Presentation on theme: "Regulatory Aspects of Clinical Trials in Malaysia"— Presentation transcript:
1 Regulatory Aspects of Clinical Trials in Malaysia Centre for Investigational New ProductNational Pharmaceutical Control Bureau, MOH
2 Clinical Research and Compliance Section OUTLINEIntroductionGuidelines and Legal RequirementsApplication ProcessAudit and Inspection
3 *NoteThese 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 *NoteThese 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.
8 Guidelines and Legal Requirements Malaysian Guidelines for Good Clinical Practice 3rd Edition (Updated Oct 2011, NPCB website)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)
9 The Guidelines Should Be Read Together In Accordance To The Legal Requirements of .. 1.Control of Drugs and Cosmetics Regulations (CDCR) 19842.The Poison Regulations (Psychotropic Substances) 19893.Sale of Drugs Act 1952where controlled medicines are involved
10 In Malaysian Guidelines for GCP 1.55 Regulatory Authoritiesare bodies having the power to regulate,includes the authoritiesthat review submitted clinical datathat 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
11 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 Bureau8 other members appointed by the Minister of Health …..
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 pharmacist in the public service3 persons from any local universities with expertise in the pharmaceutical sciences2 fully registered medical practitionersA veterinary practitioner in the public service
13 DCA’s Mission in Clinical Trials/ Research is Also Broad Ensure Implementation of Good Clinical Practice (GCP) StandardsGCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjectsGCP 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
14 Objectives of Clinical Trial Assessment Clinical Research and Compliance SectionObjectives of Clinical Trial AssessmentProtection of Clinical Trial SubjectsAdequate disclosure of potential risksTrial has scientific meritCMC is AcceptableRegulationsRegional & international guidelinesEthics ReviewSocietal benefits from trialData Integrity
15 CDCR 1984 (Revised 2009) Regulation 2 Definition of Producta 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; ora drug to be used as an ingredient for a preparation for a medicinal purpose
16 SALES OF DRUGS ACT 1952 (Revised 1989) Definition of DrugIncludes 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.
17 CDCR 1984 (Revised 2009) Regulation 7 Part III Registration and LicensingRegulation 7. Prohibition against manufacture, sale, supply, importation, possession and administrationNo 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 requiredand issued under these Regulations
18 CDCR 1984 (Revised 2009) Notification of Cosmetics Regulation 18AProhibition to manufacture, sell, supply, import or process cosmeticsNo 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.
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
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.”
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.
22 Section 12, SODA 1952 (Revised 1989) INDIVIDUALSection 12(2), SODA ’52BODY CORPORATEFirst offenceA fine not exceeding RM25,000 or to imprisonment for a term not exceeding three years or to both.A fine not exceeding RM50,000Second or Subsequent offenceA fine not exceeding RM50,000 or to imprisonment for a term not exceeding five years or to both.A fine not exceeding RM100,000
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.
24 Registration of Independent Ethics Committee with DCA All Independent Ethics Committee approving drug related trial must be registered with the Drug Control AuthorityThis directives was issued under Regulation 29, Control of Drugs and Cosmetics Regulations 1984(Revised 2006)
25 Registration with National Medical Research Register (NMRR ) for all clinical trials that require CTIL/CTXA 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
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 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.
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 1st Jan 2012 for both local and oversea BE centres.
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 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.
29 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.
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 5th Edition (Updated June 2009, NPCB website)Guidelines for Good Clinical Practice Inspection (1st Edition Oct 2010)
31 CTIL and CTX Application Type of ApplicationCTIL APPLICATIONCTX APPLICATIONCategories of ProductUnregistered products when used or assembled (formulated or packaged) in a way different from the approved form for the purpose of Clinical TrialA 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 importedUnregistered products to be manufactured locallyApplication formBorang BPFK 442.9Borang BPFK 443.5FeesRM 500 for each productFreePharmacist Required?Licence A for Poisons /drugs (where applicable)NMRR Reg No.NMRR Registration No.License/ Permit IssuanceApproval from DCAApproval from IEC/IRB
32 CTIL/ CTX Requirements: (1) Who Can Apply? Any Principal InvestigatorAn 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.
