GCP - UKM Medical Centre - Universiti Kebangsaan Malaysia

Good Clinical Practice (GCP)
Workshop 2008
GCP Compliance:
Is It Realistic
OTEH MASKON
Faculty of Medicine,
Universiti Kebangsaan Malaysia

Disclosure of Financial Relationships
with Pharmaceutical Companies
Research Grants & Contracts (Principal Investigator):
Advisory Board Member:
Deliver Lectures For The Following:

GCP adoption in the Asia Pacific Region
Original ICH GCP 1996
Since then:
Singapore GCP 1998
Malaysian GCP 1999
Chinese GCP 1999
Thailand 2000
Indonesia 2001
Malaysian GCP 1999
and 2 nd edition 2004

Malaysian Good Clinical Practice
(MGCP )

”Great
Complicated
Paperwork”

Delays in clinical trials
Difficulty in recruiting patients is the
most frequently cited cause for
delays in clinical trials…..(Reproduced
from McKinsey Quarterly “A cure for clinical trials”
May 2002)
Collection
CRF data
IRB/IEC
Approval
L o s t D a y s
18 13
19
27
23
SDV (Source Data
Verification)
Difficulty in
Recruiting
Patients
DCF(Data Clarification Form)s

Complaints about GCP Compliance 1
1. Too much time spent on paperwork. Not
enough time.
2. Why can’t I conduct the research the way I
run my clinic and ward practice
3. It is a a chore, a hassle, a burden.
You feel you have to change.
Put on a different mask
5. Why am I the only one trying to adhere to
GCP Others are indifferent and got away
with it.

Complaints about GCP Compliance 2
6. You have to do things differently
7. You have to relearn new ways of doing things
How you write in the notes, lab results are to be acknowledged (signed), use
of acronyms etc etc.
8. The anxiety about being audited
Internally or externally
The audit process
9. Someone is looking over you.
The monitor or CRA, usually your junior and non-medical (“may behaves as
though she is the expert in GCP” pardon the expression) is looking at your
writing and your work. Most of the time he or she tells you or points out to
you what ‘s wrong with your work.
10. Support from pharma or sponsors i.e. approach
taken the CRA, CRM
“No touch technique”, “Behave as though they are performing an audit”

Factors that hinder the proper
implementation of GCP 1
1. Lack of understanding (before attending a GCP course) or
appreciation of the importance (after attending a GCP
course)
Quality of the research
Protection of your patients
2. Time
Documentation
Details
3. Experience & second nature
Takes time to develop
4. Dual environment
Normal clinical practice vs research

Factors that hinder the proper
5. Research Team
implementation of GCP 2
Commitment & dedication
6. Institution, Operating Procedures
Bureaucracy
7. Funding Organisation/ Pharma/ Third Party
Replacement of sites, Protocols, Different standards
European MDEA vs. US FDA
Issue of third party ‘middle man’ conducting research
(see NEJM Oct 2007)
8. Incentives / Bonuses
Competing studies
Coercion

GCP : Practical Issues 1
1. Delay in obtaining EC/IRB approval
2. Implementation of the Study Protocol
Practicality
Scientific merit or post-marketing exercise or commercial drive
3. Informed Consent Forms
Most Important Document
4. Recruitment of Subjects
Issue of pre-screening
Inducement or enticement vs GCP violation
What is the drive
5.Investigators & Study Nurses or Coordinators
Degree of obsession
Cooperation

GCP : Practical Issues 2
6. Non-investigator health care provider
Change therapy
Communication & Understanding
Role of the subjects, Identification Card
7. Reporting of AE/SAE/Protocol Violation & Deviation
Time frame, Sponsor & IRB
8. Data Queries (DNF)
Too many queries generated
Participation of Sponsor’s CRA
9. Sponsor & Regulatory Body Audits
10.Intellectual Property & Publication Agreement
11.Too Many Clinical Drug Trials
Competing Studies

During the 1990’s, the deaths of two healthy volunteers
in the US made their way to the highest political levels
and forced a review of human subjects protections
Jesse Gelsinger
18 year old
Healthy Volunteer
Genetic Study
Ellen Roche
24 year old
Healthy Volunteer
Asthma study

The Death of a 4 year in old 2002:
An Unfortunate Mistake
A four-year-old child died at the Children's
Hospital of Eastern Ontario after he was
mistakenly given a "significant overdose"
of an experimental drug (19x Interleukin
II): honest medical error
The trial was not submitted nor approved
by Canadian regulatory authorities and
some information channels were therefore
not open.
The trial and REB were inspected by FDA,
a warning letter was issued. No measure
taken from the Canadian side.
This case alone has raised lots of
suspicion in the US about the human
subject protection regime in Canada
Ryan Lucio died
at the age of 4 in
September 2002.

