GUIDELINE FOR REGULATING THE CONDUCT OF CLINICAL TRIALS .

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GUIDELINE FOR REGULATINGTHE CONDUCT OF CLINICAL TRIALS USINGMEDICINESIN HUMAN PARTICIPANTSBOTSWANAMarch 2012

2Table of ContentsA. Guideline on Regulating the Conduct of Clinical Trials in HumanParticipants1. Scope of these Guidelines2. When to Submit an Application to Conduct a Clinical Trial3. Responsibilities Relating to Clinical Trials4. Ethical Assessment5. Insurance of Trial Subjects6. Good Clinical Practice (GCP)7. The Clinical Trial Protocol8. The Investigator’s Brochure9. Investigational medicinal product10. Labelling and Dispensing of Trial Medications11. Requirements concerning informed consent12. Clinical Trial Amendments13. Clinical Trial Records14. Premature termination of a clinical trial15. Reporting of Adverse Drug Reactions and Adverse Events16. Submission of Progress Reports17. Inspections of Clinical Trials18. Withdrawal of Authorisation to Conduct a Clinical Trial19. The Clinical Trial ApplicationB. Appendices1. Clinical Trial Application Form2. Format for Investigator’s Curriculum Vitae3. Joint Financial Declaration by Sponsor and Principal Investigator4. Declaration by Principal Investigator5. Declaration by Co-investigator6. Declaration by Regional Monitor7. Clinical Trial Protocol Amendment Form8. Application Form for Additional Investigators and SitesC. Glossary

3A. Guideline on Regulating the Conduct of Clinical Trials in Human Participants1. Scope of these Guidelines:The aim of this guideline is to provide a framework for regulating the conduct ofclinical trials in human participants. This guideline outlines the information requiredby the Drugs Regulatory Unit [DRU] from sponsors and applicants wishing toconduct clinical trials as well as defines the evaluation process for the conduct ofclinical trials. This guideline is not intended as a comprehensive guide on GoodClinical Practice (GCP) and should be read in conjunction with relevant internationalGCP guidelines. This guideline has been prepared in accordance with the followingGCP guidelines:International Conference on Harmonisation (ICH) Guideline on Good ClinicalPractice (ICH E6).Guideline for Good Clinical Practice in the Conduct of Clinical Trials in HumanParticipants (South Africa, 2000)2. When to Submit an Application to Conduct a Clinical Trial:Before initiating the clinical trial (s), the sponsor (or the sponsor and the investigator,is required to submit the required application (s) to the DRU and the HealthResearch Unit [HRU] for review, acceptance, and/or permission to begin the trial(s).The submission should be dated and contain sufficient information to identify theprotocol2.1. An application for approval to conduct a clinical trial is required for the followingcategories of medicines:2.1.1. Unregistered medicines2.1.2. Registered medicines where the proposed clinical trials are outside of theconditions of approval. These may include changes to:2.1.2.1.indication(s) and clinical use2.1.2.2.target patient population(s)2.1.2.3.route(s) of administration2.1.2.4.dosage regimen(s)2.2. An application for authorization to conduct a clinical trial described in paragraph2.1 above must be made on a form and accompanied by an application fee asdetermined by the regulatory authority.2.3. No person may conduct a clinical trial using investigational products included inparagraph 2.1 above without prior authorisation from the DRU.2.4. A clinical trial authorised by the Health Research Unit must be conducted inaccordance with guidelines for Good Clinical Practice (GCP) as may from timeto time be determined by the Authority.2.5. Approval by the Regulatory Authority to conduct post market clinical trials of aregistered medicine within the approved conditions of registration of such amedicine is not required. The authority should be notified of such a trial.However, approval by the Health Research and Development Committee isrequired prior to initiation of the trial.2.6. Treatment of an individual patient by a medical practitioner with an unregisteredmedicine or with a registered medicine outside of the approved conditions ofregistration of such a medicine is not considered to be a clinical trial and wouldusually require special approval by the Director of Health Services on a namedpatient basis.3. Responsibilities Relating to Clinical Trials:

