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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. *Note

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regulatory aspects of clinical trials in malaysia

Regulatory Aspects of Clinical Trials in Malaysia

Centre for Investigational New Product

National Pharmaceutical Control Bureau, MOH

outline
OUTLINE
  • Introduction
  • Guidelines and Legal Requirements
  • Application Process
  • Audit and Inspection
slide3

*Note

These statistics are based on the number of Clinical Trial Import License and Clinical Trial Exemption applications received by National Pharmaceutical Control Bureau.

Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug Control Authority.

slide4

*Note

These statistics are based on the number of Clinical Trial Import License and Clinical Trial Exemption applications received by National Pharmaceutical Control Bureau.

Drug-related clinical trials for registered products which do not require clinical trial import license is not controlled by the Drug Control Authority.

the guidelines should be read together in accordance to the legal requirements of
The Guidelines Should Be Read Together In Accordance To The Legal Requirements of ..
  • where controlled medicines are involved
slide11
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 …..
slide12
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
dca s mission in clinical trials research is also broad
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
cdcr 1984 revised 2009 regulation 2
CDCR 1984 (Revised 2009)Regulation 2

Definition ofProduct

  • 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
  • a drug to be used as an ingredient for a preparation for a medicinal purpose
sales of drugs act 1952 revised 1989
SALES OF DRUGS ACT 1952 (Revised 1989)

Definition ofDrug

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.

cdcr 1984 revised 2009 regulation 7
CDCR 1984 (Revised 2009)Regulation 7

Part III Registration and Licensing

Regulation 7. Prohibition against manufacture, sale, supply, importation, possession and administration

  • 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

cdcr 1984 revised 2009 notification of cosmetics
CDCR 1984 (Revised 2009) Notification of Cosmetics
  • Regulation 18A

Prohibition to manufacture, sell, supply, import or process cosmetics

  • No person sell manufacture, sell, supply, import or posses any cosmetic unless the cosmetic is a notified cosmetic.
  • For the purpose of subregulation (1), “notified cosmetic” means a cosmetic which a notification note issued by Director of Pharmaceutical Services.
cdcr 1984 revised 2009 regulation 12
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
cdcr 1984 revised 2009 regulation 15 exemptions
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.”

cdcr 1984 revised 2009 regulation 30
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.

control of drugs and cosmetics regulations 1984 revised 2009
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.

registration of independent ethics committee with dca
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)

slide25
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
slide26
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.
slide27
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.
notification by sponsor be centre to npcb for all be studies that do not required ctil ctx
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.
requirement on drug related clinical trial to register with nmrr
Requirement on Drug-related Clinical Trial to register with NMRR

The previously issued directive has expanded as follows:

All clinical trials involve drug has to be registered with NMRR.

For the IEC/IRB provide ethical approval for clinical trials without registration with NMRR, will result its registration with DCA being suspended.

slide30
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)
ctil ctx requirements 1 who can apply
CTIL/ CTX Requirements:(1) Who Can Apply?
  • *Note: Application for CTIL/ CTX containing a ‘poison/drug’ should be made by a LICENSE A HOLDER.
slide33
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
requirements 1
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.
requirements 2
Requirements (2)
  • ANNEX B- QUALITYdata 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)
requirement 3 annex c investigator s brochure
Requirement 3:Annex C (Investigator’s Brochure)

CONTENT

Safety Data of IP

Efficacy Data of IP

  • Non-Clinical Studies
  • Pharmacology; PK/PD studies
  • Toxicology Studies
  • Marketing Experience, PSUR, product status
  • Risks and ADR anticipated
  • PK/PD studies in human
  • In-house preliminary data
  • Summaries of clinical trial conducted (Phase I, II, III)
  • Published clinical data
responsibility of the applicant
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
safety decision arising from report analysis by other regulatory authority
Safety Decision Arising from Report Analysis/by Other Regulatory Authority
  • The DCA requires the sponsor to report within 48hours 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 ofany individualoverseas adverse drug reaction reports if requested.
factors affecting approval
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
timeline for approval in malaysia
TIMELINE FOR APPROVAL IN MALAYSIA

*Note: except for first in man trial, advanced therapy medicinal product (ATMP),

Biotechnology product and Herbal products.

conditions for ctil ctx in the guidelines for application of ctil ctx in malaysia
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
slide44

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

audit inspection
Audit & Inspection

5.19of M’sian GCP Guidelines

  • By the local Regulatory Authority
  • External Regulatory Authorities

e.g: FDA,USA

EMA,Europe

audit inspection1
Audit & Inspection
  • What is the difference?
in the malaysian guidelines for gcp 1 7 what is an audit
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).
in the malaysian guidelines for gcp 1 34 what is an inspection
In the Malaysian Guidelines for GCP1.34 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).
audit inspection2
Audit & Inspection
  • Audits = Sponsor function
  • Inspections= Regulatory function
  • Generally, sponsor audits are conducted along similar lines to a regulatory inspection
aims of regulatory inspections
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.
slide51

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)

slide52
USFDA has conducted 16 clinical study inspections in Malaysia, no official action indicated in any of them
slide54
The highest number of findings in the inspections were related to protocol compliance and informed consent
classification of inspection findings observations
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.
major
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.
minor
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.
fda case study 1 impact of inspection
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
slide60

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.
definition of fraud
Definition of Fraud

Three general types of fraud: