drug development process

Drug Development Drug Development ProcessProcess

22

Fundamental Clinical DevelopmentFundamental Clinical Development

Essentials of Clinical ResearchEssentials of Clinical Research• Phases of Drug DevelopmentPhases of Drug Development• Basics of Drug DevelopmentBasics of Drug Development• Clinical Research DesignClinical Research Design

Planning and Initiating a Clinical Trial Planning and Initiating a Clinical Trial Company SponsoredCompany Sponsored• Investigator SelectionInvestigator Selection• Initiating a Clinical TrialInitiating a Clinical Trial

Conducting a Clinical TrialConducting a Clinical TrialCompany SponsoredCompany Sponsored• GCPGCP• Informed ConsentsInformed Consents• Case Report Forms and Source DocumentsCase Report Forms and Source Documents• Safety ReportingSafety Reporting• Study Close-outStudy Close-out

33

Essentials of Clinical Essentials of Clinical ResearchResearch

Phases of Clinical ResearchPhases of Clinical Research

Basics of Clinical ResearchBasics of Clinical Research

Clinical Study Design Clinical Study Design

44

Research Concept & Discover Active Lead Compound

2-20 years research

8,000-10,000 potentialCandidate substances

Research Target

Discoveryof leadcompound

Selection of product candidate

Preclinical Testing

2-3 years development

20-30 remaining 5-10 remainingSubstances substances

Biological Tests

Regulatory clearance

Pharmacy/ Chemical Development

Clinical Trials


4-5 2-3Remaining substances 1 remaining

ClinicalTrialPhase 1 Phase 2 Phase 3

Biological Tests

Pharmacy/Chemical Development

Registration, Launch and Sales


1 remaining substance

Registration Launchwith andHealth Sales Authorities

Preparation forLaunch

Drug Development ProcessDrug Development Process

Phase IVPhase IIIPhase IIbPhase IIaClinical Trials

Phase 1Pre-

clinical Phase

Candidate Profiling

Phase

DiscoveryPhase

An Overview:An Overview:

Drug Development TimelineDrug Development Timeline

Life Cycle Management

FullDevelopment

Early Development

Research

Cand

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Poin

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CSP sPoC DDP FDP 3CP SDP

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Pro

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Conce

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Phase

III

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IND – Investigational New Drug NDA – New Drug Application

66

Discovery of Active Lead Discovery of Active Lead CompoundsCompounds

• Complicated, time-consuming and costly processComplicated, time-consuming and costly process– 2-20 years2-20 years

• Hundreds to thousands of chemical Hundreds to thousands of chemical compounds/biologics/botanicals must be screenedcompounds/biologics/botanicals must be screened– Up to 10,000 screenedUp to 10,000 screened

• No standard route through which drugs are developedNo standard route through which drugs are developed

• Some major sources of new drugs:Some major sources of new drugs:– Synthetic compoundsSynthetic compounds– Discovery of a new use for an old-drugDiscovery of a new use for an old-drug– Natural chemicalNatural chemical

• ProcessProcess: Research Target : Research Target

Discovery of Lead Compound Discovery of Lead Compound

Candidate SelectionCandidate Selection

77

Pre-Clinical ResearchPre-Clinical Research

• Animal pharmacology/toxicology testing – “Is Animal pharmacology/toxicology testing – “Is it safe to proceed to human trials?” it safe to proceed to human trials?”

(The Nuremberg Code)(The Nuremberg Code)

• Approximately 2-3 yrs developmentApproximately 2-3 yrs development– 20-30 substances20-30 substances

• Minimum FDA requirements:Minimum FDA requirements:– pharmacological profilepharmacological profile– Determine acute toxicity in at least 2 species of Determine acute toxicity in at least 2 species of

animalsanimals– Conduct short-term toxicity studies (2 wks – 3 Conduct short-term toxicity studies (2 wks – 3

mos)mos)

88

Investigational New Drug Investigational New Drug ApplicationApplication (IND)(IND)

• Documentation that allows investigational clinical Documentation that allows investigational clinical testing of a new medicinetesting of a new medicine

• Must be filed with FDA before drug administered to Must be filed with FDA before drug administered to humanshumans

• Studies may begin within 30 days of Studies may begin within 30 days of application…..if no response from the FDA application…..if no response from the FDA

