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Drug Development Process&
How to Get Involved in Company
Sponsored Research
Catherine Delaney Freiman, Ph.D.
Regional Scientific Associate Director, Neuroscience
Novartis US Clinical Development & Medical Affairs
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Fundamental Clinical Development
Essentials of Clinical Research Phases of Drug Development Basics of Drug Development Clinical Research Design
Planning and Initiating a Clinical TrialCompany Sponsored
Investigator Selection Initiating a Clinical Trial
Conducting a Clinical TrialCompany Sponsored GCP Informed Consents Case Report Forms and Source Documents Safety Reporting Study Close-out
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Essentials of Clinical Research
Phases of Clinical Research
Basics of Clinical Research
Clinical Study Design
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Research Concept &Discover Active Lead
Compound
2-20 years research
8,000-10,000 potential
Candidate substances
Research
Target
Discovery
of lead
compound
Selection
of
product
candidate
Preclinical Testing
2-3 years development
20-30 remaining 5-10 remaining
Substances substances
Biological
Tests
Regulatory
clearance
Pharmacy/
Chemical
Development
Clinical Trials
3-5 years development
4-5 2-3
Remaining substances1 remaining
Clinical
Trial
Phase 1
Phase 2
Phase 3
Biological Tests
Pharmacy/ChemicalDevelopment
Registration,Launch and
Sales
2-3 years development
1 remaining substance
Registration Launch
with and
Health Sales
Authorities
Preparation
for
Launch
Drug Development Process
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Phase IVPhase IIIPhase IIbPhase IIaClinical Trials
Phase 1
Pre-clinicalPhase
CandidateProfilingPhase
DiscoveryPhase
An Overview:
Drug Development Timeline
Life CycleManagement
FullDevelopment
Early
DevelopmentResearch
Candidate
SelectionPoint
CSP sPoC DDP FDP 3CP SDP
Selectedfor
ProofofConcept
Development
DecisionPoint
Full
DevelopmentP
oint
PhaseIII
Checkpoint
Submission
DecisionPoint
INDInvestigational New Drug NDA New Drug Application
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Discovery of Active Lead Compounds
Complicated, time-consuming and costly process 2-20 years
Hundreds to thousands of chemicalcompounds/biologics/botanicals must be screened Up to 10,000 screened
No standard route through which drugs are developed
Some major sources of new drugs:
Synthetic compounds Discovery of a new use for an old-drug Natural chemical
Process: Research Target Discovery of Lead Compound
Candidate Selection
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Pre-Clinical Research
Animal pharmacology/toxicology testingIs itsafe to proceed to human trials?(The Nuremberg Code)
Approximately 2-3 yrs development 20-30 substances
Minimum FDA requirements: pharmacological profile Determine acute toxicity in at least 2 species of
animals Conduct short-term toxicity studies (2 wks 3 mos)
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Investigational New Drug Application(IND)
Documentation that allows investigational clinical testingof a new medicine
Must be filed with FDA before drug administered tohumans
Studies may begin within 30 days of application..if noresponse from the FDA An IND contains the following sections
Table of contents - Protocols for each planned study Introduction - Investigator
Investigators Brochure - Facilities and IRB General investigational plan - Manufacturing and control Previous human experience - Additional information Pharmacology & toxicology
21 CFR 312.23
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Clinical Trials
IND filed first 3-5 years
Process: Clinical Trials - Phase I Phase III
On-going Biological tests (safety)
On-going formulation work
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Clinical Trials - Phases
1-5 yrsHundreds-thousands
Subjects withindications
New indications,
QoL, surveillanceIV
2-3 yrsHundreds-thousands
Subjects withindications
Safety & efficacy
Basis for labeling,
new formulations
III
1-2 yrsSeveralhundred
Subjects withindications
Short-term side
effects & efficacyII
6-12 mos20-80
Healthyvolunteers or
subj. w/indications
Safety, ADME,bioactivity,
drug-drug interaction
I
Length(per phase)
ScopeSubjectsPurposePhase
21 CFR 312.21
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Phase I
First time in human subjects Small number of healthy volunteers or
severely ill patients
Safety profile and dosage range Single and multi-dose studies Pharmacokinetics / pharmacodynamics Open label, often single center
Not always performed in the U.S.
