Ochieng et al. BMC Medical Ethics 2013, ESEARCH ARTICLEOpen AccessResearch site monitoring for compliance withethics regulatory standards: review of experiencefrom UgandaJoseph Ochieng1*, Julius Ecuru2, Frederick Nakwagala3 and Paul Kutyabami4AbstractBackground: On site monitoring of research is one of the most effective ways to ensure compliance duringresearch conduct. However, it is least carried out primarily for two reasons: presumed high costs both in terms ofhuman resources and finances; and the lack of a clear framework for undertaking site monitoring. In this paper wediscuss a model for research site monitoring that may be cost effective and feasible in low resource settings.Methods: This was a retrospective review of research site monitoring reports covering a period of four years.Results: The monitoring was conducted by the Uganda National Council for Science and Technology, the NationalDrug Authority and the National HIV/AIDS Research and Ethics Committee over the period 2007 to 2010.The monitoring team was usually three members comprising of two experts in research ethics and an assistant. Atotal of 28 site monitoring visits covering 40 research projects were reviewed. 25% of the site monitoring reportsrevealed violation of the regulatory requirement for valid ethical approval. 36% of the site reports showed someinstances of informed consent violation, 28% showed violation of the rights and welfare of research participants,38% revealed that sites did not report SAEs to regulatory authorities and many sites lacked adequate GCP andGCLP. However, most of the sites monitored had adequate facilities to conduct the respective studies and goodworking practices.Conclusion: This model employed by the monitoring teams to evaluate research compliance is effective inauditing ethical practice. Compliance monitoring is feasible and affordable in a resource limited setting. Researchprotocol non compliance is still a major problem in Uganda, and there is need for a pro-active approach to thisvice by all stake holders if ethical conduct of research is to be achieved.Keywords: Research, Monitoring, Compliance, Ethics, UgandaBackgroundReview of research by an independent research ethicscommittee (REC) is accepted as a global standard forprotecting human research participants [1-9]. Investigators submit their protocols to a research ethics committee for their review and approval prior to initiation of astudy. The research ethics committee does initial andcontinuing review until completion of the study. Continuing review is one of the major challenges of researchethics committees as it involves a number of aspects* Correspondence: [email protected] of Anatomy, School of Biomedical Sciences, College of HealthSciences, Makerere University, Mulago Hill, P.O Box 7072, Kampala, UgandaFull list of author information is available at the end of the articleincluding annual renewals, amendments to the approvedprotocols, serious adverse event monitoring, and on sitemonitoring. The investigators to a large extent play animportant role because they have to observe a high levelof integrity to comply with ethical standards as well asreport any protocol events accurately. However, researchethics committees cannot rely solely on reports by investigators since many times researchers do violate ethicalpractice [10-13]. RECs have a responsibility to monitoractivities of approved studies for ethical conduct as wellas adherence to the approved protocol .Research protocol non-compliance occurs in manyparts of the world, probably due to ineffective regulatory systems and research participants that are less 2013 Ochieng et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.
Ochieng et al. BMC Medical Ethics 2013, mpowered mainly due to power differences, povertyand ignorance [14-16]. In such settings, protocol noncompliance and violations usually occur for approvedstudies because researchers may not be sufficiently educated about their role in the ethical conduct of researchas well as the need to stick to the regulations [10,17].Hence need for continuing review through research sitecompliance monitoring in order to minimize such unethical tendencies.In many countries, a good number of research ethicscommittees do not monitor approved research protocolsfor compliance with the required ethical standards andscientific principles. Therefore, there is high likelihoodof non-compliance which may compromise the rightsand welfare of research participants.On site monitoring of research is one of the most effective ways to ensure compliance during research conduct. However, it is least carried out primarily for tworeasons: presumed high costs both in terms of humanresources and finances; and the lack of a clear framework for undertaking site monitoring . In this paperwe discuss a model for research site monitoring thatmay be cost effective and feasible in low resource settings. The model is one used in compliance monitoringby the Uganda National Council for Science and Technology for approved research projects. The discussion isbased on a comprehensive review of research compliance monitoring reports carried out on projects approved by the Uganda National Council for Science andTechnology (UNCST).ObjectiveThe objective of this paper is to demonstrate the feasibility of research compliance monitoring by researchethics committees and evaluate the effectiveness of themonitoring tool in a resource limited setting.MethodsWe undertook a retrospective review of research sitemonitoring reports covering a period of four years. Adata collection template was developed and utilized inthe evaluation of the compliance monitoring frameworkthat is employed by the UNCST and Institutional reviewCommittees.Although about 50 study projects had been monitored,the review covered only complete reports which were 28in number comprising 40 