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

Fundamental Clinical Development

Essentials of Clinical Research
Phases of Drug Development Basics of Drug Development Clinical Research Design

Planning and Initiating a Clinical Trial

Company Sponsored

Investigator Selection Initiating a Clinical Trial

Conducting a Clinical Trial

Company Sponsored

GCP Informed Consents Case Report Forms and Source Documents Safety Reporting Study Close-out Close2

Essentials of Clinical Research

Phases of Clinical Research Basics of Clinical Research Clinical Study Design

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Drug Development Process

Research Concept & Preclinical Testing Discover Active Lead Compound
2-20 years research 8,000-10,000 potential Candidate substances 2-3 years development 20-30 remaining Substances

Clinical Trials

Registration, Launch and Sales

2-3 years development 1 remaining substance

3-5 years development

2-3 5-10 remaining 4-5 Remaining substances substances 1 remaining

Research Target Discovery of lead compound Selection of product candidate

Biological Tests Regulatory clearance Pharmacy/ Chemical Development

Clinical Trial Phase 1 Phase 2 Phase 3

Registration Launch with and Health Sales Authorities

Biological Tests

Preparation for Launch

Pharmacy/Chemical Development

An Overview: Drug Development Timeline

Research
Discovery Phase Candidate Profiling Phase

Early Development
Pre- Clinical Trials clinical Phase 1 Phase

Full Development
Phase IIa Phase IIb

Life Cycle Management

Phase III Phase IV

CSP
Candidate Selection Point

sPoC
Selected for Proof of Concept

DDP
Development Decision Point

FDP
Full Development Point

3CP

SDP
Submission Decision Point

IND

Investigational New Drug

NDA

Phase III Checkpoint

New Drug Application

Discovery of Active Lead Compounds

Complicated, time-consuming and costly process time2-20 years

Hundreds to thousands of chemical compounds/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 oldNatural chemical

Process:

Research Target Discovery of Lead Compound Candidate Selection

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PrePre-Clinical Research
Animal pharmacology/toxicology testing safe to proceed to human trials? (The Nuremberg Code) Approximately 2-3 yrs development 220-30 substances 20-

Is it

Minimum FDA requirements:

pharmacological profile Determine acute toxicity in at least 2 species of animals Conduct short-term toxicity studies (2 wks 3 mos) short7

Investigational New Drug Application

(IND) Documentation that allows investigational clinical testing of a new medicine Must be filed with FDA before drug administered to humans Studies may begin within 30 days of application ..if no response from the FDA An IND contains the following sections
Table of contents - Protocols for each planned study Introduction - Investigator Investigator s Brochure - Facilities and IRB General investigational plan - Manufacturing and control Previous human experience - Additional information Pharmacology & toxicology

21 CFR 312.23 8

Clinical Trials
IND filed first 3-5 years Process:
Clinical Trials - Phase I Phase III On-going Biological tests (safety) OnOn-going formulation work On-

Clinical Trials - Phases

Phase Purpose
Safety, ADME, bioactivity, drugdrug-drug interaction ShortShort-term side effects & efficacy Safety & efficacy Basis for labeling, new formulations New indications, QoL, surveillance

Subjects
Healthy volunteers or subj. w/ indications Subjects with indications Subjects with indications Subjects with indications

Scope

Length
(per phase)

2020-80

6-12 mos

II III

Several hundred HundredsHundredsthousands HundredsHundredsthousands

21 CFR 312.21

1-2 yrs

2-3 yrs

IV

1-5 yrs
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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 multiPharmacokinetics / 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 DoubleDouble-blind, positive control or placebo, multi-center multiutilizing a limited number of subjects (100-300); often (100the first time drug is used in population for which it is intended Phase IIa proof of concept, pilot, feasibility, usually healthy volunteers Phase IIb well-controlled in target population wellFollowing completion of Phase II, meet with the FDA to pave 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, multiDoublemulticenter Study population resembles the intended population Support package labeling New Drug Application (NDA) Special population, concomitant medications, multiple illnesses, etc. IIIb studies post NDA-submission trial looking at NDAadditional indications PrePre-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 non- clinical data nonnon-clinical pharm - human toxicity - CRF s 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 21 CFR 314.50 (a CTD = Commercial Technical Document) Review process: Target 10 months (but often longer)
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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 of little or limited effectiveness, e.g. ALS).  Results of Review  Approvable  Approved  Denied  Negotiation of the labeling process 
www.fda.gov
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Registration & Launch

Product Registration and Launch 2 - 3 years Process:
Register Product with Health Authorities (FDA) Prepare Sales Teams

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Phase IV
PostPost-licensure studies to confirm the safety in large population (after NDA is filed) Phase IV commitments Possible types of studies Compared versus competition Post-marketing surveillance PostSpecial population Rare event incidences Additional long-term usage safety data longPharmacoecomonic 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 clinical research

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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Who s Who in Clinical Research

FDA Sponsor (e.g. Pharma, NIH, WHO, etc.) Contract/Clinical Research Organization (CRO)

Medical Director

Project Manager

Clinical Research Associate (CRA)

Regulatory Personnel

Investigator SubSub-Investigator Clinical Research Coordinator Study Subjects (patients)

IRB / IEC

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Clinical Research Associate (CRA)

