Principles of GCP - UKM Medical Centre

OVERVIEW OF GCP, ICH
AND MALAYSIAN GCP
PROF DR ROSLINA A MANAP
Department of Medicine
UKMMC

Scope of Lecture
• Background/definitions
• Evolution of GCP
• Principles of GCP
• Common audit findings
• Conclusions
2

Background
• GCP certification is mandatory for clinical
researchers
• Proof of certification to sponsors/IRB
• Attendance at workshop + assessment
• GCP is structured programme/workshop
• cannot be done retrospectively
• GCP ensures that research is
• done in a proper way
• of high standard
• not associated with foul play, dishonesty, cheating, hiding
of data
• not harmful to the participants
3

Good Clinical Practice
A standard for the design, conduct, performance,
monitoring, auditing, recording, analysis, 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 = GCPs
ICH GCP 1.24 / Malaysian GCP 1.28
4

Good Clinical Practice
• Compliance with this standard provides public
assurance:
That the rights, safety, integrity,
confidentiality and well being of trial
subjects are protected consistent with the
principles that have their origin in
Declaration of Helsinki.
That the data and reported results are
credible and accurate.
5

National Document
6

HISTORY
• GCP and other rules on human research in drug
development have now been formalized in many
international and national guidelines and regulations.
• FDA guidelines for sponsors and investigators in 1970s
• European Union GCP guidelines 1980s
• International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) started 1991
7

Researcher/
sponsors
Research Question
Protocol Development
IRB/IEC
Researcher
/monitors/
auditors
Researcher/
sponsors
Scientific & Conflict of Interest Reviews
Ethics Review
Recruitment & Enrolment
Data Collection
Data Analysis/Study Close-Out
Dissemination
MUST be
GCP-
compliant
8

Steps to reduce research fraud &
misconduct
• Strengthen ethical research guidelines & upgrade
guidelines into Acts of Law
• Laws and legislations (e.g. Medical Act) must include
research issues
• IRBs made more transparent and accountable for their
decisions
• Role of MMC expanded to include research misconduct
• Annual research reports & research findings accessible to
public
9

Steps to reduce research fraud &
misconduct
“Strengthening the number of medical personnel
and improving the support system in any particular
academic institution so that medical research is
done by personnel who are not too heavily burdened
by teaching or provision of clinical service. A system
where the same, small number of staff are expected
to perform “miracles” by being able to undertake
good research in the background of a multitude of
other commitments (teaching, clinical service or
administrative duties) may inadvertently encourage
a medical researcher to be fraudulent for his
“academic survival”.
Zabidi Azhar Hussin, National Ethics Seminar, 2 Dec 2006
10

Why develop GCP
• Fraud & misconduct
• Nuremberg code
• Clinical trial tragedies
11

Fraud & misconduct
• Defined as “the deliberate reporting of
false or misleading data or the
withholding of reportable data”
• 3 general types:
• Altered data
• Omitted data
• Manufactured data
12

Nuremberg Code 1947
• 10 points pertaining to human
experimentation
• Including, “voluntary
consent is absolutely
essential”
• Result of 140 days of American
military tribunal against 23
leading German physicians/
administrators for crimes
against humanity including
human experimentation
without consent
• Thousands died or permanently
crippled
• 16 found guilty; 7 executed on
2.6.48
Dr Leo Alexander points to scars on the
leg of Jadwiga Dzido’s, a Polish
underground and victim of medical
experiments at the Ravensbrueck
concentration camp
13

The Ellen Roche Story
Johns Hopkins University
Garland Hall, JHU
• 24-year-old female lab
technician
• Healthy volunteer in
asthma study
• Died on 2/7/01 after
inhalation of a non-
approved drug
• Autopsy revealed lung
destruction
14

Evolution of GCP
• 1930’s – US Food Drug & Cosmetic Act
• 1947 – Nuremberg Code
• 1960’s – Clinical trial tragedies
• 1964 – Declaration of Helsinki
• 1970’s – Sponsor/monitor obligations (US)
• 1980’s – Informed Consent Regulations (US)
• 1980’s – IRB Regulations (US)
• 1986 - ABPI Guidelines (UK)
• 1987 – Bonne Pratiques Cliniques (France)
16

Evolution of GCP
• 1989 – Nordic and Japanese Guidelines
• 1990 – Huriet Law (France)
• 1991 – European CPMP Guidelines
• 1992 – Australian Guidelines
• 1992 – WHO Guidelines
• 1996 – ICH Guidelines issued
• 1997 – ICH becomes LAW in some countries
• 1990’s European Guidelines, Asian countries
• Oct 1999 – Malaysian GCP
17