• An IND contains the following sectionsAn IND contains the following sections– Table of contentsTable of contents - Protocols for each planned study- Protocols for each planned study– IntroductionIntroduction - Investigator - Investigator – Investigator’s Brochure Investigator’s Brochure - Facilities and IRB - Facilities and IRB – General investigational planGeneral investigational plan - Manufacturing and control - Manufacturing and control – Previous human experience Previous human experience - Additional information- Additional information– Pharmacology & toxicology Pharmacology & toxicology

21 CFR 312.23

99

Clinical TrialsClinical Trials

• IND filed firstIND filed first

• 3-5 years 3-5 years

• Process: Process: – Clinical Trials - Phase I – Phase III Clinical Trials - Phase I – Phase III – On-going Biological tests (safety)On-going Biological tests (safety)– On-going formulation workOn-going formulation work

1010

Clinical Trials - PhasesClinical Trials - Phases

1-5 yrs1-5 yrsHundreds-Hundreds-thousandsthousands

Subjects with Subjects with indicationsindications

New indications, New indications,

QoL, surveillanceQoL, surveillanceIVIV

2-3 yrs2-3 yrsHundreds-Hundreds-thousandsthousands


Safety & efficacy Safety & efficacy

Basis for labeling, Basis for labeling,

new formulationsnew formulationsIIIIII

1-2 yrs1-2 yrsSeveral Several hundredhundred


Short-term side Short-term side

effects & efficacyeffects & efficacyIIII

6-12 mos6-12 mos20-8020-80

Healthy Healthy volunteers or volunteers or subj. w/ subj. w/ indicationsindications

Safety, ADME, Safety, ADME, bioactivity, bioactivity,

drug-drug drug-drug interactioninteraction

II

LengthLength(per (per

phase)phase)ScopeScopeSubjectsSubjectsPurposePurposePhasePhase

21 CFR 312.21

1111

Phase IPhase I

• First time in human subjectsFirst time in human subjects

• Small number of healthy volunteers or Small number of healthy volunteers or severely ill patients severely ill patients

• Safety profile and dosage rangeSafety profile and dosage range

• Single and multi-dose studiesSingle and multi-dose studies

• Pharmacokinetics / pharmacodynamicsPharmacokinetics / pharmacodynamics

• Open label, often single centerOpen label, often single center

• Not always performed in the U.S.Not always performed in the U.S.

1212

Phase IIPhase II

• Safety,Safety, side effects side effects• EfficacyEfficacy – dose response – dose response• Double-blind, positive control or placebo, multi-Double-blind, positive control or placebo, multi-

center utilizing a limited number of subjects center utilizing a limited number of subjects (100-300); often the first time drug is used in (100-300); often the first time drug is used in population for which it is intendedpopulation for which it is intended

• Phase IIa – proof of concept, pilot, feasibility, Phase IIa – proof of concept, pilot, feasibility, usually healthy volunteersusually healthy volunteers

• Phase IIb – well-controlled in target populationPhase IIb – well-controlled in target population• Following completion of Phase II, meet with the Following completion of Phase II, meet with the

FDA to pave the way for “pivotal trials”FDA to pave the way for “pivotal trials”

21 CFR 312.47

1313

Phase IIIPhase III

• 2 or 3 studies are 2 or 3 studies are pivotal pivotal (critical) studies(critical) studies– To prove safety and efficacy of primary endpointsTo prove safety and efficacy of primary endpoints– Double-blind, positive or placebo control, multi-centerDouble-blind, positive or placebo control, multi-center– Study population resembles the Study population resembles the intended populationintended population– Support package labelingSupport package labeling– New Drug Application New Drug Application (NDA)(NDA)

• Special population, concomitant medications, multiple Special population, concomitant medications, multiple illnesses, etc.illnesses, etc.

