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?