Guidelines For Conduct Of Clinical Trials In Kenya 2nd Revision


PPB/MIP/CTL/GUD/003Rev. No. 2MINISTRY OF HEALTHPHARMACY AND POISONS BOARDGuidelines for the Conduct of Clinical Trials inKenyaJanuary 2020

Citation of this DocumentThis Guideline is in the public domain and may be reproduced or adapted on condition thatthe recommended citation is made.Recommended CitationGuidelines for Conduct of Clinical Trials In Kenya, Pharmacy and Poisons Board, November2019.Contact the following for clarifications, comments or suggestions:The Chief Executive Officer,Pharmacy and Poisons Board,P. O. Box 27663-00506 Nairobi, KenyaTel: 254 20 3562107 254 733 884411 / 720 or cta@pharmacyboardkenya.orgii

PPB/MIP/CT/GUD/003GUIDELINES FOR CONDUCT OF Revision No. 2CLINICAL TRIALS IN KENYAEffective Date1st January 2020Review Date:31st Dec 2022Prepared by Quality Assurance OfficerSign .Date 12th November 2019 . . Reviewed by Director, MIPSignedDate 3rd December 2019Checked by Head, Quality ManagementSignedDate 4th December 2019Authorized by Chief Executive OfficerSignedDate 6th December 2019iii

Table of ContentsAbbreviations and Definition of Terms. vAcknowledgements . xiiPreface . xiiiLegal Framework .xivIntroduction.xivSECTION ONE . 21. Application Requirements. 22. Procedures for Acceptance, Review and Approval of Applications. 33. Qualifications and Responsibilities of Investigators, Sponsors and Monitors . 54. Investigator. 55. Sponsor . 86. Clinical Trial Protocol . 107. Research Involving Children . 158. Insurance Cover . 209. Pre-Submission meetings . 2110.Publication Policy. 2111.Requirements Concerning Informed Consent. 2112.The Investigator’s Brochure . 2413.Investigational Medicinal Product/ Drug Dossier (IMPD) . 2514.Phase One Clinical Trials . 2615.Labelling: . 3416.Safety Reporting. 3617.Requirements Concerning Data and Safety Monitoring Board . 3718.Manufacturing and import of Investigational products . 3919.Pharmacy . 4020.Laboratories that Perform the Analysis of Clinical Trials Samples . 4421.Controlled Human Infection Studies (CHIS) . 4922.Quality Assurance processes . 5323.Protocol Amendments . 5424.Information on On-going Trials . 5626.Integrity of Data Generated . 5827.Post-Trial Information . 5828.Inspections. 5829.Termination of Clinical Trial . 6030.Archiving . 6131.Conditions for Clinical Trial Import Licence . 6232.Kenya Clinical Trials Registry . 6233.Sanctions . 6334.Trials During Public Health Emergencies (PHE) . 63HERBAL PRODUCTS . 65Chemistry- Manufacturing- Control (CMC) Considerations for Herbal Products . 65Pre-Clinical Considerations for Herbal Products. 67Clinical Considerations for Herbal Products . 68Checklist for Submission of Request for Approval of New Application . 72Checklist for the Request for Annual Approvals of Clinical Trials . 74Declaration by Applicant . 75Declaration of Financial Disclosure/Conflict Of Interest. 80The Clinical Trials Approval Flow Chart . 84Review Flowchart . 85iv

Abbreviations and Definition of TermsThe meanings of the following words used in these guidelines are as defined herein.TermAdverse Drug ReactionAdverse EventAbbreviationADRAEApplicantMeaningAll noxious and unintended responses to a clinicaltrial study or interventional product related to anydose or all unintended noxious responses to aregistered medicinal product which occurs at dosesnormally used in humans for prophylaxis,diagnosis, or therapy of diseases or for modificationof physiological function.Any untoward medical occurrence in a patient d a study or intervention product andwhich does not necessarily have a causalrelationship with the treatment. An adverse event(AE) can therefore be any unfavourable andunintended sign (including an abnormal laboratoryfinding), symptom, or disease temporarilyassociated with the use of an investigationalmedicinal product (IMP), whether or not related tothe IMP.An investigator or sponsor applying to conduct aclinical trial – Sponsor/sponsor representativeA child’s affirmative agreement to participate inresearch, where the child is below the age of themajority but old enough to understand theproposed research in general, its expected risks andpossible benefits and the activities expected of themas participants.AssentAuditAudit CertificateAudit ReportCase Report FormCRFClinical tly of those directly involved in the trial,to determine whether the conduct of a trial complieswith the agreed study protocol and whether datareported are consistent with those on records at thesite.A declaration of confirmation by the auditor that anaudit has taken place.A written evaluation by the sponsor's auditor of theresults of the audit.A form used to record data on each trial participantduring the trial, as defined by the study protocol.Clinical trials are systematic studies aimed atdetermining the safety and efficacy of drugs ormedical devices. Clinical trials are generallyv