4An application to conduct a clinical trial may be made by a pharmaceutical company(sponsor), clinical research organisation (CRO), or in the case of investigatorinitiated academic research studies, by the research institution or principalinvestigator.3.1. INVESTIGATOR3.1.1. Investigator’s Qualifications and Agreements3.1.1.1.The investigator (s) should:3.1.1.1.1.be qualified by education, training and experience toassume responsibility for the proper conduct of the trial,3.1.1.1.2.meet all the qualifications specified by the applicableregulatory requirement (s),3.1.1.1.3.Provide evidence of such qualifications through up-to-datecurriculum vitae and/or other relevant documentation requestedby the sponsor, the IRB/IEC, and/or the regulatory authority (ies).3.1.1.2.The investigator should be thoroughly familiar with the appropriateuse of the investigational products (s), as described in the protocol, inthe current Investigator’s brochure, in the product information and inother information sources provided by the sponsor.3.1.1.3.The investigator should be aware of, and should comply with,GCP and the applicable regulatory requirements.3.1.1.4.The investigator/institution should permit monitoring and auditingby the sponsor, and inspection by the appropriate regulatory authority(ies).3.1.1.5.The investigator should maintain a list of appropriately qualifiedpersons to whom the investigator has delegated significant trial-relatedduties.3.1.2. Adequate Resources3.1.2.1.The investigator should be able to demonstrate (e.g. based onretrospective data) a potential for recruiting the required number ofsuitable subjects within the agreed recruitment period.3.1.2.2.The investigator should have sufficient time to properly conductand complete the trial within the agreed trial period.3.1.2.3.The investigator should have available an adequate number ofqualified staff and adequate facilities for the foreseen duration of thetrial to conduct the trial properly and safely.3.1.2.4.The investigator should ensure that all persons assisting with thetrial are nal product (s), and their trial-related duties and functions.3.1.3. Medical Care of Trial Subjects3.1.3.1.A qualified physician (or dentist, when appropriate), who is aninvestigator or a sub-investigator for the trial, should be responsible forall trial-related medical (or dental) decisions.3.1.3.2.During and following a subject’s participation in a trial, theinvestigator/institution should ensure that adequate medical care isprovided to a subject for any adverse events, including clinicallysignificant laboratory values, related to the trial.Theinvestigator/institution should inform a subject when medical care isneeded for intercurrent illness (es) of which the investigator becomesaware.

53.1.3.3.It is recommended that the investigator inform the subject’sprimary physician about the subject’s participation in the trial if thesubject has a primary physician and if the subject agrees to theprimary physician being informed.3.1.3.4.Although a subject is not obliged to give his/her reason (s) forwithdrawing prematurely from a trial, the investigator should make areasonable effort to ascertain the reason (s), while fully respecting thesubject’s rights.3.1.4. Communication with IRB/IEC3.1.4.1.Before initiating a trial, the investigator/institution should havewritten and dated approval from the Health Research andDevelopment Committee [HRDC] for the trial protocol, written informedconsent form, consent from updates, subject recruitment procedures(e.g., advertisements), and any other written information to be providedto subjects.3.1.4.2.As part of the investigator’s/institution’s written application to theIRB/IEC, the investigator/institution should provide the IRB/IEC with acurrent copy of the Investigator’s Brochure. If the Investigator’sBrochure is updated during the trial, the investigator/institution shouldsupply a copy of the updated Investigator’s Brochure to the IRB/IEC.3.1.5. Compliance with Protocol3.1.5.1.The investigator/institution should conduct the trial in compliancewith the protocol agreed to by the sponsor and, if required, by theregulatory authority (ies) and which were given approval/favourableopinion by the HRDC. The investigator/institution and the sponsorshould sign the protocol, or an alternative contract, to confirmagreement.3.1.5.2.The investigator should not implement any deviation from, orchanges of the protocol without agreement by the sponsor and priorreview and documented approval/favourable opinion from the IRB/IECof an amendment, except where necessary to eliminate an immediatehazard (s) to trial subjects, or when the change (s) involves onlylogistical or administrative aspects of the trial (e.g. change in monitor(s), change of telephone number (s).3.1.5.3.The investigator, or person designated by the investigator, shoulddocument and explain any deviation from the approved protocol.3.1.5.4.The investigator may implement a deviation from, or a change of,the protocol to eliminate an immediate hazard (s) to trial subjectswithout prior IRB/IEC approval/favourable opinion. As soon aspossible, the implemented deviation or change, the reasons for it, and,if appropriate, the proposed protocol amendment (s) should besubmitted:3.1.5.4.1.to the HRDC for review and approval,3.1.5.4.2.to the sponsor for agreement and, if required,3.1.5.4.3.to the DRU3.2. SPONSOR3.2.1. Quality Assurance and Quality Control3.2.1.1.The sponsor is responsible for implementing and maintainingquality assurance and quality control systems with written SOPs toensure that trial are conducted and data are generated, documented