studies and includes studysites from both the central, east, west and northernregions of the country. The method used by the compliance monitoring teams included announced or nonannounced visits to the study site. The frameworkemployed during the monitoring included reviewing theregulatory documents, informed consent process, study related documentation, participants’ welfare, seriousPage 2 of 7adverse event management and reporting, study relatedtraining and working practices at the site.The monitoring considered both study document review, observations and verbal interviews with study staffand participants.The documents reviewed included; approved studyprotocols, REC and UNCST/NDA approvals and theirvalidity, signed informed consent forms, case reportforms, data collection forms, valid practicing licenses forclinicians, study related trainings, GCP, GLP and otherresearch ethics trainings, study related meeting minutes,SAEs reports, materials transfer agreements, protocoldeviation and protocol violation reports and any otherstudy documents.Interview where applicable would be held with investigators and or study staff about their training, knowledgeof the research regulations, study related meetings, anyother studies at the site and how they handled study participants. In addition, a chat with research participantsabout their knowledge of the study they are participatingin, how they are cared for and facilitation like transportrefund. In some cases, discussions would be held withthe concerned REC.Observations included assessment of the recruitmentareas and surrounding environment, the laboratories,the clinics, dispensing areas, storage facilities for drugsand other study materials, data management areas, number of study staff and record offices. The assessment ofthe facility evaluated the available space in relation tothe approved sample size of the study, number of otherstudies at the site, frequency of study visits and thecongestion that was observed during the monitoringvisit. Others included evaluation of the reception forparticipants, waiting area, care for research participants,how research assistants handle participants includingobtaining informed consent, participant waiting time,how and what amounts were re-imbursed for participanttransportation and if participants at the study site duringlunch were fed.Ethical reviewPermission to review the site monitoring reports wassought from the Uganda National Council for Scienceand Technology. No individual identifying informationor any particular research site was revealed during therecords review.ResultsAll the reports were in the custody of the Uganda National council for Science and Technology. The monitoring had been conducted by both the Uganda NationalCouncil for Science and Technology, the National DrugAuthority (NDA) as well as the National HIV/AIDS Research and Ethics Committee (NARC), and covered the
Ochieng et al. BMC Medical Ethics 2013, eriod 2007 to 2010. Most of the research projects monitored included international collaborative studies.The monitoring team was in most of the cases madeup of three members comprising of two experts inresearch ethics and an assistant. The site monitoring reports covered studies that included clinical trials, observational, behavioral and basic science studies. And theinstitutions monitored included; academic institutions,hospitals, research organizations and research demographic sites.All the site monitoring visits were conducted in theperiod from 2007 to 2010. Eighteen reports (64.28%) ofthe reviewed reports showed that the sites visits hadbeen conducted by Uganda National Council for Scienceand Technology (UNCST), 17.86 of the reviewed reportsshowed that the sites visits had been conducted jointlyby the UNCST and the National Drug Authority (NDA),while another 17.86 of the reviewed reports showed thatthe sites visits had been conducted by the National HIV/AIDS Research Committee (NARC).Reviewing of the monitoring reports employing themodel used by the monitoring teamsThe model used by the monitoring teams looked atseven elements: regulatory issues, site facilities, informedconsent process and documentation, participant’s welfare, reporting and management of adverse events, studyrelated training and working practices. These were thecore elements which determined compliance with approved protocol and approval stipulations. They are detailed in Table 1 and discussed below:Regulatory documentsRegulatory aspects are issues to do with the administrative management of the research project to facilitateethical conduct and include aspects of documentation ofcommunications between the research site and regulatory agencies like RECs, UNCST and NDA; communication between research sites and collaborators; as well ascommunications between the study coordination teamand the other study staff. Before any conduct of researchin the country, ethical review and approval must besought from a competent and independent REC that isrecognized by the UNCST and this is followed by clearance by the UNCST.In this review, 25% of the site monitoring reportsrevealed expired REC and or UNCST approvals whichwere not renewed yet studies activities were still ongoing.The regulation stipulates that research can be conductedonly and whenever there is a valid REC approval.In addition, 25% of the site reports revealed eitherconduct of unapproved research or implementing changes in the protocol without review and approval by theconcerned RECs, UNCST and or NDA. Any change toPage 3 of 7the approved protocol can only be implemented afterapproval by an IRC unless it is done to protect the participants from eminent harm. Two sites in which wereconducted four studies did not have a regulatory file atthe sites. In such a situation it would be difficult for themonitoring team to ascertain if the studies had valid approvals