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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. Introduction Guidelines and Legal Requirements Application Process Audit and Inspection. *Note

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Regulatory Aspects of Clinical Trials in Malaysia

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  1. Regulatory Aspects of Clinical Trials in Malaysia Centre for Investigational New Product National Pharmaceutical Control Bureau, MOH

  2. OUTLINE • Introduction • Guidelines and Legal Requirements • Application Process • Audit and Inspection

  3. *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.

  4. *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.

  5. Guidelines and Legal Requirements

  6. The Guidelines Should Be Read Together In Accordance To The Legal Requirements of .. • where controlled medicines are involved

  7. In Malaysian Guidelines for GCP

  8. 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 …..

  9. 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

  10. 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

  11. Objectives of Clinical Trial Assessment

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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.”

  18. 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.

  19. Section 12, SODA 1952 (Revised 1989)

  20. 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.

  21. 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)

  22. 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

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. 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)

  28. CTIL and CTX Application

  29. CTIL/ CTX Requirements:(1) Who Can Apply? • *Note: Application for CTIL/ CTX containing a ‘poison/drug’ should be made by a LICENSE A HOLDER.

  30. 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

  31. CTIL/CTX Requirements:(2) Supporting Documents

  32. 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.

  33. 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)

  34. 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

  35. 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

  36. 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.

  37. Clinical Trial Approval

  38. 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

  39. TIMELINE FOR APPROVAL IN MALAYSIA *Note: except for first in man trial, advanced therapy medicinal product (ATMP), Biotechnology product and Herbal products.

  40. 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

  41. 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

  42. Audit & Inspection 5.19of M’sian GCP Guidelines • By the local Regulatory Authority • External Regulatory Authorities e.g: FDA,USA EMA,Europe

  43. Audit & Inspection • What is the difference?

  44. 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).

  45. 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).

  46. Audit & Inspection • Audits = Sponsor function • Inspections= Regulatory function • Generally, sponsor audits are conducted along similar lines to a regulatory inspection

  47. 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.

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