6(recorded), and reported in compliance with the protocol, GCP andthe applicable regulatory requirement (s).3.2.1.2.The sponsor is responsible for securing agreement from allinvolved parities to ensure direct access (see 1.21) to all trial relatedsites, source data/documents, and reports for the purpose ofmonitoring and auditing by the sponsor, and inspection by domesticand foreign regulatory authorities.3.2.1.3.Quality control should be applied to each stage of data handling toensure that all data are reliable and have processed correctly.3.3. Contract Research Organization (CRO)3.3.1. A sponsor may transfer any or all of the sponsor’s trial-related duties andfunctions to a Contract Research Organization, but the ultimateresponsibility for the quality and integrity of the trial data always resides withthe sponsor. The Contract research Organization should implement qualityassurance and quality control.3.3.2. Any trial-related duty and function that is transferred to and assumed by aContract research Organization should be specified in writing.3.3.3. Any trial-related duties and functions not specifically transferred to andassumed by a Contract Research Organization are retained by the sponsor.3.3.4. All references to a sponsor in this guideline also apply to a Contractresearch Organization to the extent that a Contract Research Organizationhas assumed the trial related duties and functions of a sponsor.3.4. Medical ExpertiseThe sponsor should designate appropriately qualified medical personnel who will bereadily available to advise on trial related medical questions or problems. Ifnecessary, outside consultant (s) may be appointed for this purpose.3.5. Trial Design3.5.1. The sponsor should utilize qualified individuals (e.g. biostatisticians,clinical pharmacologists and physicians) as appropriate, throughout allstages of the trial process, form designing the protocol and CRFs andplanning the analyses to analyzing and preparing interim and final clinicaltrial reports.3.5.2. For further guidance: Clinical Trial Protocol and Protocol Amendment (s)(see 6.), the ICH Guideline for Structure and Content of Clinical Studyreports, and other appropriate ICH guidance or trial design, protocol andconduct.3.6. Trial Management, data Handling and Report Keeping3.6.1. The sponsor should utilize appropriately qualified individuals to supervisethe overall conduct of the trial, to handle the data, to verify the data, toconduct the statistical analyses and to prepare the trial reports.3.6.2. The sponsor may consider establishing an independent data-monitoringcommittee (IDMC) to assess the progress of a clinical trial, including thesafety data and the critical efficacy endpoints at intervals, and torecommend to the sponsor whether to continue, modify, or stop a trial. TheIDMC should have written operating procedures and maintain writtenrecords of all its meetings.3.6.3. When using electronic trial data handling and/or remote electronic trialdata systems, the sponsor should:3.6.3.1.Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for

7completeness, accuracy, reliability and consistent intendedperformance (i.e. validation).3.6.3.2.Maintains SOPs for using these systems.3.6.3.3.Ensure that the systems are designed to permit data changes insuch a way that the data changes are documented and that there is nodeletion of entered data (i.e. maintain an audit trail, data trail, edit trail).3.6.3.4.Maintain security system that prevents unauthorized access to thedata.3.6.3.5.Maintain a list of the individuals who are authorized to make datachanges.3.6.3.6.Maintain adequate backup of the data.3.6.3.7.Safeguard the blinding, if any (e.g. maintain the blinding duringdata entry and processing).3.6.4. If data are transformed during processing, it should always be possible tocompare the original data and observations with the processed data.3.6.5. The sponsor should use an unambiguous subject identification code thatallows identification of all the data reported for each subject.3.6.6. The sponsor, or other owners of the data, should retain all of the sponsorspecific essential documents pertaining to the trial.3.6.7. The sponsor should retain all sponsor-specific essential documents inconformance withthe applicable regulatory requirement (s) of thecountry (ies) where the product is approved, and/or where the sponsorintends to apply for approval (s).3.6.8. If the sponsor discontinues the clinical development of an investigationalproduct, (i.e. for any or all indications, routes of administration, or dosageforms), the sponsor should maintain all sponsor-specific essentialdocuments for at least 2 years after formal discontinuation or inconformance with the applicable regulatory requirement (s)3.6.9. If the sponsor discontinues the clinical development of an investigationalproduct, the sponsor should notify all the trial investigators/institutions andall the regulatory authorities.3.6.10. Any transfer of ownership of the data should be reported to theappropriate authority (ies), as required by the applicable regulatoryrequirement (s).3.6.11. The sponsor specific essential documents should be retained until at least2 years after the last approval of a marketing application in an ICH regionand until there are no pending or contemplated marketing applications in anICH region or at least 2 years have elapsed since the formal discontinuationof clinical development of the investigational product. These documentsshould be retained for a longer period however if required by the applicableregulatory requirement (s) or if needed by the sponsor.3.7. Information on Investigational Product(s)3.7.1. When planning trials, the sponsor should ensure that sufficient safety andefficacy datafrom nonclinical studies and/or clinical trials are availableto support human exposure by the route, at the dosages, for the duration,and in the trial population to be studied.3.7.2. The sponsor should update the Investigator’s brochure as significant newinformationbecomes available (see 7 Investigator’s Brochure).3.8. Manufacturing, Packaging, Labelling, and Coding InvestigationalProduct(s)3.8.1. The sponsor should ensure that the investigational product(s) (includingactive comparator(s) and placebo, if applicable) is characterized as

