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Centre for Investigational New Product National Pharmaceutical Control Bureau, MOH Slide 2 OUTLINE Introduction Guidelines and Legal Requirements Application Process Audit and Inspection 2 Slide 3 *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. Slide 4 *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. Slide 5 Slide 6 Slide 7 Slide 8 Guidelines and Legal Requirements 8 Malaysian Guidelines for Good Clinical Practice 3rd Edition (Updated Oct 2011, NPCB website) Guidelines for Application of CTIL and CTX in Malaysia 5 th Edition (Updated June 2009, NPCB website) Guidelines for Good Clinical Practice Inspection (1 st Edition Oct 2010) Slide 9 The Guidelines Should Be Read Together In Accordance To The Legal Requirements of.. where controlled medicines are involved 9 1. Control of Drugs and Cosmetics Regulations (CDCR) 1984 2. The Poison Regulations (Psychotropic Substances) 1989 3. Sale of Drugs Act 1952 Slide 10 In Malaysian Guidelines for GCP 10 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 Slide 11 Regulation 3(2) Control of Drugs and Cosmetics Regulations 1984 (Revised 2009) THE DRUG CONTROL AUTHORITY (DCA) The members are : The members are : the director-general of health (chairman) 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 Slide 12 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 consultant physician in the public service; A pharmacist in the public service A pharmacist in the public service 3 persons from any local universities with expertise in the pharmaceutical sciences 3 persons from any local universities with expertise in the pharmaceutical sciences 2 fully registered medical practitioners 2 fully registered medical practitioners A veterinary practitioner in the public service A veterinary practitioner in the public service 12 Slide 13 DCAs 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 Slide 14 Objectives of Clinical Trial Assessment Protection of Clinical Trial Subjects Adequate disclosure of potential risks Trial has scientific merit CMC is Acceptable Regulations Regional & international guidelines Ethics Review Societal benefits from trial Data Integrity 14 Slide 15 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 Slide 16 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 Slide 17 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 Slide 18 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 Slide 19 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 Slide 20 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 Slide 21 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 Slide 22 Section 12, SODA 1952 (Revised 1989) 22 Section 12(1), SODA 52 INDIVIDUAL Section 12(2), SODA 52 BODY CORPORATE First offenceA fine not exceeding RM25,000 or to imprisonment for a term not exceeding three years or to both. A fine not exceeding RM50,000 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 Slide 23 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 Slide 24 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) Slide 25 Registration with National Medical Research Register (NMRR ) for all clinical trials that require CTIL/CTX A Directive had been issued effective from 1 st 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 Slide 26 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 1 st 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 31 st Dec 2012. 26 Slide 27 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 1 st Jan 2012 for both local and oversea BE centres. 27 Slide 28 Notification by sponsor/ BE centre to NPCB for all BE studies that do not required CTIL/CTX A directive had been issued effective from 1 st 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 Slide 29 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. Slide 30 Guidelines were issued under Regulation 29, Control of Drugs and Cosmetics Regulations 1984 (Revised 2009) Guidelines for Application of CTIL and CTX in Malaysia 5 th Edition (Updated June 2009, NPCB website) Guidelines for Good Clinical Practice Inspection (1 st Edition Oct 2010) 30 Slide 31 CTIL and CTX Application 31 Type of Application CTIL APPLICATIONCTX APPLICATION Categories of Product 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 442.9Borang BPFK 443.5 FeesRM 500 for each productFree Pharmacist Required? Licence A for Poisons /drugs (where applicable) NMRR Reg No. NMRR Registration No. License/ Permit Issuance Approval from DCA Approval from IEC/IRB Slide 32 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 32 *Note: Application for CTIL/ CTX containing a poison/drug should be made by a LICENSE A HOLDER. Slide 33 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 Slide 34 CTIL/CTX Requirements: (2) Supporting Documents Clinical Trial Protocol 1. Annex A Pharmaceutical Data 2. Annex B Investigators Brochure 3. Annex C 34 Slide 35 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 Slide 36 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 Slide 37 Requirement 3: Annex C (Investigators Brochure) Safety Data of IPEfficacy 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 37 CONTENT Slide 38 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 Slide 39 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 countrys 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. Safety Decision Arising from Report Analysis/by Other Regulatory Authority Slide 40 Clinical Trial Approval 40 A requirement in many countriesProcedure variesLegislation vs non legislation Slide 41 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 Slide 42 TIMELINE FOR APPROVAL IN MALAYSIA EC, MOH4 8 weeks Universities4 8 weeks National Heart Institute3 6 weeks DCA30 working days* 42 *Note: except for first in man trial, advanced therapy medicinal product (ATMP), Biotechnology product and Herbal products. Slide 43 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 Slide 44 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 Slide 45 Audit & Inspection 5.19 of Msian GCP Guidelines By the local Regulatory Authority External Regulatory Authorities e.g: FDA,USA EMA,Europe 45 Slide 46 Audit & Inspection What is the difference? 46 Audit Inspection Slide 47 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, sponsors SOPS, GCP, the applicable regulatory requirement (s). 47 Slide 48 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 sponsors and / or Contract Research Organizations (CROs) facilities, or at other establishments deemed appropriate by the regulatory authority (ies). 48 Slide 49 Audit & Inspection Audits = Sponsor function Inspections= Regulatory function Generally, sponsor audits are conducted along similar lines to a regulatory inspection 49 Slide 50 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 Slide 51 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, 23 rd November 2012 at Mumbai, India) 51 Slide 52 USFDA has conducted 16 clinical study inspections in Malaysia, no official action indicated in any of them 52 Slide 53 53 Slide 54 The highest number of findings in the inspections were related to protocol compliance and informed consent 54 Slide 55 A total of 6 large institutes in Malaysia were inspected by the USFDA, many of them multiple times 55 Slide 56 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 Slide 57 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 Slide 58 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 Slide 59 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 Slide 60 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 Slide 61 Definition of Fraud 1. ALTERED DATA Generating biased data or changing data is legitimately obtained. 2. OMITTED DATA 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 Three general types of fraud: Slide 62