drug development process cleveland, 6.23.06

8/2/2019 Drug Development Process Cleveland, 6.23.06

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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


4-5 2-3

Remaining substances1 remaining

Clinical

Trial

Phase 1

Phase 2

Phase 3

Biological Tests

Pharmacy/ChemicalDevelopment

Registration,Launch and

Sales


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


Safety & efficacy

Basis for labeling,

new formulations

III

1-2 yrsSeveralhundred


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 Characteristics

Personnel CRC : trained, certified, full-time?

Work schedules

Facility Space Equipment

IRB

Patients


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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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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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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


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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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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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

[email protected]