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Phase II
Safety, side effects Efficacy dose response Double-blind, positive control or placebo, multi-center
utilizing a limited number of subjects (100-300); often
the first time drug is used in population for which it isintended
Phase IIa proof of concept, pilot, feasibility, usuallyhealthy volunteers
Phase IIb well-controlled in target population Following completion of Phase II, meet with the FDA topave the way for pivotal trials
21 CFR 312.47
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Phase III
2 or 3 studies are pivotal (critical) studies To prove safety and efficacy of primary endpoints
Double-blind, positive or placebo control, multi-center
Study population resembles the intended population
Support package labeling
New Drug Application (NDA)
Special population, concomitant medications, multipleillnesses, etc.
IIIb studies post NDA-submission trial looking atadditional indications
Pre-NDA meeting with the FDA near conclusion of
Phase III 21 CFR 312.47
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New Drug Application (NDA)
The average NDA is 100,000 pages or longer Must provide all relevant data collected during R&D Consists of:
Index - non-clinical pharm - clinical data
non-clinical pharm - human toxicity - CRFs safety update - case report tabulations
pediatric data - statistics
PK / Bioavailability - patent information / certification
ISES (Integrated Summary of Efficacy and Safety)
CER (Clinical Expert Report summary of drug impact, how data supports)
CSR (Clinical Study Reports)
Can now be filed electronically(a CTD = Commercial Technical Document)
Review process: Target 10 months (but often longer)
21 CFR 314.50
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NDA Review Process
Review Process
standard
expedited (in the case of life threatening diseases
for which the only medications available are oflittle or limited effectiveness, e.g. ALS).
Results of Review
Approvable
ApprovedDenied
Negotiation of the labeling processwww.fda.gov
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Registration & Launch
Product Registration andLaunch
2 - 3 years
Process: Register Product with
Health Authorities (FDA)
Prepare Sales Teams
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Phase IV
Post-licensure studies to confirm the safety in largepopulation (after NDA is filed)
Phase IV commitments Possible types of studies
Compared versus competition
Post-marketing surveillance
Special population
Rare event incidencesAdditional long-term usage safety data
Pharmacoecomonic and Quality of Life (QoL)
21 CFR 312.85
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Supplemental New Drug Application
sNDA Label Changes
New Dose New Strength
New Manufacturing Process
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Essentials of Clinical Research
Phases of Clinical Research
Basics of Clinical Research
Clinical Study Design
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Factoid.
Over 700,000 physicians in the US, only
4% of them have participated in clinical
trials since 1988.1
1: www. Quintiles.com/investigative services
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Reasons physicians participate in clinicalresearch
Assist in collection of scientific information
Address questions of local importance
Raise scholarly standards
Build reputation among peers and community
Encourage creativity and independent thinking Provide novel therapies for their patients Provide source of revenue
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Whos Who in Clinical Research
FDA
Sponsor (e.g. Pharma, NIH, WHO, etc.)
Contract/Clinical Research Organization (CRO)
MedicalDirector
ProjectManager
Clinical ResearchAssociate (CRA)
RegulatoryPersonnel
InvestigatorSub-Investigator
IRB / IEC
Clinical Research Coordinator
Study Subjects (patients)
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Clinical Research Associate (CRA)
Also known as a monitor
Assures study is conducted anddocumented properly according to requirements(ICH GCP5.18.4)
Operates under FDA regulations and principles of GCP(Good Clinical Practice)
May be employees of sponsor or CRO, or independent
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Investigative Sites
Clinical research occurs in a varietyof settings
Private practice
Private practice with a separateresearch facility
Clinical research facility
Academic or hospital researchfacility
Government (e.g., NIH)
ICH GCP 1.59
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Investigator Sub -investigator
Any individual member of
the clinical trial team
designated and
supervised by the
investigator at a trial site
to perform critical trial
related procedures
and/or to make important
trial-related decisions
(ICH GCP 1.56)
Person responsible for theconduct of the clinical
trial at a trial site
If conducted by a team,the investigator is the
responsible leader of the
team and may be called
the principal investigator(PI)
(ICH GCP 1.34)
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Clinical Research Coordinator (CRC)
May also be called a Clinical Trial Coordinator Often a nurse at the site
Functions as extension of investigators
Has personal contact with the human subjects
Involved in operational duties recruiting scheduling completing CRFs administering tests
Not specifically mentioned in the FDA regulations
Rarely may be listed under FDA 1572 as a sub-investigator
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Institutional Review Board (IRB)
Required for each research institution (minimum 5 members) Must review protocol for:
merit and ethics
consent process / documents
Types Local
found at almost all university/academic centers
meets weekly to monthly Central
used by clinical research facilities which are withoutacademic affiliation.
