IRB-GCP and Timelines

1

Andrew Majewski, MSc.

1st DOLF Meeting

Washington University School of Medicine

St Louis, Missouri-USA

October 11-14th, 2010

•Finalized Protocol

•Finalized Case Report

Form (TBD)

•Finalized Consent •Country Dependent

•Selected Sited (TBD)

•Qualified Investigators •Local

•US

•Federal Wide Assurance

Factors that affect Timelines

2

•Registration (RCTs?)

•IRB Identification

•IRB Protocol Approval

•Drug and Importation Permit

•Institutional Certifications

•GCP Training (FHI)

•Equipment and Materials

•Logistics

•Monitors

•Timing: Seasons

It is easier to develop

good habits than to

correct bad ones -Anonymous

3

Overview: ICH (International

Conference on Harmonisation)

4

• Guidance document developed within a multi-

country expert working group

•Sets an international standard for the conduct of

human trials, which governments can transpose

into regulations for clinical trials involving human

subjects

•ICH Homepage:

http://www.ich.org/cache/compo/276-254-1.html

• FDA Homepage:

http://www.fda.gov/regulatoryinformation/guidanc

es/ucm122049.htm

Certification and Resources:

5

All members participating in the trials, RCT or not, must

obtain online training/certification from their respective

institution.

Other resources:

The Office of Human Research Protections (OHRP)

http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm,

Belmont report:

http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

Helsinki report (1964; current version 2008):

http://www.wma.net/en/30publications/10policies/b3/index.html

Ethical Review

Committees

(ERC)

6

Ethical Review Committee (ERC)

Responsibilities

7

Types of Ethics Committees/Boards

Role: Safeguards the rights and safety and well being of all trial

volunteers. Pays particular attention to special populations

•Local-IRB/ERC/IEC

•National Ethics Committee (NEC)

•Ministry of Health (MoH), if appropriate •In parallel (independent review)

•Sequential (after an EC has approved the study)

Guidance of ERCs

8

•ICH GCP Section 3

•WHO GCP Annex 3 section 3.2

•WHO- Operational Guidelines for EC that

Review Biomedical Research, Geneva, 2000

•WHO – Surveying and Evaluating Ethical

Review Practices, Geneva, 2000

What does the ERC need to do?

9

•Meet regularly

•Follow established procedures

•Conduct continuing review of each protocol at a

minimum of once per year

•Consider the PI’s qualifications

•Request more information to be provided to the

volunteers as needed.

•Review amount and method of payment

Documents obtained from the

ERC

10

•Protocol/amendments

•Consent forms

•Recruitment plans

•Written information

provided to volunteers

•Investigator Brochure

•Investigator CV

•Volunteer Compensation

•Modifications to documents

•Other documents

•Approval/Disapproval letters

•Termination letters

Who serves on ERCs?

11

Membership should be well balanced for

different expertise to review:•Scientific contents

•Medical Aspects

•Ethical considerations

Composed of at least 5 members for a quorum

(7-8 is best)•One member should non-scientific

•One member who is independent of the institution or trial site.

•At least 1 woman

What should the ERC procedures

include?

12

Follow written procedures

•Document meeting minutes and circulate the results to the PI

and Sponsor.

•Make decisions at announced meetings with at least a

quorum.

•Require voting members to participate in protocol review and

discussion

•Invite non-members for expertise and advice when needed.

What should the ERC procedures

include?

13

•Names and qualifications of members

•A charter-guideline for scheduling, notification and conduct

of meeting.

•Determined frequency to review protocols

•Initial and continue review of protocols

•Set term limits, if applicable

•Promptly provide meeting results, decisions and procedures

for appeal to the PI as appropriate.

What should ERC ask of PI’s?

14

PI’s are to promptly provide the following:

•Deviations or changes to the protocol

•Changes that increase risks to volunteers

•All AE’s that are serious and unexpected

•New information that might adversely affect

the safety of the volunteers.

What records should be

maintained by the ERC?