• IIIb studiesIIIb studies – post NDA-submission trial looking at – post NDA-submission trial looking at additional indicationsadditional indications

• Pre-NDA meeting with the FDA near conclusion of Phase Pre-NDA meeting with the FDA near conclusion of Phase IIIIII

21 CFR 312.47

1414

New Drug Application (NDA)New Drug Application (NDA)

• The average NDA is 100,000 pages or longerThe average NDA is 100,000 pages or longer

• Must provide all relevant data collected during R&DMust provide all relevant data collected during R&D• Consists of:Consists of:

– IndexIndex - non-clinical pharm - clinical data- non-clinical pharm - clinical data– non-clinical pharm - human toxicitynon-clinical pharm - human toxicity - CRF’s - CRF’s– safety updatesafety update - case report tabulations- case report tabulations– pediatric datapediatric data - statistics- statistics – PK / BioavailabilityPK / Bioavailability - patent information / certification- patent information / certification– ISES (Integrated Summary of Efficacy and Safety)ISES (Integrated Summary of Efficacy and Safety)– CER (Clinical Expert Report – summary of drug impact, how data supports)CER (Clinical Expert Report – summary of drug impact, how data supports)– CSR (Clinical Study Reports)CSR (Clinical Study Reports)

• Can now be filed electronically Can now be filed electronically

(a CTD = Commercial Technical Document)(a CTD = Commercial Technical Document)

• Review process: Target 10 months (but often longer)Review process: Target 10 months (but often longer)

21 CFR 314.50

1515

NDA Review ProcessNDA Review Process

Review ProcessReview Process standardstandard expedited (in the case of life threatening expedited (in the case of life threatening

diseases for which the only medications diseases for which the only medications available are of little or limited available are of little or limited effectiveness, e.g. ALS).effectiveness, e.g. ALS).

Results of ReviewResults of Review Approvable Approvable ApprovedApproved DeniedDenied

Negotiation of the labeling processNegotiation of the labeling process www.fda.gov

1616

Registration & LaunchRegistration & Launch

• Product Registration Product Registration and Launch and Launch

• 2 - 3 years2 - 3 years

• Process:Process:– Register Product with Register Product with

Health Authorities Health Authorities (FDA)(FDA)

– Prepare Sales TeamsPrepare Sales Teams

1717

Phase IVPhase IV

• Post-licensurePost-licensure studies to confirm the safety in studies to confirm the safety in large population (after NDA is filed)large population (after NDA is filed)

• Phase IV commitmentsPhase IV commitments

• Possible types of studiesPossible types of studies– Compared versus competitionCompared versus competition– Post-marketing surveillancePost-marketing surveillance– Special populationSpecial population– Rare event incidencesRare event incidences– Additional long-term usage safety dataAdditional long-term usage safety data– Pharmacoecomonic and Quality of Life (QoL)Pharmacoecomonic and Quality of Life (QoL)

21 CFR 312.85

1818

Supplemental New Drug Supplemental New Drug ApplicationApplication

• sNDAsNDA– Label ChangesLabel Changes– New DoseNew Dose– New StrengthNew Strength– New Manufacturing ProcessNew Manufacturing Process

1919

Essentials of Clinical Essentials of Clinical ResearchResearch

Phases of Clinical ResearchPhases of Clinical Research

Basics of Clinical ResearchBasics of Clinical Research

Clinical Study Design Clinical Study Design

2020

Factoid….Factoid….

Over 700,000 physicians in the US, only 4% Over 700,000 physicians in the US, only 4% of them have participated in clinical trials of them have participated in clinical trials since 1988.since 1988.11

1: www. Quintiles.com/investigative services1: www. Quintiles.com/investigative services

2121

Reasons physicians participate in Reasons physicians participate in clinical researchclinical research

• Assist in collection of scientific informationAssist in collection of scientific information

• Address questions of local importance Address questions of local importance

• Raise scholarly standardsRaise scholarly standards

• Build reputation among peers and communityBuild reputation among peers and community

• Encourage creativity and independent thinkingEncourage creativity and independent thinking

• Provide novel therapies for their patientsProvide novel therapies for their patients

• Provide source of revenueProvide source of revenue

2222

Who’s Who in Clinical Who’s Who in Clinical ResearchResearch

FDAFDA

Sponsor (e.g. Pharma, NIH, WHO, etc.)Sponsor (e.g. Pharma, NIH, WHO, etc.)

