Basics of ich gcp campus kortrijk 2012 yge

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Basics of ICH-GCP, Good Clinical Practice

Yves Geysels, PhD and Martijn Griep, PhD

Symposium Klinische Studies; ervaringen van onderzoekers,

KULeuven Campus Kortrijk

October 11, 2012

• What is ICH GCP?

– Origins/History of GCP

– Principles of ICH GCP

• Starting the Clinical Trial

– Clinical Trial Process

– Protocol and Protocol Amendments

– Investigator’s Brochure

– Ethics Committee

– Selecting the Investigator

• Responsibilities of the Clinical Investigator

– Informed Consent

Agenda 1 of 2

• Responsibilities of the Sponsor

• Safety Reporting

– Investigator and Sponsor

• Credible and Accurate Data

– Investigator and Sponsor

• Compliance

– Monitoring

– Auditing

• Role of the Regulatory Authorities

• Conclusion

Agenda 2 of 2

Origins and History of ICH-GCP

4

Good Clinical Practice is …

“an international ethical and scientific quality

standard for designing, conducting, recording,

and reporting trials that involve the participation

of human subjects”

GCP

Provides assurance that: • clinical trial data are credible and accurate • trial subjects’ rights, integrity and

confidentiality are protected

Patient Protection:

Drug disasters, fraud, abuse of rights

• Sulphanilamide incident

(1937)

• Nuremberg War Crimes Trial

• Tuskegee study (syphilis)

(1932 – 1972)

• Thalidomide (birth defects)

1938 Drug laws introduced to

regulate safe manufacturing of

drugs

1949 Nuremberg Code: required

voluntary “informed consent”

1979 Belmont report: interest of

individual is above interest of

society

1962 Kefauver Amendments:

prove drugs are both safe and

effective

World Medical Association (WMA)

Declaration of Helsinki

• Adopted by the 18th WMA general assembly,

Helsinki - June 1964

• Established ethical principles for medical

research involving human subjects

• Informed consent must be documented

• Independent review of protocol by ethics

committee (IRB/IEC*)

*IRB - Institutional Review Board / IEC- Independent Ethics Committee.

Declaration of Helsinki

• October 2000 - latest revision from 52nd WMA

General Assembly, Edinburgh

• Clarifications 2002 and 2004:

– Placebo controlled trials now appropriate to

conduct in some cases (benefit > risk)

– Sponsor should address how subjects will be

treated after study termination

– Ability of country to afford medication (i.e. AIDs

trials in Africa)

• WMA updated last in October 2008

European Union GCP - History

• 1960s: Concept of GCP in EU countries focused on

ethical responsibility of the

clinical investigator

• Sept 1991: EC Directive 91/507/EEC

• May 2001: EC Directive 2001/20/EC

• April 2005: EC Directive 2005/28/EC

The Need to Harmonize

What is ICH GCP?

The International Conference on Harmonisation of Technical

Requirements for the Registration of Pharmaceuticals for

Human Use

1990 – ICH established with government and pharmaceutical

industry representatives from USA, EU and Japan

WHO, Canadian Health Board and European Free Trade

Association observed proceedings

Set up to improve efficiency of the process for developing and

registering new medicinal products

ICH GCP = foundation of all practices

Specific Guidelines

Sponsor/Institution/Investigator

Local

Working

Practices

Sponsor/Institution/Investigator

Local Laws

Country and/or State Specific

Good Clinical Practice

ICH GCP

1. Glossary

2. Principles of ICH GCP

3. Responsibilities of ethics committees/institutional review

boards (IEC/IRB)