as well as other aspects related to administrationof the study.Other regulatory issues included absence of MaterialsTransfer Agreements for exported Human BiologicalMaterials. In Uganda such materials can only be ethicallyexported using a permit from the UNCST and based ona valid Materials Transfer agreement between the localand collaborating institutions. Some studies had beenterminated but no evident in form of documentationexisted at the site or any communication to the regulatory agencies.Proper filing of study related documents was lackingin many instances and even in situations where quickreferences would be needed like for SOPs, it was onlythe electronic copies of such documents available.One site had a principal investigator who was a foreignnational that happened to be the team leader of studyactivities without being part of the approved protocoland was not registered with any regulatory agency. Inaddition a number of other protocol violations and deviations were not reported to the concerned RECs.Site facilitiesMost of the sites monitored had adequate facilities toconduct the respective studies. However, a good numberof sites had issues like congestion at recruitment stations, pharmacies that did not appear organized, limitedtraining to study staff in study related issues and research ethics, non-restricted data storage facilities, poordata quality control mechanisms and inadequate/incomplete filing of study related records.Others included lack of quality dispensing and labelingof drugs as well as lack of SOPs at the respective dutystations.Informed consent process and documentationInformed consent is an essential requirement of ethicalresearch which demands that a research participants’rights should be respected. Respect for persons requiresthat research participants be given the opportunity tomake choices about what should be done to them. Informed consent is not just a form but a process of information exchange between the researcher and researchparticipants on the whole research process. Informationprovided should be adequate, clearly understood bythe research participant with decision making capacityand the research participant should voluntarily decideto participate.
Ochieng et al. BMC Medical Ethics 2013, age 4 of 7Table 1 Monitoring n1. Regulatory documents Approvals: REC, UNCST and NDA If approval is valid Availability of study relateddocummnets Case report forms Communication with collaborators Data collection forms Valid practicing licenses Study brochures2. Site facilities Recruitment area How many studies being conducted Availability and the amount ofat the sitespace compared to the participantpopulation Laboratories Approval status for all studies Approval letters Clinics, Number of staff for the study Available staff How it is obtained Observe the process of obtaing consent dispensing areas, storage facilities for drugs andother study materials, data management areas, study staff Record offices3. Informed consent Signed informed consent formsprocess and documentation Who witnesses How long it takes4. Participant welfare Amount approved in consent form How much is given Signature by receipient How amount is determined Who gives out the cash Ask participant what they get5. SAEs managementand reporting Records of identified SAEs andtheir management How identified Signed SAE reports How managed SAE reports Status of the SAE6. Study related training Training certificates When trainedTraining certificates Who trainedAbility to perform as trained Importance of the training Knowledge of regulations and study7. Working practices8. Debriefing Minutes of meetings Frequency of meetings Communication memosWhat is discussed in the meetings Communication with collaboratorsHow long the meetings take Availability of SOPs Delegationlogs Explaining of proceduresMeeting minutesSOPs at work stationsCommunicate findings of themonitoring team and get feedbackfrom research teamDuring the review, it was observed that 36% of the sitereports showed some instances where either consentwas not obtained, or there was no adequate documentation to prove that informed consent had been obtained. Common consent violations included incompleteconsent forms, for example, some pages missing (5%),using study staff to witness consent for illiterate participants (usually study staff have significant conflict ofinterest and may not objectively witness consent), (5%);unsigned consent forms which could imply that an investigator may have missed reviewing the consent asrequired by their own protocol (7.5%); and lack of a
Ochieng et al. BMC Medical Ethics 2013, age 5 of 7separate consent for stored specimen as required by theUgandan guidelines (20%). Five percent of the studieshad not obtained informed consent from participants,10% of the studies continued recruiting participants afterexpiry of the approved consent form, 7.5% of the studieshad consent forms with only a signature page while another 2.5% of the studies reviewed kept participants inthe study long after expiry of the time indicted in theconsent form. Finally, in a study involving children assent was obtained from children above 13 years only yetit should be children of age 8 and above as per nationalguidelines.Study related trainingParticipants’ welfareWorking practicesDuring research conduct, participant’s acceptance toparticipate does not in any way remove their rights fromthem. Thus protection of participants’ rights and welfareis an obligation for all of those involved in conduct ofresearch. Welfare would require that participants’ needslike meals and refreshments as they wait at the studysite, compensation for time due to forgone opportunitiesand transport costs for study related activities are addressed by the concerned project.In this review, it was evident that 28% of the reportsshowed that participants were either not