clinical trial in drug development

8/8/2019 Clinical Trial in Drug Development

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DRUGRecognized in the U.S. Pharmacopeia (USP),National Formulary (NF) or HomeopathicPharmacopeia of the US

Intended use for diagnosis, cure, treatment orprevention of disease in man or animal

Intended to affect the structure or function of thebody

Not a food, dietary ingredient or dietary supplement

Component of a drug is a drug.


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NEW DRUGNEW DRUG

Not been used in the country under labelingNot been used in the country under labelingconditionsconditions

Approved but now proposed to be marketed withApproved but now proposed to be marketed withmodified or new claimsmodified or new claims indications, dosage,indications, dosage,dosage form , route of administrationdosage form , route of administration

FDA, individually approved, to be combined forFDA, individually approved, to be combined forthe first time in a fixed ratio or if ratio is changedthe first time in a fixed ratio or if ratio is changed


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Investigational New DrugInvestigational New Drug

New chemical entity or aNew chemical entity or aproduct having therapeuticproduct having therapeutic

indication but which has neverindication but which has never

been earlier tested on humanbeen earlier tested on humanbeingsbeings


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DRUG DEVELOPMENT PIPELINEDRUG DEVELOPMENT PIPELINE


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Drug Development and

Approval Process Steps1. Discovery

2. Non-Clinical Animal Testing

3. Product & Process Development- Chemistry,Manufacturing and Control

4. Investigational New Drug Application (IND)

5. Clinical Trials (phase 1, 2, 3)

6. New Drug or Biologics License Application

(NDA or BLA)

7. Market Approval

8. Phase 4


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Types of Drugs & Market Submissions

New Drug Application (NDA)Classical Chemical Drugs: small molecules

Center for Drug Evaluation and Research

(CDER)

Biological License Application (BLA)

Biotechnology Derived Therapeutics: complex, large

molecules Center for Biologics Evaluation and

Research (CBER)


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FDA Regulations 21 CFR

Part 11 Electronic records and Signatures

Part 58 Good Laboratory Practices non-clinical

Part 50 Protection of Human Subjects clinical trials

Part 54 Financial DisclosurePart 56 Institutional Review Boards clinical trials

Part 312 Investigational New Drug Application (CBERCDER)

Part 314 New Drug Application (CDER)

Part 601 Biologics License Application (CBER)Part 812 Investigational Device Exemption (CDRH)

Part 807, Subpart E Pre Market Notification 510(k) CDRH

Part 814 Pre Market Approval Application Devices(CDRH)


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Modern drug discoveryModern drug discovery

Program selection (choosing a disease to work on)Program selection (choosing a disease to work on)Identification and validation a drug targetIdentification and validation a drug target

Assay developmentAssay development

Identification of a lead compoundIdentification of a lead compound

Lead optimizationLead optimizationIdentification of a drug candidateIdentification of a drug candidate

Preclinical StudyPreclinical Study

Clinical trialsClinical trials

Release of the drugRelease of the drug

FollowFollow--up monitoringup monitoring


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NDA vs ANDA Review ProcessNDA vs ANDA Review Process

Brand name drug Generic drugBrand name drug Generic drug

((NDA requirementNDA requirement) () (ANDA requirementANDA requirement))

1.1. ChemistryChemistry 1. Chemistry1. Chemistry

2.2. ManufacturingManufacturing 2. Manufacturing2. Manufacturing

3.3. ControlsControls 3. Controls3. Controls

4.4. LabelingLabeling 4. Labeling4. Labeling

5.5. TestingTesting 5. Testing5. Testing6.6. Animal studiesAnimal studies

7.7. Clinical studiesClinical studies

6. Bioequivalence studie


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Preclinical studyPreclinical study

PreclinicalPreclinical EfficacyEfficacy studiesstudies

AnimalAnimal Pharmacokinetics/ToxicokineticsPharmacokinetics/Toxicokinetics

AnimalAnimal SafetySafety PharmacologyPharmacology

AnimalAnimal ToxicityToxicity StudiesStudies


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Submission of preclinical data toSubmission of preclinical data toregulatory for conducting theregulatory for conducting the clinical trialsclinical trials