TermAbbreviationMeaningclassified into Phases I to IV.A procedure in which study participants,investigators or data analysts are kept unaware ofthe treatment assignment(s). Single-blindingusually refers to the study participant(s) beingunaware and double-blinding usually refers to thestudy participant(s), investigator(s) and dataanalyst(s) being unaware of the treatmentassignment(s).Blinding/MaskingClinical Trial anizationCRODataandSafetyMonitoring Board ormay also be called anIndependentDataMonitoringCommittee (IDMC)DSMBA written description of a trial/study of anytherapeutic or prophylactic agent conducted inhuman study participants in which the clinical andstatistical description, presentations and analysesare fully integrated into a single report.A medicinal or marketed product (Active or placebo)used as a reference in a clinical trial.Maintenance of the privacy of trial participantsincluding their personal identity and all personalmedical information.An individual or organization contracted by thesponsor to perform one or more of a sponsor’s trialrelated duties and functions.An independent data monitoring committee thatmay be established by the sponsor to assess atintervals the progress of a clinical trial, the safetydata and the critical efficacy endpoints and torecommend to the sponsor whether to continue,modify, or stop a trial.Division of MedicinesInformationandPharmacovigilanceThe Division at the PPB at the time beingresponsible for the issues of pharmacovigilance andclinical trials.DocumentationAll records, in any form, that describes themethods, conduct, and/or results of a clinical trial,the factors affecting a trial, and the actions takenDrugAny substance in a pharmaceutical product that isused to modify or explore physiological systems orpathological states for the benefit of the recipient.The term drug is used in a wider sense to includethe whole formulated and registered product,including the presentation and packaging, andaccompanying information.Emancipated MinorsA child who has been granted the status ofadulthood by a court order or other

TermAbbreviationDocuments which individually and collectivelypermit evaluation of the conduct of a clinical trialand the quality of the data produced.An authorization issued by an NACOSTI accreditedethics committee to conduct a clinical trial inKenya.Essential DocumentsEthical ClearanceGood ClinicalPracticeGood ManufacturingPracticeGCPA standard for the design, conduct, performance,and monitoring, auditing, recording, analyses andreporting of clinical trials that provide assurancethat the data and reported results are credible andaccurate and that the rights, integrity, andconfidentiality of trial study participants areprotected.GMPThat part of Quality Assurance which ensures thatproducts are consistently produced and controlledto the quality standards appropriate to theirintended use.A person, who is independent of the trial, whocannot be unfairly influenced by people involvedwith the trial, who attends the informed consentprocess if the study participant or the studyparticipant’s legally acceptable representativecannot read, and who reads the informed consentform and any other written information supplied tothe study participant.Impartial d ConsentA committee that has been formally designated toapprove, monitor, and review biomedical andbehavioural research involving humans with theaim to protect the integrity, rights, safety andwelfare of the research participants.A process by which a participant voluntarilyconfirms his or her willingness to participate in aparticular trial, after having been informed of allaspects of the trial that are relevant to theparticipant ’s decision to participate. Informedconsent is documented by means of a written,signed and dated informed consent form.InterimClinicalTrial/Study ReportA report of intermediate results and their evaluationbased on analyses performed during the course of atrial.InvestigationalDrugA pharmaceutical form of an active ingredient orplacebo being tested or used as a reference in aclinical trial, including a product with a marketingauthorization when used or assembled (formulatedor packaged) in a way different from the approvedform, or when used for an unapproved indication,or when used to gain further information about anapproved use.NewINDvii