Issues in GCP Implementation
Understand;
1. It is a law, it is an act of parliament
Before you are allowed to practice medicine you have to
abide by a code of conduct & ethics.
Among other things you are sworn to the care of the
patient, have their safety as a paramount concern,
maintain confidentiality etc etc.
Similarly…

Malaysian GCP Guideline 2004
IRB / IEC
3.2.7. An institution without IRB/IEC
may request IRB/IEC of Ministry of
Health Malaysia or the Universities to
make decisions on behalf of the said
institution.

Malaysian GCP Guideline 2004
5.20.3
The DCA will enforce the rules and punitive
action will be decided by the DCA

GCP
“Regulations tell you what you
are required to do by law.
Guidelines tell you the best
way to do it”

Mitchell Creinin from Pittsburgh:
Trial on a medical device
Inform Subject
“…informed consent document…does not identify
foreseeable risks…”
Notify IRB
“…failed to submit the sponsor’s model consent form … to
the Magee-Womens Hospital IRB…”
Adhere to Protocol
“…log forms were not completed…in specific dates.”
Report Adverse Events
“irritation or discomfort…was not recorded on …case report
forms.”
Maintain Records
“You did not maintain complete records related to
each…case history.”

Michael Gruber from NYU:
Trial using biologics
Maintain Records
“…failed to prepare and maintain…accurate case
histories…” AND “…lack of source data…”
Retain Records
“…failed to retain investigational records.”
Adhere to Protocol
“…there were many deviations from the protocol
requirements…”
Supervise
“…nurse practitioner was not listed on the Form FDA-
1572 as subinvestigator,…”

Alkis Togias of John Hopkins: Clinical drug trial
Learn Investigator’s Brochure
“…you also failed to submit supporting data…”
Notify IRB
“You failed to notify and obtain IRB approval…”
Report Adverse Events
“…you failed to promptly report…unanticipated problems…”
Adhere to Protocol
“You changed the dosing conditions set forth in the
protocol…”
Inform Subjects
“…the following essential elements…were not included…”
Maintain AND Retain Records
“You failed to systematically record..” “No records were
available…”

Recent FDA Enforcement Letters
To Clinical Investigators
Most common findings
Failure to follow the protocol
Failure to personally conduct or supervise the
study
Failure to prepare and maintain adequate
and accurate case histories
Failure to maintain drug accountability records
Failure to obtain valid informed consent

What the FDA Typically Finds
100
90
85
82
80
74
70
67
% Identified Findings
60
50
40
30
44
20
10
0
Documentation Protocol Violations Reporting
Violations
Human Subject
Safety
Device/Drug
Control

What Are They Complaining About
Informed Consent Issues
Falsification
Failure to report adverse
events
Failure to follow the
protocol
Inadequate Records
Qualifications of persons
performing physicals
Failure to get IRB
approval, report changes
in research
Failure to follow FDA
regulations
Drug accountability
Recruitment Practices
Poor Supervision
No active IND
Violations of GLP regs
Monitoring practices
Blinding
Charging for the test
article
Misleading advertisements

Clinical Investigator
Deficiency Categories*
35% 35%
35%
30%
25%
20%
15%
10%
5%
0%
19%
11% 10%
n=285
*Foreign & Domestic CDER Inspections - FY 01
12/4/01

Inspections of Ethics Committee -
Deficiencies
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
49%
43%
21%
19% 18% 18%
(FY’01: CDER assigned)
N= 129

Sponsor/Monitor/CRO Inspections
Common Deficiencies 1998-2000
n= 39
25%
20%
23%
21%
18%
Failure to adequately
monitor study
Failure to document
monitoring visits
15%
15%
13%
Failure to have or
follow SOPs
10%
10%
Failure to maintain
drug acct. records
5%
Failure to select
qualified monitors
0%
Failure to assure IRB
approval of study

Other Issues 1
1. EC / IRB Approval
2. Signatures
3. Submitted Documents
4. Informed Consent
5. Delegation, Responsibilities & Supervision
6. Documentation
7. Review of Results
8. SAE/AE Reporting
9. Drug Accountability

Other Issues 2
EC Approval
Signatures
Number of Corum
Delegation Document
Source Data
Missing Investigations
Review & verifying results
Electronic CRF
SAE & AE Reporting
Missing Drugs

Issues in GCP Implementation
Understand;
1. It is a law
2. It is introduced for a purpose
3. The purpose is two-fold
Let’s look at the definition of GCP to
understand the purpose

Good Clinical Practice (GCP)
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides
assurance that
the Data and Reported Results are Credible, and
Accurate, = Quality Data
and that
the Rights, Integrity, and Confidentiality of Trial
Subjects are Protected. = Ethics
Quality Data + Ethics = GCP

Investigator Obligations
Authorisations (Trial/Manufacturing) from CA
Approvals from Ethics Committee
GCP compliance
Patient consents
AE \ SAE reporting to Sponsor

