Rev GCP Goals Principles Roles Resp Lepay Toth-Allen FDA

8/2/2019 Rev GCP Goals Principles Roles Resp Lepay Toth-Allen FDA

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Revie w of GCP:Goals /Pr inc ip les/

Roles/Responsib i l i t ies

David A . Lepay M.D., Ph.D., and

J ean Tot h-Al le n, Ph.D.

APEC GCP Insp ec t ion Work sho p

May 27, 2008

What Th is Lec t u re w i l lAddress/Review


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Inspec t or s V iew o f aCl in ic a l Tr ia l

Premise: A clinical trial can be viewed as aseries of key activities

WHO Handbook for GCP identifies 15 keyactivities in conducting a single clinical study

The order of these activities may vary

Activities may be completed simultaneously

Multiple parties (including the investigator ---but also the sponsor, ethics committee[s], andregulator[s]) are responsible for the success ofeach of these activities

K ey Ac t i v it i es and TheProc ess Approach


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Think ing Lik e an Inspec t or :Quest ions t o Ask -1-

What are these 15 key activities ?

Which of these 15 are the responsibility of

the party I am inspecting ?

The 15 Key Ac t iv i t ies in aRegulat ed Cl in ic a l Tr i a l -1-


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The 15 Key Ac t iv i t ies in aRegulat ed Cl in ic a l Tr ia l -2-

6. Ethics Committee Review and Approval of theProtocol

7. Review by Regulatory Authorities8. Enrollment of Subjects: Recruitment, Eligibility,

and Informed Consent

9. The Investigational Product(s): Quality,Handling, and Accounting

10. Conducting the Study: Study Data Acquisition

The 15 Key Ac t iv i t ies in aRegulat ed Cl in ic a l Tr ia l -3-


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Think ing Lik e an Inspec t or :Quest ions t o Ask -2-

What information do I have about each keyactivity before I start the inspection ?

What do I ask/review on-site to assesseach key activity ?

What are the inspected partysresponsibilities in each key area and what isthe standard I use to evaluate these ?

GCP: Or ig ins in t he Succ essesand Fai lures of Researc h


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GCP in t he U.S.: A Br iefHistory -1-

In contrast to GMP (Good ManufacturingPractices) and GLP (Good Laboratory

Practices: for animal toxicology studies), theterm Good Clinical Practice (or GCP) doesnot appear in U.S. law or FDA regulations

But FDA has a long history of regulating andinspecting clinical research



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1970s

FDA regulations for each of the parties involved

in clinical research Clinical Investigators

Sponsors/Monitors/ Contract ResearchOrganizations

Ethics Committees (IRBs/IECs)

Comprehensive Bioresearch Monitoring (BIMO)Program of inspections: Inspecting each party

Extension of law/regulations to medical devices



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FDA CI In te rnat ional Inspec t ions*

Gabon 1

Germany 59

Greece 2

Guatemala 2

Hong Kong 5

Hungary 10

India 6

Ireland 1

Israel 5

Italy 36

Japan 3

Kenya 1

Latvia 5

Lithuania 2

Malawi 1

Malaysia 4

Mexico 14

Netherlands 24

New Zealand 4Nigeria** 1

Norway 5

Panama 2

Peru 6

Philippines 4

Poland 29

Portugal 2

Romania 1

Russia 35

Serbia 3

Singapore 1

Slovenia 1

South Africa 26

Spain 17

Sweden 28

Switzerland 2

Thailand 4

Turkey 6

U. K. 91

Ukraine 4

Venezuela 2

Yugoslavia 3

Zambia 1

Algeria** 1

Argentina 19

Australia 9

Austria 6

Bahamas 1

Belgium 26

Brazil 13

Bulgaria 1

Canada 151Chile 8

China 7

China, Taipei 3

Colombia 1

Costa Rica 8

Czech Republic 7

Croatia 3

Denmark 13

Dominican Rep. 1

Ecuador 1Egypt 1

Estonia 5

Finland 15

France 51

*Conducted for FDA/CDER

from 1980 through 08/8/07; total: 810

**data reviewed in U.S.



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GCP in t he 21 st Century

Beyond Drugs/Biologics ISO 14155-1: Clinical Investigation ofmedical devices

for human subjects: General requirements (2002)