15

The following Records must be retained for > or

equal to 3 years:

•Written procedures

•Membership lists

•List of members occupation and affiliation (to reduce COI)

•Submitted documents

•Meeting minutes

•Correspondence

Communications

16

Regulatory

Sponsor

Investigator

Ethics Committee

Investigator Responsibilities:

Communication with ERC

17

ICH GCP 4.4

•Before the trial begins, obtain written and date

approval of the following from the ERC:•Protocol

•Consent Forms

•Recruitment procedures

•Written information provided to subjects

•Investigator Brochure (IB)

•During the trial, provide the ERC with all the

documents required/ requested for review

Good Clinical

Practice (GCP)

18

Good Clinical Practice (GCP)

ICH Section E6

19

•International standard for Ethical and Scientific

quality for:

•Trial design

•Trial conduct

•Protection of human rights as a subjects in the trial

•Define the roles and responsibilities of the

sponsors/Investigators/Monitors

•Recording and reporting in trials involving human

subjects

Website:

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/W

C500002874.pdf

General Instructions for GCP

20

•Write legibly in black or blue ink

•Complete all sections of the form

•If the data is missing, write missing.

•Dates are in ddmmyyyy (i.e. 05OCT2010 )

•If a change needs to be made, one line across

the incorrect information, followed by initials and

date as described above

Protocols

&

Informed Consent

21

What is a Protocol?

22

•A Clear and detailed PLAN of a scientific

experiment

•Describes the PURPOSE of the study

•Defines the STUDY ENDPOINTS

•Explicitly describers EVERY PROCEDURE

The Protocol includes

23

•One Primary Objective with Primary &

Secondary endpoints

•A Treatment Schedule

•Inclusion/Exclusion Criteria

•Screening Procedures

•Enrollment Procedures

The Protocol Includes…

24

• Supplemental material:

•Investigator Brochure (IB)

•Study Operations Manual (SOM)

•SAE Manual

•Changes to the protocol can only be done with written

amendment and ERC approval

•Protocol Compliance:

•To assure the protocol is done consistently and

accurately regardless of geographical location.

•Ensure the safety of the volunteers as well as the

integrity of the data.

What is different in a Clinical

Trial?

25

Investigator works within the parameters

of the protocol

•Structured assessments

•Structured documentation: Source Docs/

CRFs

•Structured reporting requirements

•Structured guidelines

Structured Safety Assessment

and Documentation

26

Factors:

•Protocol dependent

•Forms correspond with the protocol

•Forms drive the assessment

Multiple forms exist (DCF/ CRFs)

Form Completion is the primary way to

ensure safety and the quality of data

Informed Consent

27

The Term “Consent”

28

Consent is the agreement of the volunteer to

participate in the screen (screening consent) and/or

protocol (protocol consent).

Considered more than a signature or an

agreement. A promise from the research team to

the volunteer.

OBTAINED BEFORE ANY PROCEDURES ARE

DONEWAIVER of Documentation for informed consent for minimal risk

epidemiology projects

Informed Consent: A process, Not

a Just a Form

29

When does the Process begin?

ICH GCP Guidelines 4.8-4.8.15: Describes the consent

process and a clear list of topics 4.8.10 (a-t).

What does it really mean?

The volunteer is provided all available information about

the trial and the volunteer demonstrates understanding.

Why Document the process?

30

•Chronicles the effort in obtaining true informed

consent.

•Demonstrates compliance with guidance principles

•Makes good medical sense.

•Promise to conduct the trial as described/ informed.

•The process ensures volunteer safety during trial

participation.

IF IT’S NOT DOCUMENTED,

IT’S NOT DONE

Consent Material &

Communication

31

Must be accurate and complete

•Corresponds to the protocol and consent form

•Can be written, verbal, visual information

•Informational summaries

•Discussion and informational seminars

•Illustrations and Diagrams

•Approved by the Ethics Committee

•Document everything

•Don’t overpromise or oversell-this remains research

What are the Elements of

Informed Consent?

32

ICH GCP Guideline 4.8-4.8.15

The study involved “Research”

You are being asked to participate in a clinical research

study to…

The study has a “Purpose”

The goal of this study is to evaluate if product “XYZ” and

evaluate the response to “XYZ”

What are the Elements of

Informed Consent?

33

Describes the following:

•Main parts of the study: The procedures to be followed and

the volunteers responsibilities

•Duration and Assignment

•Risks: Describes reasonable foreseeable risks or

inconveniences to the volunteer

•Benefits: Describes reasonable expected benefits to

volunteer or others

What are the Elements of

Informed Consent?

34

Describes the following:

•Alternatives: Discloses appropriate alternatives

procedures if available

•Confidentiality: Describes the extent of the

confidentiality of records identifying the volunteer

•Compensation: The compensation and/or treatment

available to the volunteer in the event of a trial related

injury.

What are the Elements of

Informed Consent?

35

Describes the following:

•Contact Information: Provides the names and phone

numbers of the people to contact about more information on

the trial, their rights, and in the event they incur a trial-related

injury

•Volunteer Participation: The right to withdraw as any time

without penalty

•Termination of Participation: Foreseeable circumstances

and/or reasons under the which participation in the trial might

be terminated

What are the Elements of

Informed Consent?