(phase I(phase I IV)IV)

In India,In India, regulatoryregulatory authority is :authority is : DrugDrug

Controller General ofIndia (DCGI)Controller General ofIndia (DCGI)


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OutlineOutline

I.I. New Drug Review Process: First PrinciplesNew Drug Review Process: First Principles

II. FDA Model of Serial Evaluation:II. FDA Model of Serial Evaluation:

Investigational New DrugInvestigational New Drug (IND)(IND)

.... Pre.... Pre--Clinical studiesClinical studies

.... Clinical Trials Phases I.... Clinical Trials Phases I IVIV

New Drug ApplicationNew Drug Application (NDA)(NDA)

PostPost--Marketing SurveillanceMarketing Surveillance


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Requirements for Drug ApprovalRequirements for Drug Approval

1938 FDA Drug Law Amendment:1938 FDA Drug Law Amendment:-- Requires drug safety prior to marketingRequires drug safety prior to marketing

1962 Kefauver1962 Kefauver--Harris Drug Amendment:Harris Drug Amendment:-- Additional requirement of adequate and wellAdditional requirement of adequate and well--

controlled studiescontrolled studies

CFR 201.56(a):CFR 201.56(a):-- The labeling shall contain a summary ofThe labeling shall contain a summary of

essential scientific information needed for safeessential scientific information needed for safeand effective use of drugand effective use of drug


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FDA:First PrinciplesFDA:First Principles

.. That subjects be exposed to least possible riskThat subjects be exposed to least possible risk-- Permissive/supportive animal safety testingPermissive/supportive animal safety testing

-- Qualified and Experienced InvestigatorsQualified and Experienced Investigators

-- Oversight by Institution Review Board (IRB)Oversight by Institution Review Board (IRB)

-- Informed consent: full disclosure of potential risks.Informed consent: full disclosure of potential risks.

. Empiricism. Empiricism-- Deliberate sequence of controlled clinical studiesDeliberate sequence of controlled clinical studies

-- Timely and sequential reliance on animal data for potentialTimely and sequential reliance on animal data for potential

irreversible, not readily apparent toxicityirreversible, not readily apparent toxicity (mutagenicity;(mutagenicity;

carcinogenicity; reproductive toxicity)carcinogenicity; reproductive toxicity)

-- PostPost--marketing surveillance; registries; epidemiologymarketing surveillance; registries; epidemiology


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Phases of Drug DevelopmentPhases of Drug Development Discovery /Screening/PreDiscovery /Screening/Pre--ClinicalClinical

INDIND::-- PrePre--Clinical studiesClinical studies

-- Clinical StudiesClinical Studies-- Phase One: Pharmacological StudiesPhase One: Pharmacological Studies

-- Phase Two: Preliminary Clinical EfficacyPhase Two: Preliminary Clinical Efficacy

-- Phase Three: Extensive Clinical trialsPhase Three: Extensive Clinical trials

...Adequate/Well...Adequate/Well--controlledcontrolled NDA ReviewNDA Review

PostPost--MarketingMarketing


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Discovery/Screening/PreDiscovery/Screening/Pre--ClinicalClinicalTesting of promising compounds inTesting of promising compounds in

animalsanimals

-- is the compound biologically active?is the compound biologically active?Pharmacodynamics (Pharmacodynamics (in vitro; in vivoin vitro; in vivo))

-- is the compound safe?is the compound safe?Safety Pharmacology and ToxicitySafety Pharmacology and Toxicity StudiesStudies

-- what is the dosewhat is the dose--response for the activityresponse for the activityand safety?and safety?Pharmacokinetic studies (ADME)Pharmacokinetic studies (ADME)


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PrePre--clinical Support for Phase Iclinical Support for Phase I--III Clinical TrialsIII Clinical TrialsPhase I:Phase I:

Safety pharmacology (CNS; CV; Respiratory)Safety pharmacology (CNS; CV; Respiratory)

