drug Development
Involves three phases of clinical trials of the drug in humans:– Phase I, II & III
Clinical Trial - Phase IClinical Trial - Phase I
Initial testing in humans Normal volunteers or patients with or at risk for the
target disease Open-label, dose escalating, safety and tolerance PK
studies Healthy volunteers and patients Intense level of monitoring Flexibility in making dosage adjustments
Phase I & Clinical PharmacologyPhase I & Clinical Pharmacology StudiesStudies
DiscoveryPhase I
Phase II Phase III
Approval MarketPreclinical
IND
NDA
•Microsomes •CACO2•Permeability•Solubility
•Human Volunteer PK Profiles•Patient PK Profiles•PK/PD Models and Simulation•PopPK Studies•IVIVC Models
•Drug Interactions •Disease States•Special Pops•BE Studies
In the 21st Century
R&D cost 800M -1.5B/drug
Regulations & A Few Guidance DocumentsRegulations & A Few Guidance Documents
21 CFR 320 ICH Guidance Documents (15+) EMEA Guidance Documents (30+) General BA/BE Guidance Population PK Guidance Exposure/Response Guidance USDA (USDA (AAnimal nimal WWelfare elfare AAct)ct) GGood ood LLaboratory aboratory PPracticesractices BCS Guidance IVIVC Guidance SUPAC Guidance documents (IR, MR and SS)
http://www.fda.gov/cder/guidance
General BA/BE GuidanceGeneral BA/BE Guidance
Intended to provide recommendations to sponsors planning to include BA and BE information for orally administered drug products in INDs, NDAs, ANDAs and supplements.
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 PK/PD: Implication in New Formulations and/or New Doses of Approved Drugs*and/or New Doses of Approved Drugs*
Where blood levels ... are not very different, it may be possible to conclude ... is effective on the basis of pharmacokinetic data alone.
Even if blood levels are quite different, if there is a well-understood 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 / Regulatory Support for Pharmacokinetics / Pharmacodynamic DataPharmacodynamic Data
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?PK/PD - Why Bother?
FDAMA, Sec. 115 Clinical InvestigationsFDAMA, 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”
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 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?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 Attrition On The R&D ProcessProcess
Preclinical Pharmacology
Preclinical Safety
7,000,000Compounds Screened
IdeaIdea DrugDrug11 - 15 Years
~100 Discovery Approaches~100 Discovery Approaches
1 - 2 1 - 2 ProductsProducts
DiscoveryDiscovery Exploratory DevelopmentExploratory Development Full DevelopmentFull Development
Phase I Phase II Phase III
00 151555 1010
Clinical Pharmacology& Safety
CHANGING THE INDUSTRY/FDA CHANGING THE INDUSTRY/FDA INTERPHASE:INTERPHASE:
A CRITICAL PATH OPPORTUNITYA CRITICAL PATH OPPORTUNITY
Target Validation Screening Lead Development Pre-Lead Lead First in Human-FDA dialogue Proof of Concept-FDA
dialogue Full Development-FDA
dialogue
Molecular Sciences And Technologies
Pharmacology
ExperimentalMedicine
Clinical Development
ExpandedScope:
•Exploratory IND•Microdosing•PK/PD•Biomarkers•Desired Human Exposure•Proof of Non-viability•Proof of Concept
Critical Path Agenda and OpportunitiesCritical Path Agenda and Opportunities 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
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 Drug/Disease Modeling and Clinical Trial Simulation: A Well-Established StrategySimulation: A Well-Established Strategy
Results Results
GraphicsGraphics
Statistical Statistical AnalysisAnalysis
Interface to Interface to SAS, EtcSAS, Etc..
– Drug Drug – DiseaseDisease– PatientsPatients
DrugDrugModelModel
ReplicationsReplications
Trial Design StrategiesTrial Design Strategies
StructureStructureScheduleScheduleEndpointsEndpoints
Subject SelectionSubject SelectionComplianceCompliance
DropoutDropout
Modify Drug ModelModify Drug Model
Modify Trial DesignModify Trial Design
Population Pharmacokinetic & Dynamic Modeling:Population Pharmacokinetic & Dynamic Modeling:A Fundamental Tool to Characterize E-R RelationshipsA Fundamental Tool to Characterize E-R Relationships
Time (h)
Dru
g C
once
ntra
tion
0 2 4 6 8 10 12
0.0
0.02
0.04
0.06
Extensive PK
Time (h)
Dru
g C
once
ntra
tion
0 1 2 3 4 5 6
0.0
0.05
0.10
0.15
0.20
Sparse PK
Time (h)
Dru
g C
once
ntra
tion
0 1 2 3 4 5 6
0.0
0.05
0.10
0.15
0.20
Mixed Effects Modeling
ExposureExposure
Exposure
Effe
ct(%
)
0 2 4 6 8
020
4060
8010
0
Efficacy
Exposure
prob
ality
(DLT
)
0 2 4 6 8 10 12
0.0
0.2
0.4
0.6
0.8
1.0
Safety
Choice of Dosage Regimen
Advanced Quantitative Modeling: Implication in Drug Advanced Quantitative Modeling: Implication in Drug Development & Approval ProcessDevelopment & 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) – based on inter-subject variability and risk assessment
Sponsor-Regulatory Agency Sponsor-Regulatory Agency CommunicationCommunication
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 brings added value or benefits to the drug development process
Communication: On What?Communication: On What?
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)
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
Comments on overall clinical development program– could be of value & provide context for role of study in overall
program
Communication: When?Communication: When? Pre-IND
– enables discussion of issues related to specific study design before protocol is finalized – e.g. dosing strategy, proposed clinical pharmacology program
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?Communication: How?Formal meetings:
desired feedback may be more urgent given the time to set up meetings
Communication: How?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?Communication: Why?
Open, timely, exchange of ideas between Sponsor and regulatory agencies
Obtain Agency’s views on questions / issues
Opportunity for specific questions to be addressed - e.g., # of special population or interaction studies
Minimize regulatory decision surprises
Facilitates good review management principles
Effective Communication StrategyEffective 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?Questions?