cceptableRepresentativeMinimum AnticipatedBiologicalEffectLevelMABELA compilation of the clinical and non-clinical dataon the investigational product(s) relevant to thestudy of the investigational product(s) in humanstudy participants.An individual or juridical or other body authorisedunder applicable law to consent, on behalf of aprospective participant , to the participant ’sparticipation in the clinical trial.Anticipated dose needed to result in a biologicaleffect in participants of a clinical trial. It is a safetywindow based on pharmacological threshold. Theminimal anticipated biological effect level isrecommended as a useful approach to calculate theSafe Starting Dose, as it is the lowest dose that isactive.All individuals from the ages of birth until the legalage of adulthood which is 18 years in torMonitoring ReportNo Observed AdverseEffect LevelNo ObservedLeve)EffectPhase I Clinical TrialA written agreement entered into by a provider anda recipient of research material, aimed at protectingthe intellectual and other property rights of theprovider while permitting research with the materialto proceed.A person appointed by, and responsible to thesponsor or Contract Research Organization (CRO)for the monitoring and reporting of progress of thetrial and for verification of data.A written report from the monitor to the sponsorafter each site visit and/or other trial-relatedcommunication according to the sponsor’s SOPs.NOAELThe highest dose level that does not produce asignificant increase in adverse effects (AEs) incomparison to the control groupNOELGreatest concentration or amount of a substance,found by experiment or observation, that causes noalteration of morphology, functional capacity,growth, development, or lifespan of the targetorganism distinguishable from those observed innormal (control) organisms of the same species andstrain under the same defined conditions ofexposure.The purpose of these trials is to obtain preliminarydata on safety of investigational products such asmedicines or vaccines, or devices. These studies arecarried out in a small number of healthy volunteers.viii

TermAbbreviationPhase II Clinical eboMeaningThe purpose of these trials is to genicity of vaccines, and to determineappropriate dose ranges or regimens. In addition,these trials obtain additional safety data. Thesestudies are routinely carried out in patients. Theyare frequently split into two phases IIA (proof ofConcept) and IIB (Dose finding). These studiesprovide early efficacy data.These are large trials aimed at determining efficacyof the investigational product. Generally, theconditions under which these trials are carried outshould be as close as possible to normal conditionsof use. The information obtained in this phase andthe other two phases is used for licensure of theinvestigational product. Safety data is also collectedin Phase III Trials. Phase IIIB are studies conductedjust before or during regulatory filing to provideevidence to support product claims and todemonstrate safety in larger and more diversepopulations.These are studies performed after registration of themedicinal product for use by the general public. Itis often referred to as Post-Marketing SurveillanceStudies, these are studies designed to monitoreffectiveness of the approved intervention in thegeneral population and to collect information aboutany adverse effects associated with the widespreaduse.An inactive substance or treatment (inertsubstances with no pharmacologic activity) thatlooks the same as, and is given in the same way as,an active drug or intervention/treatment beingstudied.Multi-centre TrialA clinical trial conducted according to a singleprotocol but at more than one site, and therefore,carried out by more than one Principal Investigator.Participant/studyParticipantAn individual who participates in a clinical trial,either as a recipient of the investigational productor as a controlix

TermAbbreviationPre-clinical StudiesPharmacyPoisons BoardandMeaningNon-Human studies of product development.PPBProtocolThe National legal Drug Regulatory Authorityestablished by Cap 244 laws of Kenya.A document that states the background, rationaleand objectives of the trial and describes its design,methodology and organization, including statisticalconsiderations, and the conditions under which itis to be performed and managed. The protocolshould be dated and signed by the investigator, theinstitution involved and the sponsor.Protocol AmendmentA written description of change(s) to or a formalclarification of a study protocol.PeriodicSafetyUpdate ReportPSURA report containing update safety data pertaining toa registered/approved medicinal product forhuman use, as well as a scientific evaluation reportregarding the product’s benefits and risks.PIAn appropriately qualified person responsible forthe conduct of the clinical trial.If there is more than one trial site in Kenya, thereshall be a Coordinator who will be responsible forall the sites in Kenya.For clinical trials conducted in Kenya the site PImust be resident in the country. The PrincipalInvestigator is the leader of the team and candelegate responsibilities to sub-investigators.QAAll those planned and systematic actions that areestablished to ensure that the trial is performed andthe data are generated, documented (recorded), andreported in compliance with good clinical practice(GCP) tiesundertaken within the quality assurance system toverify that the requirements for quality of the trialrelated activities have been fulfilled.Principal InvestigatorQuality AssuranceQuality ControlRandomizationSeriousEventAdverseSAEThe process of assigning trial participant s totreatment or control groups using an element ofchance to determine the assignments in order toreduce bias.Any untoward medical occurrence that at any dose: Results in death, Is life threatening, Requires hospitalization or prolongation ofexisting hospitalization,x