Global Harmonization Task Force (GHTF)

Globalization PAHO/PANDRH Good Clinical Practices: Document of the

Americas (2004)

WHO Handbook for Good Clinical Practice (GCP):Guidance for Implementation (2005/2006)

Global Acceptance and Expectation FDA proposed new rule for acceptance of non-U.S.

studies: expects compliance with international GCP

GCP: Overar c hing T hem es


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The Hierarc hy of GCP

Goals

Principles

RolesRoles

ResponsibilitiesResponsibilities

RequirementsRequirements

Application to the Specific Clinical TrialApplication to the Specific Clinical Trial

The Goa ls of GCP 1-


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Ensuring the quality and integrity of researchdata for regulatory decision-making

Based on a scientifically sound protocol that isdesigned to meet its stated objectives

Based on the quality conduct and oversight ofthe clinical study



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The Pr inc ip les of GCP

The identification of Principles of GCP was/is a majorachievement of ICH GCP carried through to all otherinternational GCP guidelines (ISO, PAHO, WHO)

Each of the 13 Principles can be linked to one or moreof the goals of GCP

The GCP Principles reflect internationally acceptedethical and quality principles found in otherinternationally accepted documents

Achieving a Principle requires that each party and allparties together meet their correspondingresponsibilities

A Lis t ing of t he Pr inc ip les


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A L is t ing o f t he Pr inc ip les

#3: A trial should be initiated and continuedonly if the anticipated benefit(s) for the

individual trial subject and society clearlyoutweigh the risks.

Although the benefit of the results of the trialto science and society should be taken intoaccount, the most important considerations arethose related to the rights, safety, and well-being of the trial subjects.



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#6: A trial should be scientifically sound, anddescribed in a clear, detailed protocol.

#7: Freely given informed consent should beobtained from every subject prior to trialparticipation in accordance with nationalculture(s) and requirements. When thesubject is mentally or legally incapable,

consent should be obtained from a legallyacceptable representative.



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#10: All clinical trial information should berecorded, handled, and stored in a way that

allows its accurate reporting, interpretation,and verification.

#11: The confidentiality of records that couldidentify subjects should be protected,respecting the privacy and confidentiality rules

in accordance with the applicable regulatoryrequirement(s).



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Goals and Pr inc ip les of GCP:Th ink ing L ik e an Inspec t o r

Violations so serious as to compromise thegoals and principles of GCP:

Are the most important to detect ininspection

Are most likely to result in official(enforcement) action

Must be most thoroughly documented


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Responsib le Par t ies

Study sponsor/contract research

organization (CRO) Clinical investigators (CIs)

Independent Ethics Committee(IEC)/Institutional Review Board (IRB)

Shared Responsib i l i t ies


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SPONSORSSPONSORS

Sponsor -1-


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Sponsor -2-

GCP requires certain directcommunications and interactions

between the sponsor and theregulatory authority

Cont rac t ResearchOrga nizat ion (CRO)


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Moni to r

Employee of the sponsor (or CRO) whoworks to oversee the progress of a clinical

study through on-site visits and othermeans

To ensure that the study is conducted,recorded, and reported in accordance withthe protocol, SOPs, GCP and the applicable

regulatory requirement(s). (Quality control)

Medic a l Ex per t ( Med ic a lMon i to r )


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Independent Dat a Moni t or ing

Com m it t ee (DMC; DSMB)

A committee established by, but actingindependent of, the sponsor to assess at

intervals the progress of a clinical trial, thesafety data, and the critical efficacyendpoints, and to recommend to the sponsorwhether to continue, modify, or stop a trial

Every study needs safety monitoring; but not

every study requires a DMC/DSMB

Sponsor Responsibi l i t ies -1-


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Refrain from commercialization of investigationalproducts

Control the distribution and return of

investigational products Detailed records

Proof of IEC/IRB approval before initial shipment

Select qualified clinical investigators

Credentials can vary by study & country requirements

1572 commitments for pharmaceutical studies Investigator agreements for medical device studies



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Adequately monitor clinical studies