compensatedfor their time or got inadequate compensation. For example, in some sites, participants waited for long periodswithout a snack or a meal and were not compensationfor time and work lost. In one scenario, participants whonormally would not require hospital admission whereadmitted for more than one week in order to participatein a clinical trial yet no compensation for time lost wasdone. However, many of the studies that did not adequately facilitate the participants had been approvedin that form indicating that the ethical review processhad approved the protocol without due considerationfor participant welfare.In working practices, the site monitors where interestedin aspects that facilitate coordinated execution of theconcerned study including effective communicationthroughout the study team, updates on any new findingsabout the study, study coordination and how study staffrelate to each other.Most of the sites reported good working practices likeregular study related meetings some as frequent as dailyupdates, weekly or bi-monthly meetings.However, some sites almost had no work related meetings which would mean study coordination was defective. Worse of were the sites where the principalinvestigators were too busy to monitor the conduct ofthe study on a regular basis and guide their staff, hencethe name absentee PIs.SAE: management and reportingAccording to the Uganda National Guidelines for conducting research involving humans, all serious adverseevents must be reported to the local IRC as soon as possible and in any case no later than seven calendar daysof becoming aware of the event. Thereafter, a detailedreport of the SAE should be submitted within eight days.The requirement to report adverse events to regulatoryauthorities does apply to events that are observed amongparticipants in which a health related intervention is being administered. In this review, twenty one (21) studiesmet the requirement to report SAEs. Eight of the 21 onestudies (38%) did not report SAEs to regulatory authorities, two of twenty one (9.5%) reported late while sixout of 21 (28.5%)reported SAEs not reviewed and signedby the principal investigator.It is important that study staff should be knowledgeableand adequately informed about the study they are executing in order to be able to perform efficiently and provide information to participants whenever need arises.In this review, many sites lacked adequate GCP andGCLP. In most cases, only a few members of the studystaff had had training. Some sites did not train their staffin study related aspects while most of the sites reviewedhad staff who had very little knowledge of researchethics and ignorance particularly about the UgandaNational Guidelines.DebriefingAt the end of a monitoring visit, the monitoring teamwould debrief the investigators on the key issues identified as well as recommend appropriate action for thoseissues that required immediate action as the site awaitedthe final report.DiscussionThe model employed by the site monitoring team inUganda appears to be quite comprehensive and effectivein identifying many aspects of best research practices aswell as non-compliance at the research sites. The findings of this review reveal that research protocol noncompliance is still a problem in the country. To addressthis problem, research site monitoring should be intensified, and important aspects should be evaluated including; regulatory documents, site facilities, informedconsent process and documentation, participant welfare,SAE management and reporting, study related trainingand working practices at the study site. Research ethicsaspects were found wanting in many situations and thisneeds to be improved on.Concerning regulatory issues, the reviewed reports emphasized the fact that non-compliance by investigators is
Ochieng et al. BMC Medical Ethics 2013, age 6 of 7an important issue to consider. On site compliance monitoring could be the most appropriate method to minimizesuch non-compliance, but is often ignored by the RECspurportedly due to lack of capacity, requires high cost tomaintain both in terms of human resource as well asfinancial resources.Although Uganda has 14 accredited RECs that reviewand approve research currently, only four have reportedcarrying out monitoring of approved studies at the siteand only one was found to have records at the UNCSTas evidence for conducting on site compliance monitoring (Table 2). But the current process of accreditationwhich is ongoing is expected to set standards and improve on the functionality of many RECs so that effective execution of their mandates are incorporated in theday to day business. And when such accreditation is accomplished, it will be a positive challenge to such RECswhich have in the past grossly ignored continuing reviewincluding compliance monitoring as an essential component of their obligations.Adequacy of site facilities was relatively good though agood number had issues of congestion due to limitedspace. However, sites should improve skills of study staffto make them more competent at their work stations.Investigators should also be in touch with their studysites and regularly conduct internal auditing.The informed consent process is an important component of ethical research that may not be adequatelyunderstood and or practiced by many investigators. Andthis echo’s previous studies . Proactive approacheslike sensitization, continuing education and outreach toresearchers and other stakeholders in research couldyield better outcomes than strict punitive treatment andhumiliation.Research participants may be reimbursed for lost earnings, travel costs, lunch and other expenses incurred intaking part in a study; they may also receive free medicalservices. Research participants, particularly those whoreceive no direct benefit from the research project willbe compensated for