Contract/Clinical Research Organization (CRO)Contract/Clinical Research Organization (CRO)

Medical Medical DirectorDirector

Project Project ManagerManager

Clinical ResearchClinical ResearchAssociate (CRA)Associate (CRA)

RegulatoryRegulatoryPersonnelPersonnel

InvestigatorInvestigatorSub-InvestigatorSub-Investigator

IRB / IECIRB / IEC

Clinical Research CoordinatorClinical Research Coordinator

Study Subjects (patients)

2323

Clinical Research Associate Clinical Research Associate (CRA)(CRA)

• Also known as a monitorAlso known as a monitor

• Assures study is conducted and Assures study is conducted and

documented properly according to requirements documented properly according to requirements

(ICH GCP5.18.4)(ICH GCP5.18.4)

• Operates under FDA regulations and principles of GCPOperates under FDA regulations and principles of GCP

(Good Clinical Practice)(Good Clinical Practice)

• May be employees of sponsor or CRO, or independentMay be employees of sponsor or CRO, or independent

2424

Investigative SitesInvestigative Sites

• Clinical research occurs in a Clinical research occurs in a variety of settingsvariety of settings– Private practicePrivate practice– Private practice with a Private practice with a

separate research facilityseparate research facility– Clinical research facilityClinical research facility– Academic or hospital Academic or hospital

research facilityresearch facility– Government (e.g., NIH)Government (e.g., NIH)

ICH GCP 1.59

2525

InvestigatorInvestigator Sub - Sub -investigatorinvestigator

““Any individual member Any individual member of the clinical trial of the clinical trial team designated and team designated and supervised by the supervised by the investigatorinvestigator at a trial at a trial site to perform critical site to perform critical trial related procedures trial related procedures and/or to make and/or to make important trial-related important trial-related decisions” decisions”

(ICH GCP 1.56)(ICH GCP 1.56)

• Person Person responsibleresponsible for for the conduct of the the conduct of the clinical trial at a trial clinical trial at a trial site site

• If conducted by a If conducted by a team, the investigator team, the investigator is the responsible is the responsible leaderleader of the team and of the team and may be called the may be called the principal investigator principal investigator (PI)(PI)

(ICH GCP 1.34)(ICH GCP 1.34)

2626

Clinical Research Coordinator Clinical Research Coordinator (CRC)(CRC)

• May also be called a Clinical Trial CoordinatorMay also be called a Clinical Trial Coordinator

• Often a nurse at the siteOften a nurse at the site

• Functions as extension of investigatorsFunctions as extension of investigators

• Has personal contact with the human subjectsHas personal contact with the human subjects

• Involved in operational dutiesInvolved in operational duties– recruitingrecruiting– schedulingscheduling– completing CRFscompleting CRFs– administering testsadministering tests

• Not Not specificallyspecifically mentioned in the FDA regulations mentioned in the FDA regulations

• RarelyRarely may be listed under FDA 1572 as a sub-investigator may be listed under FDA 1572 as a sub-investigator

2727

Institutional Review Board Institutional Review Board (IRB)(IRB)

• Required for each research institution (minimum 5 Required for each research institution (minimum 5 members) members)

• Must review protocol for:Must review protocol for:– merit and ethicsmerit and ethics– consent process / documentsconsent process / documents

• TypesTypes– LocalLocal

•found at almost all university/academic centersfound at almost all university/academic centers

•meets weekly to monthlymeets weekly to monthly– CentralCentral

•used by clinical research facilities which are used by clinical research facilities which are without academic affiliation.without academic affiliation.

•quicker response quicker response

2828

IRBIRB

The investigator must furnish the IRB with the The investigator must furnish the IRB with the following documents for review and approval:following documents for review and approval:

• Trial ProtocolTrial Protocol

• Written Informed Consent FormsWritten Informed Consent Forms

• Written Information for Subjects (Advertisements)Written Information for Subjects (Advertisements)

• Information about compensation to patientsInformation about compensation to patients

• Investigator BrochureInvestigator Brochure

• Available (or additional) Safety InformationAvailable (or additional) Safety Information

• Investigator’s CVInvestigator’s CV

• All amendments to study protocolAll amendments to study protocol

2929

IRBIRB

The IRB’s possible responses:The IRB’s possible responses:

• approval or favorable opinionapproval or favorable opinion

• modifications required for approvalmodifications required for approval

• disapproval or negative opiniondisapproval or negative opinion

• withdrawal or suspension of an earlier approvalwithdrawal or suspension of an earlier approval

No subjects should be enrolled until the IRB has No subjects should be enrolled until the IRB has issued an approval (21 CFR issued an approval (21 CFR §56.109)§56.109)

3030

Planning and Initiating a Clinical Planning and Initiating a Clinical TrialTrial

Investigator selectionInvestigator selection

Initiating a Clinical TrialInitiating a Clinical Trial– Study DocumentsStudy Documents– IRB/IECIRB/IEC– Contract/BudgetContract/Budget– Investigators’ MeetingInvestigators’ Meeting– Document Filing & TrackingDocument Filing & Tracking