36

Describes the following:

•New Findings: Informed in a timely manner if information

becomes available that might be relevant to the volunteer’s

willingness to continue participate in the trial

•Number of Volunteers: The approximate number of

volunteers in the study

Is the volunteer “Bound” to the

Consent Form Agreement?

37

The built in options for the volunteer to:

•Withdraw at any time with out any penalty

•Right to contact various bodies if they are

harmed or treated incorrectly

•Right to new information that might affect

their willingness to continue

Summary of Informed Consent

38

•The trial purpose, product used, number of

volunteers

•Randomization plan, if applicable

•Procedures

•Expectations of their participation

•Potential and theoretical risks

•Benefits (if any)

•Compensation (if any)

Review the Protocol Consent

Form

39

•Insure the validity date by the IRB

•Review and provide the opportunity to ask questions

•The right to withdraw at any time

•If they agree, the Volunteer must include the following:•Print Name

•Provide Signature by Volunteer

•Date of willing participation (ENROLLED)

•Signature by Witness with date on the same day

(usually someone else who delivered the message but

associated with the project)

•Copy of their Consent form to the volunteer

40

Safety &

Documentation

Who’s interested in this Safety

Reporting?

41

•Sponsor and Investigative Team

•Ethical Review Committee (IRBs)

•Data Safety Monitoring Board (DSMB)

•Subjects, Participants, Volunteers

•Community leader or Community Advisory

Boards (CABs)

•Local Office for Ministry of Health (MoH)

Trial Development: Safety during

Protocol Performance

42

Documentation = Accountability

•Drug accountability

•Subject enrollment: Consent Form

•Subject Monitoring: Case Report Forms

•Safety Data Reporting: SAE Reporting/ DSMB

Safety Related

Documentation

43

• Enrollment

• Monitoring

• Data Reporting

SAE: Serious Adverse Event

44

SAE is defined as: An adverse event is any undesirable

experience associated with the use of a medical product in

a patient. All need to be reported even if not apparently

related to test article

•Death

•Life-Threatening

•Hospitalization

(initial or prolonged)

•Disability

•Congenital Anomaly

•Requires Intervention to

Prevent Permanent Impairment

or Damage

Documentation

45

Maintain all of the following in a fire-proof filing

cabinet (locked room, locked cabinet)

•FWA registration recommended to assure

compliance with international standards

•Standard Operating Procedures (SOPs)

•Data Collection Forms (i.e. CRF)

•Volunteer information Forms

•Signed consent forms (Exceptions)

Documentation

46

ICH 8: Maintain the following in the Regulatory File

•All versions of documents from beginning to trial end

•Information given to subjects

•Financial aspects of the trial

•Insurance statement for the protection and treatment of

human subject (FWA)

•Signed agreements between institutions, PIs and CRO

•Dated, Documented Approval ERC (Regulatory, if

applicable) letters including minutes of meetings

•CVs on all staff personnel including the local PI.

Trial Timeline

Overview

47

Trial Timeline Overview

48

Idea

Grant

Protocol

Development

Product

Protocol

Finalize

IRB

Approval

(MoH)

Site

Selection Site

Qualification

Visit (SQV)

Site

Initiation

Visit

Begin

Trial

(FPFV)

TIME

USA-IRB and

Country IRB

Under Our Control

NOT in Our Control

Contracts

Federal

Wide

Assurance

US & Local

Certification

?? Registration ??

?? Drug and Drug Importation

49

Trial Timeline Overview

49

Amendment

(Requires IRB

Approval)

Annual IRB

Review

(MoH)

1ºData

Analysis

LPFV

Trial

Begins

(FPFV)

TIME

USA-IRB and

Country IRB

Under Our Control

NOT in Our Control

MonitoringAuditing

Site

Close-Out

LPLV

Sampling

STOP

FPFV

FPLV

LPFV

LPLV

Trial Timeline Overview

50

Idea

Grant

Protocol

Development

Product

Finalized

Protocol

IRB

Approval

(MoH)

Site

Selection Site

Qualification

Visit (SQV)

Site

Initiation

Visit

Begin

Trial

(FPFV)

TIME

USA-IRB and

Country IRB

Under Our Control

NOT in Our Control

Contracts

Federal

Wide

Assurance

US & Local

Certification

?? Registration ??

?? Drug and Drug Importation

51

Thank You