If you want to be an investigator……
You must make time to do the study
You must be interested in the scientific aspects
of the trial and not the financial rewards only
You must be sure that you can meet the
recruitment targets
You should not have competing trials
You must be aware of and adhere strictly to the
investigator’s GCP responsibilities

Commitments
S _______
M ______ ______
A _____ to _______
L ____ __________ ________
L et FDA Inspect
__P__ _______ _______
R etain Records
I _____ _______
N ____ _ _ _
T ____ ______

Commitments
S _______ upervise
M ______ aintain ______ Records
A _____ dhere to _______ Protocol
L ____ earn __________ Investigator’s ________
Brochure
L et FDA Inspect
Re ort Adverse Events
__P__ _______ _______
R etain Records
I nform _____ Subjects _______
N otify ____ _ EC_ _
T ____ rain ______ Staff

Commitments
P
e
o
p
l
e
N
e
e
d
s
S upervise _______
M ______ aintain Records ______
A _____ dhere to _______ Protocol
L ____ earn __________ Investigator’s Brochure ________
L et FDA Inspect
__P__ Re ort _______ Adverse _______ Events
R etain Records
I _____ nform Subjects _______
N otify ____ _ I _ R B _
T ____ ______
rain Staff
Data Quality
Ethics

Patients vs Subjects
When a person volunteers to
participate in a research trial, he/she
has become a “subject”.
Subjects may not be receiving
“standard of care” as a “patient”.
The risks may be higher
Documentation for subjects is MORE
EXTENSIVE than regular patient
documentation

If it was not documented, it
was not done

Can’t my Study Coordinator handle
this documentation stuff
The regulations hold the Investigator
responsible for assuring that the
data is correct, reliable, valid and
organised
The research documentation must
clearly show that the investigator
was involved in study evaluations
and decisions

Investigator Responsibility for Data
While a good coordinator is essential
to a well conducted trial, the
investigator should be careful to:
1. Refrain from over-delegating
2. Document his/her involvement in
activities such as eligibility
determination, adverse events, follow
up visits, outcomes, informed consent
3. Write orders for study treatments and
drugs
4. Regularly review the coordinator’s work
5. Not rely on the sponsor’s monitor to
check the coordinator’s work
6. Allow only the study team members to

Making Corrections on study records
Do:
Make one line through the entry
Write the corrected entry beside it
Initial, date and time the correction
Be able to see the incorrect entry.

Don’t
Making Corrections on study
records
Use White out (Blank-out)
Scratch through an entry
Use different colored inks
Let the monitor write on the CRF
Sign the investigator’s name

Who can obtain informed consent
Informed Consent
'Thanks for telling me your entire
medical history but I'm the hospital
barber.'

For Consent Form
Process of communication
Provide correct and understandable info.
Protect the subject
Must be approved by EC
Consent must be freely given
Must be properly documented
Informed Consent

1. Informed Consent
During an audit by a European Commission
Team, they stumbled upon a CRF without a
consent form.
a. What do you do
b. What precautionary measures do you take to
prevent this from ever happening again

2. Informed Consent
During an audit, the team stumbled upon a
consent form. Subject does not speak English but
the consent form was in English.
a. What do you do
b. What precautionary measures do you take to
prevent this from ever happening again

3. Informed Consent
During an audit, they stumbled upon two copies
of consent forms.
a. What is the problem
b. What do you do
c. What precautionary measures do you take to
prevent this from ever happening again

“Read the SMALL PRINT of the
1572” [Investigator Commitments: Box 9]
I agree…to make those records available for inspection

How to conduct clinical trials in
MOH Malaysia
• Application to MREC
• Application to NPCB
– Clinical trial import license
– Relevant permits for drug under study
• Parallel submission to DCA and EC
allowed

Research Management in
MOH
Standing Committee For Medical Research
NIH
Directorate
National
Committee For Clinical
Research
NIH
MOH departments
MREC
Animal Care &
Use Committee
DCA

Application submission
5 copies
Secretary,Standing Committee for Medical Research (SSCMR) - 1 copy
Open file;assign project code
MREC decision
Secretary, MREC (4 copies)
incomplete
Return to applicant
inform
SSCMR
complete
Open file Approval
Appeal
SSCMR
Director General
MREC
Close file
Final decision

Review process (MREC)
Preliminary assessment
Involve human subjects
YES
NO
Scientific Review
Ethical Review
Approval

GCP is not a wallpaper you paste
over your Clinical Development;
it is to be built into the Structure.

We need sound science, ethics and safety
in clinical trials to sustain the trust of
sponsors, governments, public and
especially research subjects & patients:
sustained trust is a condition to allow
research for the advancement of medicine.
Trusts at the institution,
department,
team and
individual level.
Trust

Do not differentiate your everyday clinical
practice from your research activities
Whatever you do for in your research clinic or
ward should also be practiced in your normal
clinic and ward.

Closing Remark
Look after your data !
Look after your subjects !