8appropriate to the stage of development of the product(s), is manufacturedin accordance with any applicable GMP, and is coded and labeled in amanner that protects the blinding, if applicable. In addition, the labelingshould comply with applicable regulatory requirement(s).3.8.2. The sponsor should determine, for the investigational product(s),acceptable storage temperatures, storage conditions (e.g. protection fromlight), storage times, reconstitution fluids and procedures, and devices forproduct infusion, if any. The sponsor should inform all involved parties (e.g.monitors, investigators, pharmacists, storage managers) of thesedeterminations.3.8.3. The investigational product(s) should be packaged to preventcontamination andunacceptable deterioration during transport andstorage.3.8.4. In blinded trials, the coding system for the investigational product(s)should include a mechanism that permits rapid identification of theproduct(s) in case of a medical emergency, but does not permitundetectable breaks of the blinding.3.8.5. If significant formulation changes are made in the investigational orcomparator product(s) during the course of clinical development, the resultsof any additional studies of the formulated product(s) (e.g. stability,dissolution rate, bioavailability) needed to assess whether these changeswould significantly alter the pharmacokinetic profile of the product should beavailable prior to the use of the new formulation in clinical trials.3.9. Supplying and handling Investigational Product(s)3.9.1. The sponsor is responsible for supplying the investigator(s)/institution(s)with the investigational product(s).3.9.2. The sponsor should not supply an investigator/institution with theinvestigational product(s) until the sponsor obtains all requireddocumentation (e.g. approval/favourable opinion from IRB/IEC andregulatory authority(ies)3.9.3. The sponsor should ensure that written procedures include instructionsthat the investigator/institution should follow for the handling and storage ofinvestigational product(s) for the trial and documentation thereof. Theprocedures should address adequate and safe receipt, handling, storage,dispensing, retrieval of unused product from subjects, and return of unusedinvestigational product(s) to the sponsor (or alternative disposition ifauthorized by the sponsor and in compliance with the applicable regulatoryrequirement(s).3.9.4. The sponsor should:3.9.4.1.Ensure timely delivery of investigational product(s) to theinvestigator(s).3.9.4.2.Maintain records that document shipment, receipt, disposition,return and destruction of the investigational product(s).3.9.4.3.Maintain a system for retrieving investigational products anddocumenting this retrieval (e.g. for deficient product recall, reclaimafter trial completion, expired product reclaim).3.9.4.4.Maintain a system for the disposition of unused investigationalproduct(s) and for the documentation of this disposition.3.9.5. The sponsor should:3.9.5.1.Take steps to ensure that the investigational product(s) are stableover the period of use.3.9.5.2.Maintain sufficient quantities of the investigational product(s) usedin the trials to reconfirm specifications, should this become necessary,

9and maintain records of batch sample analyses and characteristics.To the extent stability permits, samples should be retained either untilthe analyses of the trial data are complete or as required by theapplicable regulatory requirement(s), whichever represents the longerretention period.3.10.Record Access3.10.1. The sponsor should ensure that it is specified in the protocol or ot

clinical pharmacologists and physicians) as appropriate, throughout all stages of the trial process, form designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports. 3.5.2. For further guidance: Clinical Trial Protocol and Protocol Amendment (s)

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