Written SOPs desirable (required by FDA

device regulation) Requires access to site and subject records

(privacy laws applicable)

Provides quality control for assurance ofsubject protections and data integrity

Enables assurance of clinical investigatorcompliance



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Financing/Compensat ion

FDA regulations Do not address the financing of clinical studies or

compensation to research subjects

Are silent on liability for injury to subjects in a clinicalstudy

Address financial disclosure by investigators and otherstudy staff

ICH GCP recommends The financial aspects of the study be documented in an

agreement between the sponsor and investigator

Compensation, insurance, and any costs of treatment inthe event of study-related injury be addressed in thesponsors policies


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Cl in ic a l Invest igat or

ICH GCP definition: A person responsible for theconduct of the clinical trial at a t r ial site

Suggests an investigator at each site; multisitestudy may have a coordinating investigator, butthere should be a responsible party at each site

The investigator is

THE contact with study subjects

Responsible for study site compliance with GCP

Subinvest igator(s)


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Invest igat or Responsib i l i t ies -1-

Personally conduct and/or supervise thestudy

Cannot contract out any responsibilities; isentirely responsible for study conduct at site

Needs to ensure qualifications and training ofanyone delegated study duties and meet withstudy staff on a regular basis

SOPs for sites conduct of studies andhandling of problems



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Protocol compliance

No deviation without prior sponsor andIEC/IRB approval unless to eliminate animmediate hazard to subjects

Protocol should be designed to facilitatecompliance

Control of investigational products

Detailed records receipt, use, & disposition

Proper storage and handling as defined inthe protocol



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Recordkeeping

Accurate and complete case histories for eachstudy subject both those to whom

investigational product was administered andcontrols

Includes Source documents (Hospital charts, clinical laboratory

reports, x-rays, ECGs, subject diaries, pharmacy records)

Case report forms

Correspondence Other study-related documents e.g., protocol, with all

amendments; Investigators Brochure, screening logs



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Reporting

Safety reports

Progress reports

To sponsor

To IEC/IRB for continuing review

Final report



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IEC (U.S. = IRB)IEC (U.S. = IRB)

References


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Role of an IndependentEt h ic s Com m it t ee (IEC) -1-

Safeguarding the dignity, rights, safety,and well-being of all actual or potential

research participants Providing independent , competent, and

timely ethical review of the proposedstudy

Considering both the scientific and ethical

aspects of the study since scientificallyunsound research is not ethical

Role of t he IEC -2-


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Right s o f Researc h Subject s

Subjects have the right to

Be informed

NOT participate

Withdraw at any time

Protection of their privacy

Declaration of Helsinki In medical research onhuman subjects, considerations related to thewell-being of the human subject should takeprecedence over the interests of science andsociety.

IEC Responsib i l i t ies -1-


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Obtain and review pertinent documents Protocols and amendments

Proposed informed consent document

Subject recruiting materials

Investigators Brochure

Available safety information

Investigators curriculum vitae, including allactive studies

Other as pertinent to specific study and IECrequirements



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Perform ethical reviews Ensure proper expertise for scientific review

Review target subject population to ensure adequate

inclusion/exclusion criteria and proper recruiting Review investigators qualifications and ability to

supervise and conduct the study at the site

Review proposed compensations to investigator andsubjects

Consider subject privacy and data confidentiality

Review issues that may raise community concerns

Ensure proposed informed consent process and formare appropriate



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Communicating decisions

In writing to investigator, including

responsibilities an approval entails Suggestions for revision when modifications

are required

Reasons for disapproval ortermination/suspension of prior approval



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The IEC:Clos ing Perspec t ives

The credibility of the IEC will affect thecredibility (and acceptability) of clinicalstudies and study sites

Developing high quality clinical trialsdepends on developing high quality IECs

Developing methods to assess theiradequacy is an important consideration for

regulatory bodies


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Disc la imer :

The in format ion w i th in th is p resent a t ion

is based on the presenter 's exper t ise and

ex per ience, and represents t he v iew s o f

t he presenter for t he purposes of a

t ra in ing w orkshop .

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Rev GCP Goals Principles Roles Resp Lepay Toth-Allen FDA

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