Declaration of Helsinki
• Adopted by World Medical Association
General Assembly, Helsinki, Finland, June
1964
• Amended 5 times, most recently in October
2000 in Edinburgh, Scotland
18

Declaration of Helsinki
• 32 points, including:
• “…the health of my patients will be my first
consideration”
• “…to protect the life, health, privacy and dignity
of the human subject”
• “…the well-being of the human subject should take
precedence over the interests of science and
society”
• “…the responsibility of the human subject must
always rest with a medically qualified person and
never rest on the subject of the research, even
though the subject has given consent”
19

ICH and Malaysian GCP
• International Conference on Harmonisation Guideline for Good
Clinical Practice
• Tripartite harmonisation initiatives (EU, USA, Japan)
• Drafted 17/8/95, endorsed 30/4/96, and effective from 9/5/97
• MGCP very similar to ICH GCP but with modifications to cater for
local needs – drafted 6/99, finalised 9/99, launched 2/11/99, and
revised 2004
20

Aims of International Conference on
Harmonisation (ICH)
1. Unify registration requirements for new products
2. Reduce medicinal product development costs: more
economical use of animal, human and material
resources.
3. Accelerate medicinal product licensing times: avoid
repeat testing in different regions.
4. Increases patent protection times through reducing
delay in licensing times.
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Malaysian GCP Subcommittee
2 nd Edition 2004
• Tan Sri Datuk Dr Mohd Ismail Merican
• Prof Dr Abd Rashid Abd Rahman
• Dr Nor Shahidah Khairullah
• Prof Dr Lang Chim Choy
• Prof Dr Tariq bin Abdul Razak
• Prof Dato’ Dr Khalid bin Yusoff
• Dr Muruga Vadivale
• Dr Lokman Hakim Sulaiman
• Dato’ Dr Zaki Morad Mohd Zaher
• Ms Fudziah Dato Ariffin
• Ms Norhayati Hanafiah
22

• 2nd edition of Malaysian
GCP Guidelines – Jan 2004
• The guideline is developed
in line with the current
local regulatory
requirements on the
manufacture of
Investigational medicinal
products, prerequisite of
an approved GCP training
and the current ICH GCP
guidelines
• (CPMP/ICH/135/95)
• This guideline is available
at
http://www.bpfk.gov.my
23

Malaysian vs. ICH GCP
Amendments & additions
Comprehensively addresses:
• Use of alternative medicine (1.29)
Plant/animal-derived materials or products with
therapeutic or other human health benefits which
contain either raw or processes ingredients from one or
more plants/animals.
• Role/authority of DCA (1.26, 5.20.3)
A regulatory authority established for the purpose of
regulatory the control of drugs and cosmetics
regulations, 1984 24

Malaysian vs. ICH GCP
• Importance of approved training in GCP,
NCCR (1.6)
• Training which is approved by the National
Committee for Clinical Research (NCCR).
The content of the training must
incorporate the co-curriculum curriculum as stipulated
by the committee
25

Malaysian vs. ICH GCP
• Clinical trial import licence/exemption/customs (1.14,
1.13, 5.14.2)
• A license in Form 4 in the schedule of The Control of
Drugs and Cosmetics Regulations of 1984,
authorizing the licensee to import any product for
purposes of clinical trials, notwithstanding that the
product is not a registered product.
• An approval by the DCA authorizing the applicant
to manufacture any local product for the purpose of
clinical trial.
26

Malaysian vs. ICH GCP
• Role of IRB/IEC of MOH (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
National Committee for Clinical Research (NCCR) (1.46)
• A committee established for the purpose of
coordinating and promoting clinical research in
Malaysia, chaired by the Deputy Director of Health
(Research & Technical Support), MOH
27

Investigator
• (4.1.1) The investigator(s) should be qualified by
education, approved training in Good Clinical Practice and
experience to assume responsibility for the proper
conduct of the trial, should meet all the qualifications
specified by the applicable regulatory requirement(s), and
should provide evidence of such qualifications through up-
to-date curriculum vitae and/ or other relevant
documentation requested by the sponsor, the IRB/IEC,
and /or the regulatory authority(ies) 28

Investigator
• Both the informed consent discussion and the
written informed consent form and any other
written information to be provided to subjects
should include explanations of (a)-(u):
29

Investigator
• All serious adverse events (SAEs) detected or being notified
should be reported within 2 working days to the sponsor
except for those SAEs that the protocol or other document
(eg., Investigator’s Brochure) identifies as not needing
immediate reporting. The immediate report should be
followed within 7 days by detailed, written report. The
investigator must comply with the applicable regulatory
requirement(s) related to the reporting of unexpected
serious adverse drug reactions to the regulatory
authority(ies) and IRB/IEC
30

Investigator
• Alternative use of thumbprint for consent
(4.8.9) If a subject is unable to read or if a legally
acceptable representative is unable to read, an
impartial witness should be present……. …………….
the subject or the subject’s legally acceptable
representative orally consented to the subject’s
participation in the trial and, if capable of doing so,
has signed and/or thumbprinted and personally
dated the informed consent form, the witness
should sign and personally date the consent form.
4.8.10 (u) The source of the investigational product
that may be culturally unacceptable. 31

Sponsor
• 5.6.1 The sponsor is responsible for selecting the investigator (s)/
institution(s). Each investigator should be qualified by training
(including approved GCP training) and should have adequate
resources to properly conduct the trial for which the investigator is
selected.
• 5.8.1 If required by the applicable regulatory requirement(s), the
sponsor must provide insurance or must indemnify (legal and
financial coverage) the investigator/ institution against claims
arising from the trial, except for claims that arise from malpractice
and/or negligence
32

Sponsor
• 5.14.2 The sponsor should not supply an
investigator/institution with the investigational
product(s) until the sponsor obtains all required
documentation (e.g. approval/favourable
opinion from
IRB/IEC and regulatory authority(ies). All importation
of clinical trial drugs should go through customs even
though a clinical trial import licence has been
obtained.
33

Principles of GCP
Safety and Protection of Subjects
• “The health of my patient will be
my first consideration” Declaration
of Helsinki
Trials should be conducted in
accordance with the ethical
principles that have their origin in
the Declaration of Helsinki, and
that are consistent with GCP and
regulatory requirement(s).
34

Principles of GCP
Safety and Protection of Subjects
• The rights, safety, and well-being of the trial
subjects are the most important
considerations and should prevail over
interests of science and society
Before a trial is initiated, foreseeable risks
and inconveniences should be weighed
against the anticipated benefit for the
individual subject and society.
Ethics committee
• Freely given informed consent should be
obtained from every subject prior to clinical
trial participation
35

Principles of GCP
Safety and Protection of Subjects
• The available non clinical and clinical
information on an investigational product
should be adequate to support the proposed
clinical trial.
• Clinical trials should be scientifically sound, and
described in a clear, detailed protocol.
• A trial should be conducted in compliance with
the protocol that has received prior institutional
review board (IRB)/independent ethics
committee (IEC) approval/favourable
opinion
36

Principles of GCP
Safety and Protection of Subjects
• A trial should be initiated and
continued only if the anticipated
benefits justify the risks
• All clinical trial information should be
recorded, handled, and stored in a way
that allows its accurate reporting,
interpretation and verification
37

Principles of GCP
Safety and Protection of Subjects
• The confidentiality of records that
could identify subjects should be
protected, respecting the privacy and
confidentiality rules in accordance with
the applicable regulatory
requirement(s)
• The medical care given to, and medical
decisions made on behalf of, subjects
should always be the responsibility of a
qualified physician or, when
appropriate, of a qualified dentist 38

Principles of GCP
Safety and Protection of Subjects
• Each individual involved in conducting a
trial should be qualified by education,
training, and experience to perform his
or her respective task(s).
• Investigational products should be
manufactured, stored and handled in
accordance to GMP, and should only be
used as per approved protocol
• Systems with procedures that assure
the quality of every aspect of the trial
should be implemented 39

Written Informed Consent
• Study specific procedures performed before consent
• Wrong version being used (LANGUAGE)
• Backdating/dated by site staff
• Not re-consenting following protocol amendment
• Copy not given to patient
• Missing consent forms
40

Study Protocol/Amendments
• Recruiting ineligible subjects
• Protocol procedures not done/done properly
• Additional procedures performed
• Implementation of amendment prior to ethics approval
• Amendments not distributed to investigational staff at sites
• Incorrect version used
41

Study Drug
• Inadequate drug accountability
• Inadequate storage conditions
• Lack of restricted access
• Inadequate temperature monitoring
42

AE/SAE Reporting
• Delays in reporting of SAEs
• AEs not thought to be drug-related related not reported in case
report forms (CRF)
• AEs on CRF not recorded in medical records
• AEs not followed up at next visit or after study
• Doctor not understanding definitions of AE/SAE
43

Conclusions
• Being GCP compliant ensures that:
• Subjects are properly protected
• Studies are based on good science, well
designed, and properly analyzed
• Study procedures are properly undertaken and
adequately documented
• Being non-GCP compliant results in:
• Subjects being at risk
• Data collection being unreliable
• Risk of rejection by regulatory bodies
44