Acute/Sub acute ToxicityAcute/Sub acute ToxicityInitial genotoxicityInitial genotoxicity

Initial reproductive toxicologyInitial reproductive toxicology

Local toleranceLocal tolerance

PharmacokineticPharmacokinetic

Phase II/III:Phase II/III:

Completed battery of GenotoxicityCompleted battery of GenotoxicityCompleted battery Reproductive toxicity (male/female)Completed battery Reproductive toxicity (male/female)

Extended repeated dose toxicityExtended repeated dose toxicity

Extended pharmacokinetic studiesExtended pharmacokinetic studies

Phase III:Phase III:Chronically used drugs:Chronically used drugs:

Chronic toxicity (rodent; nonChronic toxicity (rodent; non--rodent)rodent)

CarcinogenicityCarcinogenicity

Supplemental studies (special safety concerns, as alerted)Supplemental studies (special safety concerns, as alerted)M3 Guidance for Industry: NonM3 Guidance for Industry: Non--clinical Safety Studies for the Conduct of Humanclinical Safety Studies for the Conduct of Human

Clinical trials for Pharmaceuticals (ICH)Clinical trials for Pharmaceuticals (ICH)


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NonNon--clinical informationclinical information

The results of all relevant:-

Non-clinical pharmacology, toxicology,pharmacokinetic, and investigational

product metabolism

studies should be provided in summary

form.


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Information in a formatInformation in a format

Species tested

Number and sex of animals in

each group

Unit dose (e.g., milligram/kilogram(mg/kg))

Dose interval

Route of administration


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Duration of dosing

Information on systemic distribution

Duration of post-exposure follow-up

Results, including the following aspects


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- Nature and frequency of pharmacologicalor toxic effects

- Severity or intensity of pharmacological ortoxic effects

- Time to onset of effects

Duration of effects

Dose response


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IND Submission to FDAIND Submission to FDA

Investigational New Drug Application (IND)Investigational New Drug Application (IND)

Required for drug administration to humans inRequired for drug administration to humans inU.S.U.S.

Contains results of animal testing, and identifies aContains results of animal testing, and identifies a

safe dose for initial human exposuresafe dose for initial human exposure

IND effective if FDA does not disapprove withinIND effective if FDA does not disapprove within

30 days30 days


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Regulatory authoritiesRegulatory authorities

Ministry of Chem &

Fertilizers

NPPANational

Pharmaceutical

Pricing Authority

PricingRegulations

Ministry of Sci &

Tech

DBT

Department of

Biotechnology

Ministry of

Enviro

AdditionalSecretary

State Drug Regulatory Authority :FDA

GEAC

Genetic

Engineering

Approval

Committee

DCGI

Drug Controller

General of India

DGHSDirector General of

Health Services

Health Secretary

Ministry of Health

CDL/CDTL

Gov. Drug Testing

Laboratories


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Clinical trialClinical trial

Any investigation in human subjectsintended to discover or verify:-

the clinicalpharmacological

pharmacodynamic effects

of aninvestigational product(s)


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To identify any adverse reactions to aninvestigational product(s)

To study absorption, distribution, metabolism,and excretion of an investigational product(s)with the object of ascertaining its safety and/orefficacy.

The terms clinical trial and clinical study aresynonymous.


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PHASEPHASE--II

Phase I studies may involve risks even

though an investigational drug has

passed the Pre-clinical phase of testing.

Phase 1 studies typically offer little or no

benefit to the volunteer subjects; thereforethey typically are compensated for their

time and effort.


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Although usually conducted with healthy

volunteers

phase 1 trials are sometimes conducted with

severely or terminally ill patients, for example

those with AIDS or cancer.

A phase 1 trial takes several months to

complete.

About 70 % of experimental drugs pass this

initial phase of testing.


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Phase I trials are concerned primarily withestablishing a new drugs safety and dose

range in about 20-100 healthy volunteers.

How a drug is absorbed, distributed,metabolized and excreted by the humanbody is called Pharmacokinetics.

