Transcript Regulatory Aspects of Clinical Trials in Malaysia

Centre for Investigational New Product
National Pharmaceutical Control Bureau, MOH
OUTLINE
 Introduction
 Guidelines and Legal Requirements
 Application Process
 Audit and Inspection
2
Number of Clinical Trials Conducted in Malaysia
Year 2002 - 2013
(excluding Bioequivalence Studies)
100
90
89
85
80
70
60
59
69
66
64
64
67
57
50
52
40
38
40
30
20
10
0
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
Year
*Note
1. These statistics are based on the number of Clinical Trial Import License and Clinical Trial Exemption applications received by
National Pharmaceutical Control Bureau.
2. Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug
Control Authority.
Phase of Clinical Trials Conducted in Malaysia
(excluding Bioequivalence Studies)
60
50
40
Phase I
30
Phase II
Phase III
20
Phase IV
10
0
2003
2004
2005
2006
2007
2008
Year
2009
2010
2011
2012
2013
*Note
1. These statistics are based on the number of Clinical Trial Import License and Clinical Trial Exemption applications received by
National Pharmaceutical Control Bureau.
2. Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug
Control Authority.
No. of CTs Conducted by Therapeutic Class
2003 - 2013
120
100
80
60
40
20
0
No. of CT by Therapeutic Class for Year 2013
(excluding bioequivalence studies)
Antineoplastic and Immunomodulating Agents
Alimentary Tract and Metabolism
Antiinfectives for Systemic Use
Cardiovascular System
Blood and Blood Forming Organs
Nervous System
Various
Respiratory System
Genito Urinary System and Sex Hormones
Musculo-skeletal System
Systemic Hormonal Preparations, excl. Sex Hormones and Insulins
Sensory System
0
2
4
6
8
10
12
14
16
18
Number of CTIL and CTX issued
from Year 2004 to 2013
CTIL
CTX
350
12
300
4
250
15
4
6
2
10
2
0
200
11
313
150
100
277
282
277
231
210
212
234
224
164
50
0
2004
2005
2006
2007
2008
2009
Year
2010
2011
2012
2013
Guidelines and Legal Requirements
Malaysian
Guidelines for Good
Clinical Practice 3rd
Edition (Updated
Oct 2011, NPCB
website)
8
Guidelines for
Application of CTIL
and CTX in Malaysia
5th Edition (Updated
June 2009, NPCB
website)
Guidelines for Good
Clinical Practice
Inspection (1st
Edition Oct 2010)
The Guidelines Should Be Read Together In
Accordance To The Legal Requirements of ..
1.
• Control of Drugs and Cosmetics Regulations
(CDCR) 1984
2.
• The Poison Regulations (Psychotropic
Substances) 1989
3.
• Sale of Drugs Act 1952
 where controlled medicines are involved
9
In Malaysian Guidelines for GCP
1.55 Regulatory
Authorities
• are bodies having the
power to regulate,
• includes the authorities
• that review submitted
clinical data
• that conduct inspection
• (Competent
Authorities)
1.26 Drug Control
Authority (DCA)
• An authority established
for the purpose of
regulating the Control of
Drugs and Cosmetics
Regulations, 1984
10
Regulation 3(2) Control of Drugs and Cosmetics
Regulations 1984 (Revised 2009)
THE DRUG CONTROL AUTHORITY (DCA)
The members are :
the director-general of health
(chairman)
the director of pharmaceutical
services (alternate chairman)
the director of the National
Pharmaceutical Control Bureau
8 other members appointed by
the Minister of Health …..