3131

Investigator SelectionInvestigator Selection

• FDA mandates that a sponsor shall select FDA mandates that a sponsor shall select only investigators (21 CFR only investigators (21 CFR §312.53, ICH §312.53, ICH GCP 4) that:GCP 4) that:

– Are qualified by training and experience as Are qualified by training and experience as appropriate experts to investigate the drugappropriate experts to investigate the drug

– Provide evidence of such qualifications Provide evidence of such qualifications

3232


• Investigator CharacteristicsInvestigator Characteristics

• PersonnelPersonnel– CRC : trained, certified, full-time?CRC : trained, certified, full-time?– Work schedulesWork schedules

• FacilityFacility– SpaceSpace– EquipmentEquipment

• IRBIRB

• PatientsPatients

3333


Investigator’s Characteristics (general)Investigator’s Characteristics (general)

• Prior clinical research experiencePrior clinical research experience

• Experience conducting similar research Experience conducting similar research trialstrials

• Research interestsResearch interests

• Experience with new and marketed drugsExperience with new and marketed drugs

• Publications from previous researchPublications from previous research

• Current competing trialsCurrent competing trials

3434


Investigator’s Characteristics Investigator’s Characteristics

(protocol-specific)(protocol-specific)

• Is investigator interested in the study?Is investigator interested in the study?

• Does the site have the necessary patient Does the site have the necessary patient population? (e.g. minority %, drug-naïve, population? (e.g. minority %, drug-naïve, etc)etc)

• If special procedures are necessary, does If special procedures are necessary, does this site have the capability to do this?this site have the capability to do this?

• Central vs. local IRB. What is the timetable Central vs. local IRB. What is the timetable for this study?for this study?

3535


Sponsor’s Tour of Facility / Site visitSponsor’s Tour of Facility / Site visit• Drug StorageDrug Storage

• On-site LaboratoryOn-site Laboratory

• Exam Rooms and Storage areaExam Rooms and Storage area

– CRFs, lab kits, and other study suppliesCRFs, lab kits, and other study supplies

• Special EquipmentSpecial Equipment– ECG, Freezer, lab equipment, defibrillator and ECG, Freezer, lab equipment, defibrillator and rescue medsrescue meds

• Place for CRA to monitorPlace for CRA to monitor– Desk, phone, access to copier, CRFs, source docs, etc.Desk, phone, access to copier, CRFs, source docs, etc.

• Sample of source documentsSample of source documents

3636

Planning and Initiating a Clinical Planning and Initiating a Clinical TrialTrial

Investigator selectionInvestigator selection

Initiating a Clinical TrialInitiating a Clinical Trial– Study DocumentsStudy Documents– IRB/IECIRB/IEC– Contract/BudgetContract/Budget– Investigators’ MeetingInvestigators’ Meeting– Document Filing & TrackingDocument Filing & Tracking

3737

Study DocumentsStudy Documents

• Protocol and Signed Protocol Signature PageProtocol and Signed Protocol Signature Page

• Approved Informed ConsentApproved Informed Consent

• Signed Form FDA 1572Signed Form FDA 1572

• Investigator BrochureInvestigator Brochure

• Case Report Form (CRF)Case Report Form (CRF)

• Clinical Trial Agreements and BudgetClinical Trial Agreements and Budget

• IRB Approvals and membership rosterIRB Approvals and membership roster

• Curriculum Vitae of Investigator(s) and Copy of Curriculum Vitae of Investigator(s) and Copy of Medical LicenseMedical License

• Lab Normal Ranges and CertificationsLab Normal Ranges and Certifications

• Financial Disclosure FormsFinancial Disclosure Forms

3838


Informed Consent FormInformed Consent Form

• Informed consent is a Informed consent is a processprocess

• A joint effort by the sponsor and the A joint effort by the sponsor and the investigatorinvestigator

• Must be approved by the IRB and the Must be approved by the IRB and the sponsor, and accepted by the investigatorsponsor, and accepted by the investigator

3939


Form FDA 1572 Form FDA 1572

The regulatory document which, when The regulatory document which, when signed by the investigator, commits signed by the investigator, commits him/her to follow the regulatory him/her to follow the regulatory requirements under penalty of law.requirements under penalty of law.