This is determined through frequent blood

draws (usually in an inpatientenvironment) to check for the level of drugin the blood plasma.


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Pharmacokinetic trials are usually considered

phase 1 trials regardless of when they areconducted during a drugs development.

Dosage range of a new drug is determined by

administering increasingly larger doses to one or

more groups of subjects, who are closely

monitored for harmful side effects.

The goal is to learn the maximum tolerated dose

that does not produce unacceptable side effects.


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Clinical Trials Phase IIClinical Trials Phase II:: Preliminary EfficacyPreliminary EfficacyPurposePurpose::

.. Explore early efficacy and safety in patientsExplore early efficacy and safety in patients-- dosedose--selection/intervalselection/interval-- use of surrogatesuse of surrogates

.. Early ADME data to guide phase III trial designEarly ADME data to guide phase III trial design

Subjects:Subjects:.. Ordinarily only targeted disease/condition.Ordinarily only targeted disease/condition.

.. Late phase II patients may have disease / therapyLate phase II patients may have disease / therapy

in addition to targetedin addition to targeted

.. Seldom more than 200 patientSeldom more than 200 patient--subjects.subjects.

PHASE - II


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Phase II studies determine the effectiveness of

an experimental drug on a particular disease or

condition in approximately 100 to 300

volunteers.

This phase may last from several months to two

years. A phase II trial answers the question,"Does Drug X improve Disease Y?"

A secondary objective for a phase II trial is to

ascertain therapeutic dose level and dosing

frequency.


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This answers the questions:

"What quantity of Drug X works better onDisease Y, (1 mg, 2 mg or 3 mg)?" and "Does

Drug X work better on Disease Y taken once or

twice a day?"

Most phase II studies are randomized, whichmeans that subjects are assigned randomly (by

chance not by choice) to receive theexperimental drug, a standard treatment or a

placebo (harmless, inactive substance).


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Those who receive the standard treatment or

placebo are called a control group.

Randomized phase II studies are often doubleblind, which means that both subject andphysician dont know which treatment is beingused.

Blinding prevents any unscientificinfluence on the study results that could be

caused by knowledge of the treatment.


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In a single-blind study, only the subject is unawareof the treatment used.

Larger numbers of patients receive a treatment in phaseII studies than in phase I studies,

There is a greater chance to observe and compile sideeffect information.

Subjects in a phase II trial may benefit from theirparticipation if they receive an active treatment.

Approximately 33 % of experimental drugs, which pass

phases I and II, will go on to phase III.


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Clinical Trials Phase IIIClinical Trials Phase III Large controlled trials in patients with targeted diseaseLarge controlled trials in patients with targeted disease ClinicallyClinically -- meaningful endpointsmeaningful endpoints

Trial design planned with FDATrial design planned with FDA.. Adequate and WellAdequate and Well--controlledcontrolled

Subjects:Subjects:.. Typically two or more multiTypically two or more multi--center trialscenter trials

comprised of several thousand patientcomprised of several thousand patient--subjectssubjects

.... Rigorous exclusion/inclusion criteriaRigorous exclusion/inclusion criteria

.... Placebo and/or active drugPlacebo and/or active drug--controlled designcontrolled design

Considerations:Considerations:.. PlaceboPlacebo -- controlled design least ambiguouscontrolled design least ambiguous

.. Ethics of placeboEthics of placebo--controlled studies?controlled studies?

.. DrugDrug--Drug interactionsDrug interactions

PHASE - III


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Phase III studies are conducted at multiple

centers with several hundred to severalthousand patients for whom the drug is

intended.

Massive testing of a drug provides continued

generation of data on a drugs safety andefficacy.


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As in phase II, most phase III studies are

randomized and blinded.

Phase III trials provide the bulk of information

needed for the package insert and labeling ofa medicine, after it has been F.D.A. approved.

A drug in this phase can be studied for severalyears and may be one of 25-30 % that pass

phases I, II and III.


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Once a phase III study is completed, a

pharmaceutical company can request F.D.A.approval to market the drug.

This is called a New Drug Application(NDA).