11
Regulation 3(2) Control of Drugs and
Cosmetics Regulations 1984 (Revised
2009)
THE DRUG CONTROL AUTHORITY (DCA)
…. The 8 other members appointed by the Minister of
Health are :
 A consultant physician in the public service;
 A pharmacist in the public service
 3 persons from any local universities with expertise in the
pharmaceutical sciences
 2 fully registered medical practitioners
 A veterinary practitioner in the public service
12
DCA’s Mission in Clinical Trials/
Research is Also Broad
 Ensure Implementation of Good Clinical Practice
(GCP) Standards
 GCP is an international ethical and scientific quality
standard for designing, conducting, recording, and
reporting trials that involve the participation of human
subjects
 GCP embraces trial objectives, trial design, study
oversight, data collection and quality assurance, study
analysis, as well as human subject protection in studies
that support product applications
13
Objectives of Clinical Trial Assessment
Regulations
Regional &
international
guidelines
CMC is
Acceptable
Ethics Review
Trial has
scientific
merit
Adequate
disclosure of
potential risks
Societal
benefits from
trial
Protection
of Clinical
Trial
Subjects
Data Integrity
14
CDCR 1984 (Revised 2009)
Regulation 2
Definition of Product
(a) a drug in a dosage unit or otherwise, for use
wholly or mainly by being administered to
one or more human beings or animals for a
medicinal purpose; or
(b) a drug to be used as an ingredient for a
preparation for a medicinal purpose
15
SALES OF DRUGS ACT 1952
(Revised 1989)
Definition of Drug
Includes any substance, product or article
intended to be used or capable, or purported or
claimed to be capable, of being used on humans
or any animal, whether internally or externally,
for medicinal purposes.
16
CDCR 1984 (Revised 2009)
Regulation 7
Part III Registration and Licensing
Regulation 7. Prohibition against manufacture,
sale, supply, importation,
possession and
administration
(1) No person shall manufacture, sell, supply, import or
possess or administer any product unless
(a) the product is a registered product; and
(b) the person holds the appropriate licence required
and issued under these Regulations
17
CDCR 1984 (Revised 2009)
Notification of Cosmetics
 Regulation 18A
Prohibition to manufacture, sell, supply, import
or process cosmetics
(1) No person sell manufacture, sell, supply, import or
posses any cosmetic unless the cosmetic is a notified
cosmetic.
(2) For the purpose of subregulation (1), “notified
cosmetic” means a cosmetic which a notification
note issued by Director of Pharmaceutical Services.
18
CDCR 1984 (Revised 2009)
Regulation 12
Regulation 12(1)(c): Clinical Trial Import
Licence (CTIL)
A Clinical trial import licence in Form 4 in
the Schedule,
• authorising the licensee to import any
product for purposes of clinical trials,
notwithstanding that the product is not
a registered product
19
CDCR 1984 (Revised 2009)
Regulation 15 Exemptions
Regulation 15(5) : Clinical Trial Exemption (CTX)
“Any person who wishes to manufacture any
products solely for the purpose of producing
samples for clinical trials, for registration or
issuance of notification note under these
Regulations may on application be exempted
by the Director of Pharmaceutical Services
from the provisions of regulation 7(1) or
regulation 18A.”
20
CDCR 1984 (Revised 2009)
Regulation 30
General Penalty
(1) Any person who contravenes
any of the provisions of these
Regulations or any condition of
any licence issued under these
Regulations or any condition
subject to which a product is
registered
under
these
Regulations commits an offence.
21
Section 12, SODA 1952 (Revised
1989)
Section 12(1), SODA ’52
INDIVIDUAL
Section 12(2), SODA ’52
BODY CORPORATE
First offence
A fine not exceeding
A fine not exceeding
RM25,000 or to
RM50,000
imprisonment for a term
not exceeding three years or
to both.
Second or
Subsequent offence
A fine not exceeding
RM50,000 or to
imprisonment for a term
not exceeding five years or
to both.
A fine not exceeding
RM100,000
22
Control of Drugs and Cosmetics
Regulations 1984 (Revised 2009)
Regulation 29. Directions
(1) The Director of Pharmaceutical Services
may issue written directives or guidelines to any person
or a group of persons as he thinks necessary for the
better carrying out of the provisions of these
Regulations and in particular relate to(l) clinical trials or
(2) Any person to contravenes any directives or guidelines
issued by the Authority under subregulation (1)
commits an offence.