4. Responsibilities of the Investigator

5. Responsibilities of the Sponsor

6. Clinical Trial Protocol and Protocol Amendments

7. Investigator’s Brochure

8. Essential Documents for the Conduct of a Clinical Trial

Basic Principles of ICH GCP

1 of 2

1. Studies conducted according to Declaration of Helsinki and GCP

2. Anticipated benefits must justify the risk

3. Subjects rights, safety and well being come first

4. Adequate information available to support the proposed study

5. Protocol – scientifically sound, clearly described and detailed

6. Ethical committee approval

7. Qualified physician responsible for medical care and decisions

Basic Principles of ICH GCP

2 of 2

8. All individuals involved – qualified by education,

training and experience

9. Freely given fully informed consent

10. Accurate reporting, interpretation and verification of data

11. All records to be confidential

12. Products manufactured to GMP (Good Manufacturing Practice) and used only according to the protocol

13. Systems with procedures that assure quality of every aspect to be implemented

Objectives of the ICH GCP Guideline

• Protect the subject/patient

– Approval by IRB/IEC

– Informed consent

– Qualified Physician responsible for medical care and decisions

– Assessment of safety information

– Confidentiality

– Compensation for trial related injury

• Ensure credible/accurate data

– Provide a unified standard (specifically for EU, USA, Japan)

– Enhance the mutual acceptance of clinical data by regulatory

authorities

Investigator Responsibilities

1 of 4

• (4.1) Qualifications and agreements

• (4.2) Have adequate resources

• (4.3) Medical care of trial subjects

• (4.4) Communicate with the ethics committee

• (4.5) Comply with the protocol

• (4.6) Be accountable and manage the investigational

product as per sponsor’s instructions including explaining

use to subject

Investigator Responsibilities

2 of 4

• (4.7) Follow randomisation procedures and unblinding

• (4.8) Informed consent of subjects

• (4.9) Records and reports

• (4.10) Progress reports

• (4.11) Safety reporting

• (4.12) Premature termination or suspension

• (4.13) Final report

Credible and Accurate Data

Records

• Investigator should ensure the accuracy, completeness, legibility,

and timeliness of the data

• Data on CRF are derived from and consistent with source

documents

• Change or correction to CRF should be dated, initialled, and

explained, if necessary

– not obscure original entry

– audit trail maintained

ALCOACCEA

• Accurate: all data required are captured and data are captured in a consistent manner.

• Legible: readable at the input and output stage in a form meaningful to an independent

reviewer

• Contemporaneous: the recording of a clinical observation is made at the same time as

when the observation occurred.

• Original: this must be the first record made by the appropriate person.

• Attributable: the person undertaking the action should be recorded by the system

(Unique user identification is necessary). It is important that electronic data are

time/date stamped when the data are created/generated.

• Complete and consistent: it should be possible to fully reconstruct the activities

performed, changes should be traceable. There should only be one source defined at

any time for any data element.

• Enduring, Available when needed: protected from destruction, continue to be available,

readable and understandable by a human being when required.

(European Medicines Agency, 09 June 2010, Reflection paper on expectations for

electronic source data and data transcribed to electronic data collection tools in clinical

trials )

Delegation

• It is common practice for investigators to delegate certain study-

related tasks to

– employees,

– colleagues, or

– other third parties (individuals or entities not under the direct

supervision of the investigator).

• When tasks are delegated by an investigator, the investigator is

– responsible for providing adequate supervision of those to

whom tasks are delegated.

– accountable for regulatory violations resulting from failure to

adequately supervise the conduct of the clinical study.

FDA assessment of adequacy of

supervision by an investigator

• FDA focuses on four major areas:

1. whether individuals who were delegated tasks were qualified to

perform such tasks,

2. whether study staff received adequate training on how to

conduct the delegated tasks and were provided with an

adequate understanding of the study,

3. whether there was adequate supervision and involvement in

the ongoing conduct of the study, and

4. whether there was adequate supervision or oversight of any

third parties involved in the conduct of a study to the extent

such supervision or oversight was reasonably possible.

Documentation of qualification

• The investigator should maintain a list of the appropriately

qualified persons to whom significant trial-related duties

have been delegated.

1. describe the delegated tasks,

2. identify the training that individuals have received that

qualifies them to perform delegated tasks, and

3. identify the dates of involvement in the study.

Adequate Supervision of the Conduct

of an Ongoing Clinical Trial

Level of supervision:

– Sufficient time

– A plan for supervision and oversight, even for highly

qualified individuals.

ISSUES noted in trials with

Inexperienced study staff

Demanding workload for study staff

Complex clinical trials (e.g., many observations, large amounts of data

collected)

Large number of subjects enrolled at a site

A subject population that is seriously ill

Conducting multiple studies concurrently

Protocol Violations that Present

Unreasonable Risks

• There are occasions when a failure to comply with the protocol may be

considered a failure to protect the rights, safety, and welfare of subjects

because the non-compliance exposes subjects to unreasonable risks. – For example, failure to adhere to inclusion/exclusion criteria that are specifically

intended to exclude subjects for whom the study drug or device poses

unreasonable risks (e.g., enrolling a subject with decreased renal function in a trial

in which decreased function is exclusionary because the drug may be

nephrotoxic) may be considered failure to protect the rights, safety, and welfare of

the enrolled subject.

• Similarly, failure to perform safety assessments intended to detect drug

toxicity within protocol-specified time frames (e.g., CBC for an oncology

therapy that causes neutropenia) may be considered failure to protect the

rights, safety, and welfare of the enrolled subject.

• Investigators should seek to minimize such risks by adhering closely to the

study protocol.

Peer Reviewed study

• Haeusler, Jean-Marc C. “Certification in good clinical

practice and clinical trial quality: A retrospective analysis

of protocol adherence in four multicenter trials in the

USA.” Clinical Research and Regulatory Affairs, 2009;

26 (1-2), pp20-23.

Assess the impact of formal training in GCP on the

quality of clinical trials

Quality Endpoint = # Protocol Deviations

Methodology= Retrospective Analysis of 4 U.S.

Multicenter Trials

Odds Ratio (OR) of Protocol Deviations

Compared To No Certified PI or CRC

• OR = 1.20

• 95% Confidence

• [0.852–1.688]

• p = NS

CCRC Only

• OR = 0.70

• 95%Confidence

• [0.513–0.953]

• p = 0.0256

CPI Only

• OR = 0.37

• 95% Confidence

• [0.273–0.507]

• p < 0.0001

CCRC and CPI

Profile of Ideal site, practical

• Facilitating and encouraging clinical trials

• Added value to make clinical trials visible

• Realistic and timely estimate of feasibility

• Suitable medical records

• Principal investigator is project manager and has

adequately delegated the tasks

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• Timely detection of staff changes

• Backups for critical functions

• Perform only tasks for which staff is trained

• Adequate temperature control for medication storage

• Validation of equipment

• Realistic recruitment plan taking into account inclusion

criteria

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• For each inclusion criterium clear how it is assessed and

documented

• Traceability of inclusion criteria in medical file

• Carefull handling of SUA reports

• Insight in the protocol and how assessments are

performed by whom, how and when

• Anticipate potential protocol deviations

• Compy with protocol even if it differes from routine

medical care

• Planning and follow up of subject visits

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• Ensure all SAEs are detected and notified within 24

hours

• Deficitions of clinical significance according to protocol

and GCP

• 24 hour reachability for urgent medical questions and

deblinding

• Availability during monitoring visits

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• Understanding international environment

• Proactive approach and collaboration

• Acceptance of global competitive recruitment

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Summary / Conclusion

Summary - Conclusion

Basics of ICH-GCP

ICH GCP

• Guidance that describes the responsibilities and

expectations of all participants in the conduct of

clinical trials, including investigators, monitors,

sponsors and ethics committees.

• Guidance that cover aspects of monitoring, reporting

and archiving of clinical trials and incorporating

addenda on the Essential Documents and on the

Investigator's Brochure

ICH GCP Objectives

Protection of

trial subjects

Credibility and reliability of

study data

SOPs ICH GCP

EMA Requirements for Electronic

Source Document

Attributable

Legible

Contemporaneous

Original

Accurate

Complete

Consistent

Enduring

Available when needed

ALCOACCEA

ALCOA

Thank you !

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