The NDA contains all the scientific data that the

company has gathered throughout the phases

in all trials.


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Adequate and WellAdequate and Well --Controlled TrialControlled Trial(21CFR 314.126)(21CFR 314.126)

Clear statement of objectivesClear statement of objectives

Summary of methods of analysisSummary of methods of analysis Precise description of study designPrecise description of study design

-- valid controlvalid control

-- duration of treatmentduration of treatment

-- sample size calculationssample size calculations

-- adequate inclusion/exclusion criteriaadequate inclusion/exclusion criteria

-- wellwell--defined and appropriate efficacy, safetydefined and appropriate efficacy, safety

markersmarkers


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Submission of NDASubmission of NDA

(New Drug Application)(New Drug Application)

Contains all Information known aboutContains all Information known aboutdrug, chemical, predrug, chemical, pre--clinical, and clinicalclinical, and clinical

-- typically 200typically 200--500 volumes of material500 volumes of material

Review by FDA takes 6 to 12 monthsReview by FDA takes 6 to 12 months-- 6 months for priority review6 months for priority review

-- 1010--12 months for standard review12 months for standard review


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NDA Review TeamNDA Review Team Medical OfficerMedical Officer-- Assesses drug safety and efficacyAssesses drug safety and efficacy

ChemistryChemistry

-- Assesses drug purity, stability, sterilityAssesses drug purity, stability, sterility

Pharmacology/ToxicologyPharmacology/Toxicology-- Assesses preAssesses pre--clinical pharmacologic, safety , and PK dataclinical pharmacologic, safety , and PK data

StatisticsStatistics-- Assesses drug efficacy ( prospectively defined endAssesses drug efficacy ( prospectively defined end--points)points)

BiopharmaceuticsBiopharmaceutics-- Assesses drug metabolism and drugAssesses drug metabolism and drug--drug interactionsdrug interactions

Project ManagementProject Management -- Coordination & industry liaisonCoordination & industry liaison


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Clinical Trials:Phase IV (Post marketing )Clinical Trials:Phase IV (Post marketing )

Purpose:Purpose:

.. Further elucidation of adverse events and/orFurther elucidation of adverse events and/or

pharmacologypharmacology

.. Large scale /longLarge scale /long--term assessment of morbidity andterm assessment of morbidity and

mortalitymortality

.. Further testing of drugs whichFurther testing of drugs which -- in interest ofin interest of

public healthpublic health -- were released prior to fullwere released prior to fullassessment of safetyassessment of safety

.. Special population (pediatric; geriatric)Special population (pediatric; geriatric)


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ICHICH--GCP guidelinesGCP guidelines

Good clinical practice (GCP) is aninternationalethicaland scientific qualitystandardfor :-

designingconducting

recording

reporting trialsthat involve the participationof human subjects.


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Compliance with this standard provides

public assurance that

rights

safety

and wellbeing

of trial subjects are protected

Consistency with the principles that have

their origin in the Declaration of Helsinki,

and that the clinical trial data are credible.


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Objective ofICHObjective ofICH--GCPGCP

To provide a unified standard for the

European Union(EU)

Japanthe United States

to facilitate the mutual acceptance

of clinical data by the regulatoryauthorities in these jurisdictions.


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1.1. GlossaryGlossary

The terms used to conduct the clinical studyThe terms used to conduct the clinical study

and throughout the entire period of trialand throughout the entire period of trial

These terms are definedThese terms are defined


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2. THE PRINCIPLES OF ICH GCP

2.1Clinical trials should be conducted in accordance with theethical principles that have their origin in the Declaration ofHelsinki, and that are consistent with GCP and theapplicable regulatory requirement's.

2.2 Before a trial is initiated, foreseeable risks andinconveniences should be weighed against the anticipatedbenefit for the individual trial subject and society. A trialshould be

initiated and continued only if the anticipated benefits justify the

risks.

2.3 The rights, safety, and well-being of the trial subjects arethe most important considerations and should prevail overinterests of science and society.