23
Registration of Independent Ethics Committee with DCA
• All Independent Ethics
Committee approving drug
related trial must be registered
with the Drug Control
Authority
• This directives was issued
under Regulation 29, Control
of Drugs and Cosmetics
Regulations 1984
(Revised 2006)
Registration with National Medical Research
Register (NMRR ) for all clinical trials that require
CTIL/CTX
 A Directive had been issued effective from 1st January
2010, all Clinical Trial that require CTIL/CTX must
register with NMRR, failure to register shall result in
non-issuance of CTIL/CTX by DCA
Requirements to conduct BE studies for all generic
products that contained controlled medicine and
accreditation of the BE centres (1)
 A directive had been
issued effective from 1st Jan
2012, all new generic
products that apply for
registration must have a BE
study.
 A directive had been
issued for those generic
products that want to
renew their registration
must have a BE studies for
renewal after 31st Dec 2012.
26
Requirements to conduct BE studies for all generic
products that contained controlled medicine and
accreditation of the BE centres (2)
 All BE centres that conduct
BE studies must be
accredited by NPCB
effective from 1st Jan 2012
for both local and oversea
BE centres.
27
Notification by sponsor/ BE centre to NPCB for
all BE studies that do not required CTIL/CTX
 A directive had been issued effective
from 1st Jan 2012:
 For local pharmaceutical company,
notification must be given to NPCB
if they want to conduct the BE
studies either locally (for generic
product that do not required
CTIL/CTX) / oversea.
 For foreign pharmaceutical company
that conduct BE studies oversea must
fulfill certain requirements before
product registration.
28
Requirement on Drug-related
Clinical Trial to register with NMRR
The previously issued
directive has expanded as
follows:
1) All clinical trials involve
drug has to be registered
with NMRR.
2) For the IEC/IRB provide
ethical approval for
clinical trials without
registration with NMRR,
will result its registration
with DCA being
suspended.
Guidelines were issued under Regulation 29,
Control of Drugs and Cosmetics Regulations
1984 (Revised 2009)
 Guidelines for Application of CTIL and CTX in
Malaysia 5th Edition (Updated June 2009, NPCB
website)
 Guidelines for Good Clinical Practice Inspection (1st
Edition Oct 2010)
30
CTIL and CTX Application
Type of
Application
Categories of
Product
CTIL APPLICATION
CTX APPLICATION
Unregistered products when used or assembled (formulated
or packaged) in a way different from the approved form for
the purpose of Clinical Trial
A traditional product with a marketing authorisation with
indication for "traditionally used" when used for unapproved
indication/ therapeutic claims for clinical trial purpose.
Unregistered products to be
imported
Unregistered products to be
manufactured locally
Application
form
Borang BPFK 442.9
Borang BPFK 443.5
Fees
RM 500 for each product
Free
Licence A for Poisons /drugs (where applicable)
Pharmacist
Required?
NMRR Reg No.
NMRR Registration No.
License/ Permit
Issuance
 Approval from DCA
 Approval from IEC/IRB
31
CTIL/ CTX Requirements:
(1) Who Can Apply?
Any Principal Investigator
An authorised person from a LOCALLY
REGISTERED PHARMACEUTICAL COMPANY
(sponsor) / Clinical Research Organization with a
permanent address in Malaysia
*Note: Application for CTIL/ CTX containing a ‘poison/drug’ should be made by a
LICENSE A HOLDER.
32
Note:
 The holder of CTIL/CTX need not necessarily
conduct the clinical trial himself/herself
 The PI / Sponsor is allowed to submit parallel
application to the DCA and IEC
 A CTIL will only be issued when both approval
from DCA and IEC/IRB are obtained
33
CTIL/CTX Requirements:
(2) Supporting Documents
1. Annex A
• Clinical Trial Protocol
2. Annex B
• Pharmaceutical Data
3. Annex C
• Investigator’s Brochure
34
Requirements (1)
Annex A- Clinical Trial Protocol
 Name and dosage form of product
 Title and aim of the trial
 Description of the trial design
 Description of the subjects
 Treatment profile
 Operational aspects
 Adverse events
 Evaluation of results
 Approval by the principal investigator of the institution(s)
where the clinical trial is to be done.