quicker response
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IRB
The investigator must furnish the IRB with the
following documents for review and approval:
Trial Protocol
Written Informed Consent Forms Written Information for Subjects (Advertisements) Information about compensation to patients Investigator Brochure Available (or additional) Safety Information Investigators CV All amendments to study protocol
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IRB
The IRBs possible responses:
approval or favorable opinion modifications required for approval disapproval or negative opinion withdrawal or suspension of an earlier approval
No subjects should be enrolled until the IRB has issuedan approval (21 CFR56.109)
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Planning and Initiating a Clinical Trial
Investigator selection
Initiating a Clinical Trial
Study Documents
IRB/IEC
Contract/Budget
Investigators Meeting
Document Filing & Tracking
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Investigator Selection
FDA mandates that a sponsor shall select onlyinvestigators (21 CFR312.53, ICH GCP 4) that:
Are qualified by training and experience asappropriate experts to investigate the drug
Provide evidence of such qualifications
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Investigator Selection
Investigator Characteristics
Personnel CRC : trained, certified, full-time?
Work schedules
Facility Space Equipment
IRB
Patients
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Investigator Selection
Investigators Characteristics (general) Prior clinical research experience Experience conducting similar research trials
Research interests Experience with new and marketed drugs Publications from previous research
Current competing trials
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Investigator Selection
Investigators Characteristics(protocol-specific)
Is investigator interested in the study?
Does the site have the necessary patientpopulation? (e.g. minority %, drug-nave, etc)
If special procedures are necessary, does this sitehave the capability to do this?
Central vs. local IRB. What is the timetable forthis study?
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Investigator Selection
Sponsors Tour of Facility / Site visit Drug Storage
On-site Laboratory
Exam Rooms and Storage area CRFs, lab kits, and other study supplies
Special Equipment ECG, Freezer, lab equipment, defibrillator and
rescue meds
Place for CRA to monitor Desk, phone, access to copier, CRFs, source docs, etc.
Sample of source documents
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Planning and Initiating a Clinical Trial
Investigator selection
Initiating a Clinical Trial
Study Documents IRB/IEC
Contract/Budget
Investigators Meeting
Document Filing & Tracking
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Study Documents
Protocol and Signed Protocol Signature Page Approved Informed Consent Signed Form FDA 1572
Investigator Brochure Case Report Form (CRF) Clinical Trial Agreements and Budget IRB Approvals and membership roster
Curriculum Vitae of Investigator(s) and Copy of MedicalLicense
Lab Normal Ranges and Certifications Financial Disclosure Forms
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Study Documents
Informed Consent Form
Informed consent is a process
A joint effort by the sponsor and the investigator
Must be approved by the IRB and the sponsor,and accepted by the investigator
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Study Documents
Form FDA 1572
The regulatory document which, when signed by
the investigator, commits him/her to follow theregulatory requirements under penalty of law.
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Study Documents
Investigator Brochure (IB)
Provides Information on the drugs Pharmacology,
Toxicology
Adverse experience profile
Updated each year Or sooner if needed, due to amendments
21 CFR 312.53
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Study Documents
Source Documents
First place where information is recorded, either onpaper or computer
All entries must be signed and dated
Include any deviations from the study protocol orprocedures
Record of explanations for unexpected occurrences
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Study Documents
Case Report Forms (CRFs)
Used to record data on all subjects
Monitored to verify that trial records and data are valid,accurate, complete, and up to date
Provide data for analysis and reporting after the trial iscompleted
Often electronic (eCRFs)
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Study Documents
Clinic charts, doctors notes, nursing notes, pharmacynotes, original laboratory results, and patient diaries foreach study subject must be available for review by the
sponsor and the FDA
Records of all study events and patient visits need to bemaintained
All source documents must be available during routinemonitoring visits
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Investigators Meeting
Review protocol and procedures
Get better acquainted with the sponsor and otherinvestigators
Answer outstanding questions
Generate enthusiasm for the trial
and for recruitment
Identify potential problems
May serve as the initiation visit
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Investigators Meeting
Study Coordinators and sub-investigators shouldalso attend the meeting or hold a separatediscussion of their own
Sponsor participants include the medical expert,biostatistician, CRAs, and CRO personnel
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Conducting a Clinical Trial I
Good Clinical Practice
Drug Accountability
Subject Recruitment
Informed ConsentProtocol Adherence
Case Report Form & Source Document
Sponsor Monitoring
Safety Reporting
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GOOD CLINICAL PRACTICE (GCP)BASIC TENETS
Study is well-designed and follows scientific principles
IRB approval is required to insure rights and safety ofsubjects
Informed consent freely given
Sponsor/institution monitors study for GCP compliance
Investigator accountable for all drugs/devices
Records must be kept properly
Data must be complete and accurate
Quality assurance plans must be in place
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Drug Accountability
Study Medication
Cannot be shipped until the sponsor obtains all requireddocumentation (e.g. IRB approval, CVs, etc).
