TRAINING MANUAL

ICH GCP

EU Clinical Trial and GCP Directives
FDA CFR Title 21 Part 312




Background
CONTENTS


1. History of Clinical Trial Legislation
1.1 Code of Federal Regulations
1.2 Declaration of Helsinki
1.3 European GCP Guidelines
1.4 ICH
1.5 EU Directives
1.6 Regulatory Bodies
1.7 Summary



2. ICH GCP
2.1 Overview of ICH GCP
2.2 Roles and Responsibilities
2.3 IRB/IEC
2.4 Investigator
2.5 Sponsor
2.5.1 Monitor
2.6 Protocol and amendments
2.7 Investigator Brochure
2.8 Essential Documents
2.9 Ultimate responsibilities under ICH



3. Europe
3.1 EU Clinical Trials Directive
3.2 EU GCP Directive
3.3 GMP Directive



4. USA
4.1 FDA Code of Federal Regulations Title 21 Part 312
4.2 FDA 21 CFR Part 11



5. Self Assessments
5.1 ICH GCP Chapter 3: Ethics Committees
5.2 ICH GCP Chapter 4: Investigators
5.3 ICH GCP General
5.4 EU CT Directive
5.5 EU GCP Directive
5.6 FDA 21 CFR Part 312
5.7 Case Study model answer
3.4. GMP Directive and Annexe 13
At this stage it is important that you are of the existence of these documents, and
the fact that the manufacture, shipping, storage, dispensing, return and destruction
of Investigational Medicinal Product (IMP) is subject to strict control. For every
clinical trial there should be detailed procedures for all of these steps and you
should follow closely any instructions you are given.


3.5. EU Guidelines and Recommendations
There are also many guidelines and recommendations which supplement the
directives and these can be accessed via Eudralex Volume 10. New guidelines and
recommendations are being issued on a regular basis so it is important to check
regularly what the latest requirements are.
Finally another reminder that EU legislation is being revised and the new legislation
is likely to come into force in 2016.
5. SELF ASSESSMENT


5.1 ICH GCP Chapter 3


1. How often should an Ethics Committee review an on going clinical trial?

A At least once per year
B At the beginning
C At the beginning and the end
D Every 6 months



2. How many members should an Ethics Committee have?

A At least 3
B At least 5
C At least 7
D There is no specification


3. How long should Ethics Committees keep records for a clinical trial?

A 2 years after last marketing authorisation
B 3 years after end of clinical trial
C 5 years after end of clinical trial
D 15 years after end of clinical trial


4. With which of the following should Ethics Committees comply?

A SOPs, regulatory requirements and the protocol
B SOPs and the protocol
C Regulatory requirements and the protocol
D SOPs and regulatory requirements


5. What role can the investigator play in the Ethics Committee review of a study?

A None- they cant attend
B They can give information and vote
C They can give information but may not vote
D They can vote, but cant give any further information about the study




Answers: A, B, B, D, C
5.2 ICH GCP Chapter 4


1. With which of the following should Investigators comply?

A Sponsor SOPs, regulatory requirements and the protocol
B Sponsor SOPs and the protocol
C Regulatory requirements and the protocol
D Sponsor SOPs and regulatory requirements



2. Which of the following may be implemented WITHOUT prior approval by the
Ethics Committee?

A Deviation from the protocol to avoid immediate hazard to the subjects
B Minor changes to the Informed Consent Form
C Deviations from the protocol for practical reasons
D Protocol amendments



3. Which of the following does not appear in the list of information to be given to
subjects?

A Aspects of the trial which are experimental
B Payment to the investigator
C Compensation available in the event of a trial-related injury
D That records identifying the subject will be kept confidential



4. According to ICH GCP which of the following is NOT a requirement for
informed consent where the subject or their representative can read and
write?

A The subject should receive a copy of the consent form
B The subject or their legal representative should sign and personally date
the consent form
C It should be witnessed
D It should be obtained before the subject enters the study



5. Who is responsible for study drug at the site?

A The investigator/institution
B The pharmacist
C The sponsor
D The monitor


Answers: C, A, B, C, A
5.3 ICH GCP General


1. According to ICH GCP when, under normal circumstances, should the monitor visit
the site?

A They dont have to visit
B Before, during and after the study
C Every 4-6 weeks
D At Least once


2. According to chapter 8 of ICH GCP where should routine monitoring visit report be
filed?

A In the sponsor files, but not the investigator file
B In the sponsor files and the investigator files
C In the investigator files, but not the sponsor files
D It doesnt have to be kept


3. Which geographical regions are involved in ICH?

A US and Europe
B US, Europe and Australia
C US, Europe and Russia
D US, Europe and Japan


4. According to ICH GCP what is the most important consideration when conducting
clinical research?

A Quality of data
B Speed to market
C Protection of trial subjects
D Cost


5. Which responsibilities are covered under ICH GCP E6

A The Sponsor and the Investigator
B The investigator and the Ethics Committee
C The Sponsor, the Investigator and the Ethics Committee
D The Sponsor, the Investigator and the Regulatory Authority





Answers: B, A, D, C, C
5.4 EU CT Directive


1. According to the EU Clinical Trials Directive governing clinical trials what are the
timelines for a Clinical Trial Authorisation?