35
Requirements (2)
ANNEX B- QUALITY data of the
investigational product
GMP
statement from manufacturing /
Certificate from Regulatory body
Certificate of analysis
Stability data (storage conditions)
Manufacturing data & formulation
Product labeling (coded & labeled:
blinding)
36
Requirement 3:
Annex C (Investigator’s Brochure)
CONTENT
Safety Data of IP
Efficacy Data of IP
 Non-Clinical Studies
 PK/PD studies in human
 Pharmacology; PK/PD
 In-house preliminary data
studies
 Toxicology Studies
 Marketing Experience, PSUR,
product status
 Risks and ADR anticipated
 Summaries of clinical trial
conducted (Phase I, II, III)
 Published clinical data
37
Responsibility of the applicant
 Responsible for the product and all information
supplied for the CTIL/CTX application and updating
the information
 If a service of CRO is used, a letter /authorization
should be submitted to DCA
 Any person who knowingly supplies any false or
misleading information in connection with his
application for CTIL/CTX commits an offence under
Control of Drugs and Cosmetics Reg.1984
38
Safety Decision Arising from Report
Analysis/by Other Regulatory Authority
 The DCA requires the sponsor to report within 48
hours of any significant safety issues which has
arisen from an analysis of overseas reports or action
with respect to safety which has been taken by
another country’s regulatory agency.
 Sponsors should inform any Malaysian investigator(s)
and, through the investigator, the IEC of this
information.
 The DCA also requires that sponsors be able to
provide promptly clinical details of any individual
overseas adverse drug reaction reports if requested.
Clinical Trial Approval
A requirement in many countries
Procedure varies
Legislation vs non legislation
40
Factors Affecting Approval
The speed of approval depends on: How complete is the information submitted?
 How fast sponsor/ PI respond to queries ?
 Enquiry should be answered within 30 working
days. Failure with this requirement, CTIL/CTX
will be rejected.
 Adherence to established procedures
 Ethical Approval
41
TIMELINE FOR APPROVAL IN
MALAYSIA
EC, MOH
Universities
National Heart Institute
DCA
4 – 8 weeks
4 – 8 weeks
3 – 6 weeks
30 working days*
*Note: except for first in man trial, advanced therapy medicinal product (ATMP),
Biotechnology product and Herbal products.
42
CONDITIONS FOR CTIL/CTX
IN THE GUIDELINES FOR APPLICATION OF
CTIL/CTX IN MALAYSIA
 CTIL Valid for 3 years (Regulation 12(5) of the
CDCR 1984)
 Renewal of CTIL should be made within 3 months
of the expiry date.
 Endorsement of CTIL/CTX-evidence of
importation & delivery of the product to the
investigator(s)
 Reporting of Suspected Unexpected Serious
Adverse Reaction (SUSAR)
 Changes of Information
43
 Discontinuation of trial with reasons. CTIL/CTX
should be returned
 End of Study Summary, Interim & Final Study
Report
 Drug Accountability/Disposal
Records/document : shipment, receipt
 System for retrieving and documentation
 System for the disposition of unused
investigational products
 Archiving
-responsibility of the investigator and the sponsor
to archive safely all documents related to the trial
44
Audit & Inspection
5.19 of M’sian GCP Guidelines
By the local Regulatory Authority
External Regulatory Authorities
e.g:
FDA,USA
EMA,Europe
45
Audit & Inspection
Audit
Inspection
What is the difference?
46
In the Malaysian Guidelines for
GCP 1.7 What is an Audit?