33 Note:The holder of CTIL/CTX need not necessarily conduct the clinical trial himself/herselfThe PI / Sponsor is allowed to submit parallel application to the DCA and IECA CTIL will only be issued when both approval from DCA and IEC/IRB are obtained
35 Requirements (1) Annex A- Clinical Trial Protocol Name and dosage form of productTitle and aim of the trialDescription of the trial designDescription of the subjectsTreatment profileOperational aspectsAdverse eventsEvaluation of resultsApproval by the principal investigator of the institution(s) where the clinical trial is to be done.
36 Requirements (2) ANNEX B- QUALITY data of the investigational product GMP statement from manufacturing / Certificate from Regulatory bodyCertificate of analysisStability data (storage conditions)Manufacturing data & formulationProduct labeling (coded & labeled: blinding)
37 Requirement 3: Annex C (Investigator’s Brochure) CONTENTSafety Data of IPEfficacy Data of IPNon-Clinical StudiesPharmacology; PK/PD studiesToxicology StudiesMarketing Experience, PSUR, product statusRisks and ADR anticipatedPK/PD studies in humanIn-house preliminary dataSummaries of clinical trial conducted (Phase I, II, III)Published clinical data
38 Responsibility of the applicant Responsible for the product and all information supplied for the CTIL/CTX application and updating the informationIf a service of CRO is used, a letter /authorization should be submitted to DCAAny 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
39 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.
40 Clinical Trial Approval A requirement in many countriesProcedure variesLegislation vs non legislation
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 proceduresEthical Approval
42 TIMELINE FOR APPROVAL IN MALAYSIA EC, MOH4 – 8 weeksUniversitiesNational Heart Institute3 – 6 weeksDCA30 working days**Note: except for first in man trial, advanced therapy medicinal product (ATMP),Biotechnology product and Herbal products.
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
44 Discontinuation of trial with reasons. CTIL/CTX should be returned End of Study Summary, Interim & Final Study ReportDrug Accountability/DisposalRecords/document : shipment, receiptSystem for retrieving and documentationSystem for the disposition of unused investigational productsArchiving-responsibility of the investigator and the sponsor to archive safely all documents related to the trial
45 Audit & Inspection 5.19 of M’sian GCP Guidelines By the local Regulatory AuthorityExternal Regulatory Authoritiese.g: FDA,USAEMA,Europe
46 Audit & InspectionAuditInspectionWhat is the difference?
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, sponsor’s SOPS, GCP, the applicable regulatory requirement (s).
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 sponsor’s and / or Contract Research Organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority (ies).
49 Audit & Inspection Audits = Sponsor function Inspections= Regulatory functionGenerally, sponsor audits are conducted along similar lines to a regulatory inspection
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.
51 The USFDA has conducted 16 inspections of clinical studies in Malaysia 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)
52 USFDA has conducted 16 clinical study inspections in Malaysia, no official action indicated in any of them
54 The highest number of findings in the inspections were related to protocol compliance and informed consent
55 A total of 6 large institutes in Malaysia were inspected by the USFDA, many of them multiple times
56 CLASSIFICATION OF INSPECTION FINDINGS/OBSERVATIONS CRITICALConditions, 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.
57 MAJORConditions, 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.
58 MINORConditions, 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.
59 FDA Case Study #1: Impact of Inspection Drug X in Long-Term Treatment of Condition YObjective of the study to test the efficacy of drug X in outpatients when compare to placebo, as measured by the number of days until relapseBasis for site selection: site Eastern Europe showed a significant treatment response
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.
61 Definition of Fraud Three general types of fraud: 1. ALTERED DATA Generating biased data or changing data is legitimately obtained.2. OMITTED DATANot reporting data which has an impact on the study outcomeE.g.Removing subjects from study population during analysisNot reporting or disguising adverse events3. MANUFACTURED DATAFabricating information or creating results without performing the workFilling in data in the CRF when work is not donePhotocopying data and using it for multiple subjectsCreating fictitious subjects