Form 1572

4040


Investigator Brochure (IB)Investigator Brochure (IB)

• Provides Information on the drug’sProvides Information on the drug’s– Pharmacology,Pharmacology,– ToxicologyToxicology– Adverse experience profileAdverse experience profile

• Updated each yearUpdated each year– Or sooner if needed, due to amendmentsOr sooner if needed, due to amendments

21 CFR 312.53

4141


Source DocumentsSource Documents

• First place where information is recorded, either on First place where information is recorded, either on paper or computer paper or computer

• All entries must be All entries must be signed and datedsigned and dated

• Include any deviations from the study protocol or Include any deviations from the study protocol or proceduresprocedures

• Record of explanations for unexpected occurrencesRecord of explanations for unexpected occurrences

4242


Case Report Forms (CRFs)Case Report Forms (CRFs)

• Used to record data on all subjectsUsed to record data on all subjects

• Monitored to verify that trial records and data are valid, Monitored to verify that trial records and data are valid, accurate, complete, and up to dateaccurate, complete, and up to date

• Provide data for analysis and reporting after the trial is Provide data for analysis and reporting after the trial is completedcompleted

• Often electronic (eCRF’s)Often electronic (eCRF’s)

4343


• Clinic charts, doctors’ notes, nursing notes, Clinic charts, doctors’ notes, nursing notes, pharmacy notes, original laboratory results, and pharmacy notes, original laboratory results, and patient diaries for each study subject must be patient diaries for each study subject must be available for review by the sponsor and the FDA available for review by the sponsor and the FDA

• Records of all study events and patient visits Records of all study events and patient visits need to be maintainedneed to be maintained

• All source documents must be available during All source documents must be available during routine monitoring visitsroutine monitoring visits

4444

Investigator’s MeetingInvestigator’s Meeting

• Review protocol and proceduresReview protocol and procedures

• Get better acquainted with the sponsor and other Get better acquainted with the sponsor and other investigatorsinvestigators

• Answer outstanding questionsAnswer outstanding questions

• Generate enthusiasm for the trialGenerate enthusiasm for the trial

and for recruitmentand for recruitment

• Identify potential problemsIdentify potential problems

• May serve as the initiation visitMay serve as the initiation visit

4545

Investigator’s MeetingInvestigator’s Meeting

• Study Coordinators and sub-investigators Study Coordinators and sub-investigators should also attend the meeting or hold a should also attend the meeting or hold a separate discussion of their ownseparate discussion of their own

• Sponsor participants include the medical Sponsor participants include the medical expert, biostatistician, CRAs, and CRO expert, biostatistician, CRAs, and CRO personnelpersonnel

4646

Conducting a Clinical Conducting a Clinical Trial ITrial I

Good Clinical Practice Good Clinical Practice

Drug AccountabilityDrug Accountability

Subject RecruitmentSubject Recruitment

Informed Consent Informed Consent

Protocol AdherenceProtocol Adherence

Case Report Form & Source DocumentCase Report Form & Source Document

Sponsor Monitoring Sponsor Monitoring

Safety ReportingSafety Reporting

4747

GOOD CLINICAL PRACTICE (GCP) GOOD CLINICAL PRACTICE (GCP) BASIC TENETSBASIC TENETS

• Study is well-designed and follows scientific principlesStudy is well-designed and follows scientific principles

• IRB approval is required to insure rights and safety of subjectsIRB approval is required to insure rights and safety of subjects

• Informed consent freely givenInformed consent freely given

• Sponsor/institution monitors study for GCP complianceSponsor/institution monitors study for GCP compliance

• Investigator accountable for all drugs/devicesInvestigator accountable for all drugs/devices

• Records must be kept properlyRecords must be kept properly

• Data must be complete and accurateData must be complete and accurate

• Quality assurance plans must be in placeQuality assurance plans must be in place

4848


Study MedicationStudy Medication

• Cannot be shipped until the sponsor obtains all Cannot be shipped until the sponsor obtains all required documentation (e.g. IRB approval, CV’s, required documentation (e.g. IRB approval, CV’s, etc). etc).