TermAbbreviationMeaning ity, orIs a congenital anomaly/birth defect. All information in original records and certifiedcopies of original records of clinical findings,observations or other activities in a clinical trialnecessary for the reconstruction and evaluation ofthe trial. Source data are contained in sourcedocuments (original records or certified copies).An individual, company, institution or organizationwhich takes legal responsibility for the initiation,management and/or financing of a clinical trial.Original documents, data and records (e.g. hospitalrecords, clinical and office charts, laboratory notes,memoranda, study participants' diaries ecordeddatafromautomatedinstruments, copies or transcriptions certified afterverification as being accurate copies, microfiches,photographic negatives, microfilm or magneticmedia, x-rays, study participant files, and recordskept at the pharmacy, at the laboratories and atmedico-technical departments involved in theclinical trial).Source DataSponsorSource DocumentsAny individual member of the clinical trial teamdesignated and supervised by the principalinvestigator at a trial site to perform critical trialrelated procedures and/or make important trialrelated decisions.Sub-InvestigatorSuspectedUnexpected SeriousAdverse ReactionTrial SiteVulnerableParticipantsStudySUSARA serious adverse reaction that is not Identified inpractice, severity or frequency by the referencesafety information.A facility with appropriate infrastructure to supportthe conduct of a specific clinical trial.Individuals whose decision to participate in aclinical trial may be unduly influenced by n, or by coercion. This includes but isnot limited to medical students, members of theuniformed forces, prisoners, minors, orphans,homeless, unemployed, refugees and the mentallychallenged.xi

AcknowledgementsThe Pharmacy and Poisons Board acknowledges the contribution of the following in theresearch and compilation of these guidelines:The Ministry of HealthOur stakeholders,Partners and clientsWe take this early opportunity to thank all the researchers, investigators, sponsors,pharmaceutical manufacturers, distributors, retailers and respondents who offered theirvaluable contributions to the editing of this guideline.We thank the trial participants who will be the ultimate beneficiaries of this guideline.LIST OF CONTRIBUTORSThe Pharmacy and Poisons Board acknowledges the immense contribution of the following fortheir research, compilation and commitment in developing this guideline.The ECCT members1. Prof Gilbert Kokwaro, B. Pharm, PhD, FKNAS,FAAS2. Prof Walter Jaoko, MBChB, MTropMed, PhD, PGD3. Dr Monique Wasunna, MBChB, MSc, PhD, DTM&H, FRSHTM4. Dr Bernhards Ogutu, MBChB, MMed (Peds), PhD5. Prof George Osanjo, B.Pharm., MSc. (UoN), PhD.6. Dr Grace Kaguthi, MBChB, MSc. Clinical Trials7. Dr James Kimotho, B. Pharm, MSc. Molecular Medicine, PhD8. Prof Gabriel Kimutai Kigen; B. Pharm, MPhil, PhD,9. Dr Marion Wangui Kiguoya; BSc Medical Microbiology, MSc, PhD10. Dr Josphat Kiprop Kosgei; MSc Infectious Diseases, MBChB,11. Dr Robert Kimutai, MBChB, MMED, MPH,12. Prof Kenneth Ngure BSN, MPH, MSc Clinical Trials, PhD,The ECCT Secretariat1. Dr Edward Abwao, B. Pharm, MSc MedStat, MSc Clinical Trials2. Dr Lydia Tuitai, B. Pharm, MSc Clinical Trialsxii

PrefacePharmacy and Poisons Board (PPB) is the authority mandated, by Cap 244 Laws of Kenya, toregulate clinical trials.The Pharmacy and Poisons Board recognizes the importance of Research and Developmentof new medicines, medical devices or procedures in the attainment of national health, socialand economic goals. Clinical research must nonetheless be conducted under conditions thatsatisfy ethical and scientific quality standards.PPB will endeavour to provide a regulatory environment that avoids unnecessary delays inthe clinical trial authorisation process while providing safeguards for quality, efficacy andpublic health.Consequently, the Expert Committee on Clinical Trials (ECCT) of the PPB has developed theseguidelines to assist clinicians, researchers, pharmaceutical industry, sponsors andinvestigators to easily navigate the Kenyan clinical trial authorisation process.The guidelines provide information on the current minimum requirements for authorisationto conduct clinical studies involving investigational drugs, medical devices or herbal drugs.It provides an application form and specifies procedures for approval of protocol amendments.It gives requirements for reporting serious adverse events (SAEs) and suspected unexpectedserious adverse events (SUSARs). Also provided is information regarding data and safetymonitoring board (DSMB), submission of progress reports, procedures for termination ofclinical trials, and inspection of trial sites.The appropriate forms have been attached as appendices at the end of the guidelines. Wehope you will find this document beneficial in your daily practice in clinical research.We undertake to review these guidelines and incorporate up-to-date practices, as may benecessary for our setting. Hence, your feedback is valuable to us. Do send us your comments.Dr F. M SiyoiCEO, Pharmacy and Poisons Boardxiii