Must be verified upon receipt
Must be stored in a secured cabinet preferably in a secured room/area per investigators brochure, protocol, or package
insert A current log must be maintained. Verified by CRA
during visits. ICH 5.18.14
ICH 5.14, 21 CFR 312.61, 21 CFR 312.57
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Subject Recruitment
Investigators patient population
Referrals from other physicians and clinics
Direct advertisement, which must be approved bythe IRB
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Informed Consent
Must be obtained beforesubjects participate in anyclinical trialprocedure (21 CFR 50), and mustbe dated.
Should be written at the 7th grade reading level
Must explain medical terms
Should be provided in patients native language
Should not make it appear that rights have been waived by theparticipant or liability released by the investigator, sponsor orinstitution
Consent is aprocess
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Informed Consent
Eight basic elements of informed consent (21 CFR50.25) Trial involves research, purpose of the research
A description of any reasonably foreseeable risks or discomforts
A description of any benefits to the subject which may reasonable be
expected from the research A disclosure of appropriate alternative procedures or treatment that
may be available to the subject
A statement describing the extent to which confidentiality of recordsidentifying the subject will be maintained
An explanation as to whether any compensation and whether anymedical treatments are available if injury occurs
An explanation of whom to contact for answers to questions about theresearch and research subjects rights
A statement that participation is voluntary
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Case Report Form &
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Case Report Form &Source Document
Definition: Case Report Form (CRF)
A printed, optical, or electronic document designed to
record all of the protocol-required information to bereported to the sponsor on each trial subject. (ICHGCP1.11)
Generally organized by subject, visit, andsequential/chronological order
Case Report Form &
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Case Report Form &Source Document
Definition: Source Documents (SD) Original documents, data, and records (e.g., hospital
records, clinical and office charts laboratory notes [sic],memoranda, subjects diaries or evaluation checklists,
pharmacy dispensing records, recorded data fromautomated instruments, copies or transcriptions certifiedafter verification as being accurate and complete,microfiches, photographic negatives, microfilm or
magnetic media, x-rays, subject files, and records kept atthe pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial).(ICH GCP 1.52)
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Sponsor Monitoring
Types of Monitoring visits
Pre-study or evaluation (screening visit)
Initiation
Interim-monitoring
Audit Close-out
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Safety Reporting
A Federal regulation:an investigator shallpromptly report to the sponsor any adverse
effect that may reasonably be regarded ascaused by, or probably caused by, the drug.If the adverse effect is alarming, theinvestigator shall report the adverse effect
immediately. (21 CFR 312.64)
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Safety Reporting
Investigator should report SAEs to sponsor and to IRB
within 24 hours
Serious does not mean severe, which describes intensity
Follow up required with subject, sponsor and IRB
ICH GCP 4.11.1
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Closing Out a Clinical Trial
Close-out Visit
Drug Accountability
Record Retention
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Objectives of the Close-Out Visit
Verify that the investigators study files arecomplete
Ensure that regulatory requirements for retentionof records are understood
Review final reporting requirements with theinvestigator
Ensure all data is complete
Ensure that all supplies arereturned, destroyed or
placed in compassionate use
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Drug Accountability
A final reconciliation of allstudy drug
Drug dispensing logs will beverified against a physical
inventory
All drug on-site at the close-outvisit will either be disposed of at
the visit or shipped back to the sponsor
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Record Retention
Essential documents should be retaineduntil at least 2 years. CFR 312.62
(Novartis requires 15 years)
It is the responsibility of the sponsor toinform the investigator/institution as towhen these documents no longer needto be retained.
ICH GCP 4.9.5
If an investigator leaves an institution,he/she must transfer responsibilities forrecord retention to another physicianand notify the sponsor in writing.
How to Get Involved in Company
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How to Get Involved in CompanySponsored Research
Company Planned Work with PI to gain experience
Get to know Clinical Research Associate or Regional
Scientific Director/Medical Liaison
Investigator Initiated Research
Each company has different process Work with Regional Scientific Director/Medical Liaison
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Questions?
Contact Info:
Catherine D. Freiman, PhD