Also known as a monitor Assures study is conducted and documented 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 variety of settings Private practice Private practice with a separate research facility Clinical research facility Academic or hospital research facility Government (e.g., NIH)
ICH GCP 1.59

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Investigator
Person responsible for the conduct 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)

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 trialtrial-related decisions (ICH GCP 1.56)

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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 sub-

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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 without academic affiliation. quicker response 27

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 Investigator s CV All amendments to study protocol
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IRB
The IRB s 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 issued an approval (21 CFR 56.109)

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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 only investigators (21 CFR 312.53, ICH GCP 4) that:
Are qualified by training and experience as appropriate experts to investigate the drug Provide evidence of such qualifications

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Investigator Selection
Investigator Characteristics Personnel
CRC : trained, certified, full-time? fullWork schedules

Facility
Space Equipment

IRB Patients
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Investigator Selection
Investigator s 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
Investigator s Characteristics (protocol(protocol-specific) Is investigator interested in the study? Does the site have the necessary patient population? (e.g. minority %, drug-nave, etc) drugIf special procedures are necessary, does this site have the capability to do this? Central vs. local IRB. What is the timetable for this study?
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Investigator Selection
Sponsor s Tour of Facility / Site visit
Drug Storage OnOn-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 Medical License 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 the regulatory requirements under penalty of law.

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Study Documents
Investigator Brochure (IB) Provides Information on the drug s
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 on paper or computer All entries must be signed and dated Include any deviations from the study protocol or procedures 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 is completed Often electronic (eCRF s)
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Study Documents
Clinic charts, doctors notes, nursing notes, pharmacy notes, original laboratory results, and patient diaries for each study subject must be available for review by the sponsor and the FDA Records of all study events and patient visits need to be maintained All source documents must be available during routine monitoring visits
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Investigator s Meeting
Review protocol and procedures Get better acquainted with the sponsor and other investigators Answer outstanding questions Generate enthusiasm for the trial and for recruitment Identify potential problems May serve as the initiation visit
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Investigator s Meeting
Study Coordinators and sub-investigators should subalso attend the meeting or hold a separate discussion 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 Consent Protocol 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 wellIRB approval is required to insure rights and safety of subjects 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 required documentation (e.g. IRB approval, CV s, etc). Must be verified upon receipt Must be stored ICH 5.14, 21 CFR 312.61, 21 CFR 312.57 in a secured cabinet preferably in a secured room/area per investigator s brochure, protocol, or package insert A current log must be maintained. Verified by CRA during visits. ICH 5.18.14
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Subject Recruitment
Investigator s patient population Referrals from other physicians and clinics Direct advertisement, which must be approved by the IRB

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Informed Consent
Must be obtained before subjects participate in any clinical trial procedure (21 CFR 50), and must be dated. Should be written at the 7th grade reading level Must explain medical terms Should be provided in patient s native language Should not make it appear that rights have been waived by the participant or liability released by the investigator, sponsor or institution Consent is a process
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Informed Consent
Eight basic elements of informed consent 50.25) (21 CFR
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 records identifying the subject will be maintained An explanation as to whether any compensation and whether any medical treatments are available if injury occurs An explanation of whom to contact for answers to questions about the research and research subjects rights A statement that participation is voluntary
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Protocol Adherence
Research studies must be conducted as detailed in the study protocol Amendments to the protocol are conveyed to the PI in writing; the PI must sign and return signature page to sponsor Amendment or any change requires IRB approval
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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 be protocolreported to the sponsor on each trial subject. (ICH GCP1.11) Generally organized by subject, visit, and sequential/chronological order

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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 from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at xthe pharmacy, at the laboratories, and at medicomedicotechnical departments involved in the clinical trial).
(ICH GCP 1.52)

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Sponsor Monitoring
Types of Monitoring visits PrePre-study or evaluation ( screening visit ) Initiation InterimInterim-monitoring Audit CloseClose-out
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Sponsor Monitoring
Purpose To verify
protection of rights and well-being of subjects wellreported trial data is accurate, complete, and verifiable trial is in compliance with:
Protocol and amendments Regulatory requirements Enrollment Drug supply
ICH GCP 5.18.1
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Safety Reporting
A Federal regulation: an investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator 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 58

Closing Out a Clinical Trial

CloseClose-out Visit Drug Accountability Record Retention

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CloseClose-Out Visit
A study close-out visit closeis required
at study completion decision to terminate the study short of completion Drop-out of a site Drop-

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Objectives of the Close-Out Visit CloseVerify that the investigator s study files are complete Ensure that regulatory requirements for retention of records are understood Review final reporting requirements with the investigator Ensure all data is complete Ensure that all supplies are returned, destroyed or placed in compassionate use
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Drug Accountability
A final reconciliation of all study drug Drug dispensing logs will be verified against a physical inventory All drug on-site at the close-out onclosevisit will either be disposed of at the visit or shipped back to the sponsor
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Record Retention
Essential documents should be retained until at least 2 years. CFR 312.62
(Novartis requires 15 years)

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

If an investigator leaves an institution, he/she must transfer responsibilities for record retention to another physician and notify the sponsor in writing.
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How to Get Involved in Company Sponsored 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 Catherine.freiman@novartis.com 734-424734-424-3783

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