Legal FrameworkThe regulation for the conduct of clinical trials is governed under the provisions of thePharmacy and Poisons Act, Cap 244 Laws of Kenya (hereinafter referred to as the “Act”) andthe Subsidiary Legislation thereunder.Under the provisions of Section 2 of the Health Laws (Amendment) Act, 2019 (hereinafterreferred to as “the Health Laws (Amendment”) which amended the Act, Clinical Trial isdefined as, any systematic study on pharmaceutical products in human subjects, whether inpatients or other volunteers, in order to discover or verify the effects of, identify any adversereacting to investigational products, to study the absorption, distribution, metabolism andexcretion of the products with the object of ascertaining their efficacy and safety.The Board is statutorily empowered to undertake various duties in execution of her mandateregarding regulation of medicines. With respect to Clinical Trials, the Board is empoweredamongst others under Section 3 of the Health Laws (Amendment) to;(b) Grant or withdraw authorization for conducting clinical trials of medical products(f) Investigate conduct related to the manufacture, import, export, storage,distribution, sale and use of medical products(i) Constitute technical and expert advisory committees(j) Institute administrative, civil and criminal proceedings(o) Approve the use of any unregistered medicinal substance for purposes of clinicaltrials and compassionate use(p) Approve and regulate clinical trials on medicinal substances(r) Collaborate with other national, regional and international institutions on medicinalsubstances regulation.In addition to the foregoing, it is a requirement for every practicing registered pharmacist andenrolled pharmaceutical technologist, practicing in their private capacity, government, faithbased institutions, non-governmental organizations, training institutions, researchorganizations or any other institution, to have a valid practicing licence under the provisionsof Section 9C (3) of the Health Laws (Amendment).Section 25A of the Health Laws (Amendment) gives and elaborate outline on regulation ofclinical trials as provided hereunder(1) A pharmaceutical product shall not be used for clinical trial unless an approval isgranted by the Board with the approval of the relevant ethics body.xiv

(2) Any person who intends to commence a clinical trial on a pharmaceutical productshall make an application to the Board in the prescribed form and the application shallbe accompanied by the study protocol in the prescribed format and the prescribed fee.(3) The study protocol submitted under subsection (2) shall include a post-trial accessprogram to ensure access of investigational medicinal substances by participants in atrial before grant of marketing authorization by the Board.(4) The Board shall prescribe guidelines for evaluation of applications made undersubsection (2) to be implemented for accelerated evaluations during emergencysituations, epidemics and outbreaks.(5) A person granted an approval under section 25A (1) shall put up a robust qualityassurance system to ensure that the clinical trial is carried out so as to ensure theintegrity of data generated, the safety and well-being of study participants.(6) The Board shall carry out inspections of the clinical trials so as to ensure complianceof the clinical trials with the prescribed requirements.xv

IntroductionClinical trials are a very important part in the process of drug development. In the recentpast, Africa and Kenya in particular has seen increased numbers of requests forapproval to conduct clinical trials. In order to facilitate research and the continuousdiscovery of medicines, but to also ensure the safety, well-being of participants andintegrity of the data generated, PPB has developed this new guideline.As the institution responsible for the regulation of medicines and also the final approvalof conduct of clinical trials in Kenya, the Pharmacy and Poisons Board developed thefirst guidelines on conduct of clinical trials in the year 2011. Since then, there are anumber of changes that have taken place necessitating the development of this secondedition.Some of the additions in this edition are; clarification on safety reporting timelinesClarification on protocol amendmentsRequirements concerning reporting of protocol deviations and protocol violationsRequirements concerning IB, DSUR and IMPDRequirements concerning Post Trial Access ProgramGuidance on pre-submission meetingsInformation on Controlled Human Infection Studi

clinical trials. Documentation All records, in any form, that describes the methods, conduct, and/or results of a clinical trial, the factors affecting a trial, and the actions taken Drug Any substance in a pharmaceutical product that is used to modify or explore physiological systems or pathological states for the benefit of the recipient.