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2.4 The available non-clinical and clinicalinformation on an investigational product shouldbe adequate to support the proposed clinicaltrial.

2.5 Clinical trials should be scientifically sound,

and described in a clear, detailed protocol.

2.6A trial should be conducted in compliance

with the protocol that has received priorinstitutional review board (IRB)/independentethics committee (IEC) approval/favorableopinion.


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2.7 The medical care given to, and medical decisionsmade on behalf of, subjects should always be theresponsibility of a qualified physician

2.8 Each individual involved in conducting a trialshould be qualified by education, training, andexperience to perform his or her respective task(s).

2.9 Freely given informed consent should beobtained from every subject prior toclinical trialparticipation.

2.10All clinical trial information should be recorded,handled, and stored in a way that allows its accuratereporting, interpretation, and verification.

2 11 The confidentiality of records that could identify


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2.11The confidentiality of records that could identify

subjects should be protected, respecting the privacy

and confidentiality rules in accordance with the

applicable regulatory requirement's.

2.12 Investigational products should be manufactured,

handled, and stored in accordance with applicable

good manufacturing practice (GMP). They should be

used in accordance with the approved protocol.

2.13 Systems with procedures that assure the qualityof every aspect of the trial should be implemented.


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3. IRB/IEC3. IRB/IEC

3.1 Responsibilities

3.2 Composition, Functions, and Operations

3.3 Procedures

3.4 Records


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4. Investigator

4.1 Investigator's Qualifications and

Agreements

4.2 Adequate Resources

4.3 Medical Care of Trial Subjects

4.4 Communication with IRB/IEC

4.5 Compliance with Protocol4.6 Investigational Product(s)


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4.7 Randomization Procedures and

Unblinding4.8 Informed Consent of Trial Subjects

4.9 Records and Reports

4.10 Progress Reports4.11 Safety Reporting

4.12 Premature Termination or

suspension of a Trial4.13 Final Report(s) by

Investigator/Institution . .


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55 Sponsor Sponsor

5.1 Quality Assurance and Quality Control

5.2 Contract Research Organization (CRO)

5.3 Medical Expertise

5.4 Trial Design

5.5 Trial Management, Data Handling,Recordkeeping, and Independent DataMonitoring Committee

5 6 I ti t S l ti


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5.6 Investigator Selection

5.7 Allocation of Duties and Functions

5.8 Compensation to Subjects andInvestigators

5.9 Financing

5.10 Notification/Submission to RegulatoryAuthority(ies)


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5.11 Confirmation of Review by IRB/IEC

5.12 Information on Investigational Product(s)

5.13 Manufacturing, Packaging, Labeling, andCoding Investigational

5.14 Supplying and Handling InvestigationalProduct(s)

5.15 Record Access


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5.16 Safety Information

5.17 Adverse Drug Reaction Reporting

5.18 Monitoring

5.19 Audit

5.20 Noncompliance


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5.21 Premature Termination or

Suspension of a Trial

5.22 Clinical Trial/Study Reports

5.23 Multicenter Trials . .


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6.6. Clinical trial protocol and itsClinical trial protocol and its

amendmentamendment

6.1 General Information

6.2 Background Information

6.3 Trial Objectives and Purpose

6.4 Trial Design

6.5 Selection and Withdrawal of Subjects


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6.6 Treatment of Subjects

6.7 Assessment of Efficacy

6.8 Assessment of Safety

6.9 Statistics

6.10 Direct Access to Source

Data/Documents


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6.11 Quality Control and Quality Assurance

6.12 Ethics

6.13 Data Handling and Recordkeeping

6.14 Financing and Insurance

6.15 Publication Policy

6.16 Supplements


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For more informationFor more information

FDA guidances for industryFDA guidances for industry

www.fda.gov/cder/guidance/index.htmwww.fda.gov/cder/guidance/index.htm

FDA division office of genericsFDA division office of generics

www.fda.gov/cder/ogdwww.fda.gov/cder/ogd

United states pharmacopoeiaUnited states pharmacopoeia

www.usp.orgwww.usp.org