• Must be verified upon receiptMust be verified upon receipt• Must be stored Must be stored

– in a secured cabinetin a secured cabinet– preferably in a secured room/areapreferably in a secured room/area– per investigator’s brochure, protocol, or per investigator’s brochure, protocol, or

package insertpackage insert• A current log must be maintained. Verified by CRA A current log must be maintained. Verified by CRA

during visits.during visits. ICH 5.18.14 ICH 5.18.14

ICH 5.14, 21 CFR 312.61, 21 CFR 312.57

4949

Subject RecruitmentSubject Recruitment

• Investigator’s patient populationInvestigator’s patient population

• Referrals from other physicians and clinicsReferrals from other physicians and clinics

• Direct advertisement, which must be Direct advertisement, which must be approved by the IRBapproved by the IRB

5050

Informed ConsentInformed Consent

• Must be obtained Must be obtained beforebefore subjects participate in subjects participate in anyany clinical clinical trial procedure (21 CFR trial procedure (21 CFR §§ 50), and 50), and mustmust be dated. be dated.

• Should be written at the 7Should be written at the 7thth grade reading level grade reading level

• Must explain medical termsMust explain medical terms

• Should be provided in patient’s native languageShould be provided in patient’s native language

• Should Should notnot make it appear that rights have been waived by make it appear that rights have been waived by the participant or liability released by the investigator, the participant or liability released by the investigator, sponsor or institutionsponsor or institution

• Consent is a Consent is a processprocess

5151

Informed ConsentInformed Consent• Eight basic elements of informed consent (21 CFR Eight basic elements of informed consent (21 CFR

§§ 50.25) 50.25)– Trial involves research, purpose of the researchTrial involves research, purpose of the research– A description of any reasonably foreseeable risks or discomfortsA description of any reasonably foreseeable risks or discomforts– A description of any benefits to the subject which may reasonable A description of any benefits to the subject which may reasonable

be expected from the researchbe expected from the research– A disclosure of appropriate alternative procedures or treatment that A disclosure of appropriate alternative procedures or treatment that

may be available to the subjectmay be available to the subject– A statement describing the extent to which confidentiality of records A statement describing the extent to which confidentiality of records

identifying the subject will be maintainedidentifying the subject will be maintained– An explanation as to whether any compensation and whether any An explanation as to whether any compensation and whether any

medical treatments are available if injury occursmedical treatments are available if injury occurs– An explanation of whom to contact for answers to questions about An explanation of whom to contact for answers to questions about

the research and research subjects’ rights the research and research subjects’ rights – A statement that participation is voluntaryA statement that participation is voluntary

5252

Protocol AdherenceProtocol Adherence

• Research studies Research studies mustmust be be conducted conducted as detailedas detailed in the in the study protocolstudy protocol

• Amendments to the protocol are Amendments to the protocol are conveyed to the PI in writing; conveyed to the PI in writing; the PI must sign and return the PI must sign and return signature page to sponsorsignature page to sponsor

• Amendment or any change Amendment or any change requires IRB approvalrequires IRB approval

5353

Case Report Form &Case Report Form &Source DocumentSource Document

Definition: Case Report Form (CRF)Definition: Case Report Form (CRF)

• ““A printed, optical, or electronic document A printed, optical, or electronic document designed to record all of the protocol-required designed to record all of the protocol-required information to be reported to the sponsor on each information to be reported to the sponsor on each trial subject.” (ICH GCP1.11)trial subject.” (ICH GCP1.11)

• Generally organized by subject, visit, and Generally organized by subject, visit, and sequential/chronological ordersequential/chronological order

5454

Case Report Form & Case Report Form & Source DocumentSource Document

Definition: Source Documents (SD)Definition: Source Documents (SD)• ““Original documents, data, and records (e.g., Original documents, data, and records (e.g.,

hospital records, clinical and office charts hospital records, clinical and office charts laboratory notes [sic], memoranda, subjects’ laboratory notes [sic], memoranda, subjects’ diaries or evaluation checklists, pharmacy diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated dispensing records, recorded data from automated instruments, copies or transcriptions certified after instruments, copies or transcriptions certified after verification as being accurate and complete, verification as being accurate and complete, microfiches, photographic negatives, microfilm or microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the medico-technical departments involved in the clinical trial).” clinical trial).” (ICH GCP 1.52)(ICH GCP 1.52)

5555

Sponsor MonitoringSponsor Monitoring

Types of Monitoring visitsTypes of Monitoring visits

• Pre-study or evaluation (“screening visit”)Pre-study or evaluation (“screening visit”)