 A systematic and independent examination of
trial related activities and documents to
determine whether the evaluated trial related
activities were conducted, and the data
recorded, analyzed, and accurately reported
according to the protocol, sponsor’s SOPS,
GCP, the applicable regulatory requirement (s).
47
In the Malaysian Guidelines for GCP
1.34 What is an inspection ?
 The act by regulatory authority (ies) of conducting an
official review of documents, facilities, records, and
any other resources that are deemed by the authority
(ies) to be related to the clinical trial and that may be
located at the site of the trial, at the sponsor’s and /
or Contract Research Organization’s (CRO’s) facilities,
or at other establishments deemed appropriate by
the regulatory authority (ies).
48
Audit & Inspection
 Audits = Sponsor function
 Inspections= Regulatory function
 Generally, sponsor audits are conducted along
similar lines to a regulatory inspection
49
Aims of Regulatory Inspections:
 To determine the right, safety and well-being of a
study subject has been protected.
 To determine whether the trial was conducted in
accordance
with
applicable
regulatory
requirements, ethical standards and Malaysian
Guidelines for Good Clinical Practice.
 To determine whether the data submitted in the
dossier are credible and accurate.
 To assure the integrity of scientific testing and
study conduct.
50
The USFDA has conducted 16 inspections of clinical studies in Malaysia.
(*based on Clinical Trial in South East Asia (CTSE) 2012 Brief report on Thailand and Malaysia , presented at CTSE Conference and Yearly Update,
23rd November 2012 at Mumbai, India)
51
USFDA has conducted 16 clinical study inspections in
Malaysia, no official action indicated in any of them
52
53
The highest number of findings in the inspections were
related to protocol compliance and informed consent
54
A total of 6 large institutes in Malaysia were inspected
by the USFDA, many of them multiple times
55
CLASSIFICATION OF INSPECTION
FINDINGS/OBSERVATIONS
CRITICAL
 Conditions, practices or processes that adversely affect the
rights, safety or well being of the subjects and/or the quality
and integrity of data.
 Critical observations are considered totally unacceptable.
 Possible consequences: rejection of data and/or legal action
and/or regulatory action required.
 Remark: Observations classified as critical may include a
pattern of deviations classified as major, bad quality of the
data and/or absence of source documents. Fraud belongs to
this group.
56
MAJOR
 Conditions, practices or processes that might
adversely affect the rights, safety or well-being of the
subjects and/or the quality and integrity of data.
 Major observations are serious deficiencies and are
direct violations of GCP principles.
 Possible consequences: rejection of data and/or
regulatory action required.
 Remark: Observations classified as major, may include
a pattern of deviations and/or numerous minor
observations.
57
MINOR
 Conditions, practices or processes that would not be
expected to adversely affect the rights, safety or well
being of the subjects and/or the quality and integrity
of data.
 Possible consequences: Observation classified as
minor, indicate the need for improvement of
conditions, practices and processes.
 Remark: Many minor observations might indicate a
bad quality and the sum might be equal to a major
finding with its consequences.
58
FDA Case Study #1:
Impact of Inspection
Drug X in Long-Term Treatment of Condition
Y
 Objective of the study to test the efficacy of
drug X in outpatients when compare to
placebo, as measured by the number of days
until relapse
 Basis for site selection: site Eastern Europe
showed a significant treatment response
59
 FDA inspectional findings: there were
in-patient hospitalizations for 24
subjects out of 35 subjects enrolled.
 DSI recommended to review division to
reject data from this site.
60
Definition of Fraud
Three general types of fraud:
1. ALTERED DATA
2. OMITTED DATA
• Generating biased data
or changing data is
legitimately obtained.
• Not reporting data
which has an impact on
the study outcome
• E.g.
• Removing subjects
from study population
during analysis
• Not reporting or
disguising adverse
events
3. MANUFACTURED
DATA
• Fabricating
information or creating
results without
performing the work
• E.g.
• Filling in data in the
CRF when work is
not done
• Photocopying data
and using it for
multiple subjects
• Creating fictitious
subjects
61