Drug Development

Process
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
2
 Essentials of Clinical
Research

Phases of Clinical Research

Basics of Clinical Research

Clinical Study Design

3
 Drug Development Process
arch Concept & Preclinical Testing Clinical Trials Registration,
over Active Lead Launch and
mpound Sales

ars research 2-3 years development 3-5 years development 2-3 years development

0,000 potential 20-30 remaining 5-10 remaining 4-5 2-3 1 remaining substance
ate substances Substances substances Remaining substances
1 remaining

h Biological Clinical Registration Launch

Tests Trial with and
Discovery Phase 1 Health Sales
of lead Regulatory Phase 2 Authorities
compound clearance Phase 3

Selection Pharmacy/ Preparation

of Chemical for
product Development Biological Tests Launch
candidate

Pharmacy/Chemical
Development 4
 An Overview:
Drug Development Timeline

Early Full Life Cycle

Research
Development Development Management
Candidate Pre-
Clinical Trials
Discovery
Phase
Profiling clinical Phase 1 Phase IIa Phase IIb Phase III Phase IV
Phase Phase

CSP sPoC DDP FDP 3CP SDP

Development Point
Proof of Concept
Selection Point

Decision Point

Decision Point
Development
Selected for

Checkpoint

Submission
Candidate

Full

Phase III

IND – Investigational New Drug NDA – New Drug Application

 Discovery of Active Lead
Compounds
• Complicated, time-consuming and costly process
– 2-20 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
– Natural chemical

• Process: Research Target 

Discovery of Lead Compound 
Candidate Selection

6
 Pre-Clinical Research

• Animal pharmacology/toxicology testing – “Is

it safe 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 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)
– On-going formulation work

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 Clinical Trials - Phases
Length
Phase Purpose Subjects Scope (per
phase)
Safety, ADME, Healthy
bioactivity, volunteers or
I drug-drug subj. w/
20-80 6-12 mos
interaction indications

Short-term side Subjects with Several 1-2 yrs

II effects & efficacy indications hundred

Safety & efficacy

Hundreds-
III Basis for labeling, Subjects with
thousands
2-3 yrs
new formulations indications

New indications, Hundreds-

IV QoL, surveillance
Subjects with
thousands
1-5 yrs
indications
10
21 CFR 312.21
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 is intended
• Phase IIa – proof of concept, pilot, feasibility, usually healthy volunteers
• Phase IIb – well-controlled in target population
• Following completion of Phase II, meet with the FDA to pave the way for
“pivotal trials”

21 CFR 312.47 12
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, multiple illnesses, etc.
• IIIb studies – post NDA-submission trial looking at additional
indications
• Pre-NDA meeting with the FDA near conclusion of Phase III

21 CFR 312.47 13
 New Drug Application (NDA)
• The average NDA is 100,000 pages or longer
• Must provide all relevant data collected during R&D
• Consists
Index
of:
- non-clinical pharm - clinical data
–
– non-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

(a CTD = Commercial Technical Document)
• Review process: Target 10 months (but often longer)

21 CFR 314.50

14
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
15
 Registration & Launch

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

16
Phase IV
• Post-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
– Special population
– Rare event incidences
– Additional long-term usage safety data
– Pharmacoecomonic and Quality of Life (QoL)

21 CFR 312.85
17
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

19
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 Project Clinical Research Regulatory

Director Manager Associate (CRA) Personnel

Investigator IRB / IEC

Sub-Investigator

Clinical Research Coordinator

Study Subjects (patients)

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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

24
Investigator Sub
-investigator
“Any individual member of
• Person responsible for
the clinical trial team
the conduct of the designated and supervised
clinical trial at a trial by the investigator at a
site trial site to perform critical
trial related procedures
• If conducted by a and/or to make important
team, the investigator trial-related decisions”
is the responsible (ICH GCP 1.56)
leader of the team and
may be called the
principal investigator
(PI)
(ICH GCP 1.34) 25
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

26
 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. 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)

29
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

31
Investigator Selection
• Investigator Characteristics

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

• Facility
– Space
– Equipment

• IRB

• Patients

32
 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

33
 Investigator Selection
Investigator’s Characteristics
(protocol-specific)
• Is investigator interested in the study?
• Does the site have the necessary patient
population? (e.g. minority %, drug-naïve,
etc)
• If 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

• 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

35
Planning and Initiating a Clinical
Trial

Investigator selection
Initiating a Clinical Trial
– Study Documents
– IRB/IEC
– Contract/Budget
– Investigators’ Meeting
– Document Filing & Tracking

36
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.
572
1
o rm
F

39
 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
40
 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

41
 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)

42
 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

44
 Investigator’s Meeting

• Study Coordinators and sub-investigators

should also 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

46
 GOOD CLINICAL PRACTICE (GCP)
BASIC TENETS
• Study is well-designed and follows scientific principles

• IRB 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
– in a secured cabinet
ICH 5.14, 21 CFR 312.61, 21 CFR 312.57
– 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

48
 Subject Recruitment

• Investigator’s patient population

• Referrals from other physicians and clinics

• Direct advertisement, which must be

approved by the IRB

49
 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 (21 CFR §
50.25)
– 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 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

52
 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 reported to the sponsor on each
trial subject.” (ICH GCP1.11)

• Generally organized by subject, visit, and

sequential/chronological order

53
 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 the pharmacy, at the laboratories, and at
medico-technical departments involved in the
clinical trial).” (ICH GCP 1.52)
54
 Sponsor Monitoring
Types of Monitoring visits

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

• Initiation
• Interim-monitoring

• Audit
• Close-out

55
 Sponsor Monitoring

Purpose
• To verify
– protection of rights and well-being of subjects
– reported 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

56
 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)

57
 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

Close-out Visit
Drug Accountability
Record Retention

59
 Close-Out Visit

• A study close-out
visit is required
– at study completion
– decision to
terminate the study
short of completion
– Drop-out of a site

60
 Objectives of the Close-Out
Visit
• Verify 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

61
 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

visit will either be disposed of at
the visit or shipped back to the
sponsor
62
 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.

63
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?

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