• Initiation Initiation

• Interim-monitoring Interim-monitoring

• AuditAudit

• Close-out Close-out

5656

SponsorSponsor Monitoring Monitoring

PurposePurpose

• To verifyTo verify– protection of rights and well-being of subjectsprotection of rights and well-being of subjects– reported trial data is accurate, complete, and verifiable reported trial data is accurate, complete, and verifiable

– trial is in compliance with:trial is in compliance with:

• Protocol and amendmentsProtocol and amendments

• Regulatory requirementsRegulatory requirements

• EnrollmentEnrollment

• Drug supplyDrug supply

ICH GCP 5.18.1ICH GCP 5.18.1

5757


A Federal regulation:A Federal regulation: “an investigator “an investigator shall promptly report to the sponsor any shall promptly report to the sponsor any adverse effect that may reasonably be adverse effect that may reasonably be regarded as caused by, or probably regarded as caused by, or probably caused by, the drug. If the adverse caused by, the drug. If the adverse effect is alarming, the investigator shall effect is alarming, the investigator shall report the adverse effect immediately.” report the adverse effect immediately.” ((21 CFR 21 CFR §§ 312.64) 312.64)

5858


• Investigator should report SAEs to sponsor and to IRB Investigator should report SAEs to sponsor and to IRB within 24 hourswithin 24 hours

• ““Serious” does not mean “severe,” which describes Serious” does not mean “severe,” which describes intensityintensity

• Follow up required with subject, sponsor and IRBFollow up required with subject, sponsor and IRB

ICH GCP 4.11.1ICH GCP 4.11.1

5959

Closing Out a Clinical TrialClosing Out a Clinical Trial

Close-out VisitClose-out Visit


Record RetentionRecord Retention

6060

Close-Out VisitClose-Out Visit

• A study close-out A study close-out visit is requiredvisit is required – at study completionat study completion– decision to decision to

terminate the study terminate the study short of completionshort of completion

– Drop-out of a siteDrop-out of a site

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Objectives of the Close-Out Objectives of the Close-Out VisitVisit

• Verify that the investigator’s study files are Verify that the investigator’s study files are complete complete

• Ensure that regulatory requirements for Ensure that regulatory requirements for retention of records are understoodretention of records are understood

• Review final reporting requirements with Review final reporting requirements with the investigatorthe investigator

• Ensure all data is completeEnsure all data is complete

• Ensure that all supplies are Ensure that all supplies are

returned, destroyed or returned, destroyed or

placed in compassionate useplaced in compassionate use

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• A final reconciliation of all A final reconciliation of all

study drugstudy drug

• Drug dispensing logs will be Drug dispensing logs will be

verified against a physical verified against a physical

inventory inventory

• All drug on-site at the close-out All drug on-site at the close-out

visit will either be disposed of at visit will either be disposed of at

the visit or shipped back to the the visit or shipped back to the sponsorsponsor

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Record RetentionRecord Retention

• Essential documents should be Essential documents should be retained until at least 2 years. retained until at least 2 years. CFR CFR 312.62312.62

(Novartis requires 15 years)(Novartis requires 15 years)

• It is the responsibility of the sponsor to It is the responsibility of the sponsor to inform the investigator/institution as inform the investigator/institution as to when these documents no longer to when these documents no longer need to be retained. need to be retained. ICH GCP 4.9.5ICH GCP 4.9.5

• If an investigator leaves an institution, If an investigator leaves an institution, he/she must transfer responsibilities he/she must transfer responsibilities for record retention to another for record retention to another physician and notify the sponsor in physician and notify the sponsor in writing.writing.

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How to Get Involved in Company How to Get Involved in Company Sponsored ResearchSponsored Research

• Company PlannedCompany Planned– Work with PI to gain experienceWork with PI to gain experience– Get to know Clinical Research Associate or Get to know Clinical Research Associate or

Regional Scientific Director/Medical LiaisonRegional Scientific Director/Medical Liaison

• Investigator Initiated ResearchInvestigator Initiated Research– Each company has different processEach company has different process– Work with Regional Scientific Director/Medical Work with Regional Scientific Director/Medical

LiaisonLiaison

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Questions?Questions?

drug development process

Documents

remaining clinical trial

clinical data nonclinical

clinical trials ind

completion of phase

phase iisafety

conclusion of phase

yrs10 phase

clinical trials registration