A 30 days
B 60 days
C 90 days
D 120 days


2. According to the EU CT Directive governing clinical trials what are the timelines for
an Ethics Committee Approval?

A 30 days
B 60 days
C 90 days
D 120 days


3. According to the EU CT Directive governing clinical trials what are the timelines for
Reporting Fatal and Life-threatening Suspected Unexpected Serious Adverse
Reactions (SUSARs) to the Competent Authority and Ethics Committee?

A Immediately
B 24 hours
C 7 days
D 15 days



4. According to the EU CT Directive governing clinical trials what are the timelines for
Reporting to the Regulatory Authority and the Ethics Committee that the study is
complete under normal circumstances?

A 15 days
B 30 days
C 60 days
D 90 days


5. According to the EU CT Directive governing clinical trials what are the timelines for
Reporting to the Regulatory Authority and the Ethics Committee that the study is
complete in the event of an early termination of a study?

A 15 days
B 30 days
C 60 days
D 90 days



Answers: B, B, C, D, A
5.5 EU GCP Directive


1. According to the EU GCP Directive how long should the Sponsor and
Investigator keep trial related documentation?

A 2 years after last marketing authorisation
B 3 years after end of clinical trial
C 5 years after end of clinical trial
D 15 years after end of clinical trial



2. Which version of the Declaration of Helsinki is referred to in the EU GCP
Directive?

A The version is not specified
B 1964
C 1996
D 2000


3. Who is responsible for ensuring the conduct of a clinical trial comples with
regulatory requirements if the sponsor delegates all of his trial-related functions
to a company?

A It is not specified
B The company they have delegated to
C They both have responsibility
D The sponsor remains responsible


4. Under what circumstances is manufacturing authorisation not required?

A It is always required
B When drug is being reconstituted prior to use or packaging in a hospital by a
pharmacist and used in that institution
C When drug is being imported from a non-EU country
D When the investigator is the sponsor


5. How often should the Investigators Brochure be validated and updated?

A At least once a year
B Every 2 years
C When new information becomes available
D There is no specification



Answers: C, C, D, "# $
5.6 FDA 21 CFR part 312


1. Under FDA regulations who is responsible for selecting monitors?

A The Investigator
B The Sponsor
C The IRB
D The FDA


2. What does IRB stand for?

A Investigational Review Board
B Investigational Research Board
C Institutional Review Board
D Investigational Review Board


3. Under FDA regulations how long does the Sponsor have to keep the clinical trial
records?

A 2 years after marketing authorisation of discontinuation of drug
B 3 years after end of clinical trial
C 5 years after end of clinical trial
D 15 years after end of clinical trial


4. How often does the Sponsor have to submit reports on study progress to the
FDA?

A At the end of the study
B Every 6 months
C Every 12 months
D Every 2 years


5. For how long after the end of the study does the investigator have to inform FDA
of changes in their financial disclosure information?

A They dont have to notify changes after the end of the study
B 1 year
C 2 years
D 5 years





Answers: B, C, A, C, B
5.7 Case Study Model Answer: Sponsor Responsibilities Exercise

In taking on the role of sponsor the investigator assumes a large amount of
responsibility, some of which can be costly and onerous.
Investigational Product: The pharmaceutical company would be responsible for
some aspects of the Investigational Product. This may include manufacturing,
packaging, labeling, randomization, blinding and coding of the product, although it
may be that the company are just providing bulk drug and the investigator is doing
the packaging, labeling and coding himself, in which case the pharmaceutical
company is only responsible for manufacture and shipping of the product. The
pharmaceutical company would also be responsible for providing and updating the
Investigator's Brochure. The investigator/sponsor would be responsible for the drug
at site, including drug storage, accountability and destruction. It would be important
that these responsibilities are clearly documented and that the investigator's role as
sponsor is also clearly documented.
Other Responsibilities: In this situation the pharmaceutical company would also
need to update the investigator if any new safety information comes to light but the
investigator takes on all other sponsor responsibilities including: Quality Assurance
and Quality Control; providing medical expertise; designing the trial using
appropriately qualified individuals (e.g. Statisticians etc.); trial management; data
handling; record keeping (both trial master file and investigator site file see ICH
GCP chapter 8); compensation; insurance and indemnity; finance; Regulatory
Authority approval; Ethics Committee approval; record access; keeping up to date
with safety information; reporting adverse reactions to the regulatory authority and
ethics committees; monitoring i.e. appointing someone to act as monitor for the
study ; audit the investigator might need to consider bringing in an auditor;
ensuring compliance with GCP, regulatory requirements and the protocol and also
dealing with any noncompliance; notifying ethics committees and regulatory
authorities if the trial ends early; and finally, writing the clinical trial report. It is also
important to remember that the investigator/sponsor would also have to undertake
all investigator responsibilities as defined in ICH GCP chapter 4.