inconvenience and time spent. Thecompensation or medical services shall not be out ofproportion so as to induce prospective research participants to consent to participate in the research againsttheir better judgment [1,4]. Investigators risk compromising the participant welfare if they (investigators) falselyTable 2 Regulatory agencies and sites reviewedRegulatoryagencyNumberof sitesPercentagesitesNumberof think that that such facilitation to participants could result in undue inducement and or coercion. It is betterfor a competent REC to decide on amount of facilitationacceptable and will not appear to coerce the participants.Participants should not bear the burden of participatingin research as well as paying for expenses related to theirparticipation in a study. Investigators and institutionalreview boards make payment decisions and that bothhealthy and ill subjects in some studies are paid for theirtime, for inconvenience, for travel, as incentive, or forincurring risk. Most organizations require that paymentbe prorated and described in the consent document. It should be noted that in this review, many of theresearch participants were not well facilitated due to lackof due consideration for their compensation and welfareby the RECs at the time of approval of the study.None reporting of SAEs and reporting such SAEsinappropriately are violations of what should be considered good clinical practice. Ideally, no clinical trialsshould be initiated unless all the study staff have undergone training in good clinical practice and where appropriate good laboratory practice in addition to beingequipped with an adequate SAE management and reporting plan. The Investigator undertakes prime responsibility for monitoring and reporting of adverse events tothe regulatory authorities. (1) Both investigators and regulatory agencies should ensure that study staff accessGCP and related training prior to initiation of the study.SOPs must be present and accessible at each duty station and should be adhered to. In this review, the highrate of non-reporting of such SAEs is a reminder that research ethics and GCP trainings are mandated, shouldbe appreciated and practiced.In Uganda based on records available at the UNCST,about 50 research projects had been monitored over theperiod 2007 to 2010 though only three regulatory agencies had actually conducted the visits. Compliance monitoring should be scaled up and taken up by RECsbecause it is feasible even in a low resource setting.Doing so would be a great break through which wouldenhance the protection of the rights and welfare of human research participants and promote ethical conductof research.ConclusionThis model employed by the monitoring teams inUganda to evaluate research compliance appears to beeffective in auditing ethical practice and if implementedappropriately can lead to improved ethical conduct byresearchers as well as improved protection of the rightsand welfare of human research participants.Compliance monitoring is feasible and affordable in aresource limited setting as evidenced by this review.
Ochieng et al. BMC Medical Ethics 2013, esearch protocol non compliance is still a major problem in Uganda, and there is need for a pro-active approach to this vice by all stake holders including researchregulators, community leaders, political leaders and researchers if ethical conduct of research is to be achieved.Only competent RECs with compliance monitoring plansin their activities should be allowed to review and approveresearch studies.Knowledge for both local and international regulationsguiding the conduct of research is still largely ignored bymany researchers with resultant violation of the approvedprotocols. As a policy, all study staff should undergomandatory training in the relevant guidelines before evergetting in contact with any study participants.Page 7 of 22.214.171.124.8.9.10.Limitations of the study The relatively small number of reports reviewed. Some reports were incomplete hence not includedin the study. Lack of adequate detail in some of the reportsbecause the monitors were different and also thereasons for monitoring in some cases were different.126.96.36.199.15.16.Competing interestThe authors declare that they have no competing interests.Authors’ contributionJO Literature search, study design, data collection, data analysis, datainterpretation, drafting, writing, proof reading and approval of manuscript; JEstudy design, data collection, data analysis, proof reading and approval ofmanuscript; FN study design, proof reading and approval; PK proof readingand approval of manuscript. All authors read and approved the finalmanuscript.AcknowledgementWe commend the UNCST and the Uganda Society of Health Sciences forhaving spear headed this important activity of compliance monitoring.Appreciation to the NDA for co-funding monitoring of clinical trials, theBioethics Working group for the monitoring expertise and the NARC. We aregrateful to the support rendered by the UNCST staff who provided thesecretariat for the monitoring teams.Author details1Department of Anatomy, School of Biomedical Sciences, College of HealthSciences, Makerere University, Mulago Hill, P.O Box 7072, Kampala, Uganda.2Uganda National Council for Science and Technology, Plot 6 Kimera Road,Ntinda, P.O Box 6884, Kampala, Uganda. 3Mulago Hospital, Mulago Hill, P.OBox 7051, Kampala, Uganda. 4Department of Pharmacy, College of HealthSciences, Makerere University, P.O Box 7072, Kampala, Uganda.Received: 16 October 2012 Accepted: 31 May 2013Published: 5 June 2013References1. Uganda Nati
monitoring tool in a resource limited setting. Methods We undertook a retrospective review of research site monitoring reports covering a period of four years. A data collection template was developed and utilized in the evaluation of the compliance monitoring framework that is e