MEDICINES CONTROL COUNCIL

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1 Oversight and Mnitring in Clinical Trials MEDICINES CONTROL COUNCIL OVERSIGHT AND MONITORING IN CLINICAL TRIALS This guideline assists spnsrs f clinical investigatins in develping mnitring strategies and plans fr investigatinal studies f medical prducts, including human medicine and bilgical prducts, medical devices, and cmbinatins theref. The verarching gal is t enhance human participant prtectin and the quality f clinical trial data by fcusing spnsr versight n the mst imprtant aspects f study cnduct and reprting. While this guideline makes it clear that spnsrs, and clinical research rganisatins (CROs) acting n their behalf, can use a variety f appraches t fulfil their respnsibilities fr mnitring Principal investigatr (PI) cnduct and perfrmance in investigatinal studies. It must be highlighted that the respnsibility fr adequate versight f the cnduct f a clinical trial, including the justificatin fr and selectin f mnitring methds, remains that f the spnsr slely. Cuncil reserves the right t request any additinal infrmatin and may make amendments in keeping with the knwledge which is current at the time f cnsideratin. Guidelines and applicatin frms are available frm the ffice f the Registrar f Medicines and the website. Versin 1 as Clinical Trial (risk-based mnitring) published fr cmment May 2016 Due date fr cmment 30 June 2016 Versin 1 with new title and number 2.43 published fr implementatin Nvember 2016 DR JC GOUWS REGISTRAR OF MEDICINES 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 1 f 16

2 Oversight and Mnitring in Clinical Trials TABLE OF CONTENTS Page 1 INTRODUCTION BACKGROUND Definitins Current Mnitring Practices Apprach t Risk-Based Mnitring OVERVIEW OF MONITORING METHODS On-site and Centralised Mnitring On-site Mnitring Centralised Mnitring Examples f mnitring practices and activities Cmmunicatin with study site staff Review f site s prcesses, prcedures, and recrds Surce data verificatin and crrbratin RISK-BASED MONITORING Identify critical data and prcesses t be mnitred Risk assessment Factrs t cnsider when develping a mnitring plan Mnitring plan Descriptin f Mnitring Appraches Cmmunicatin f Mnitring Results Management f Nncmpliance Ensuring Quality Mnitring Mnitring Plan Amendments Dcumenting mnitring activities ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY Prtcl and Case Reprt Frm design Principal Investigatr training and cmmunicatin Delegatin f mnitring respnsibilities t a CRO _Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 2 f 16

3 Oversight and Mnitring in Clinical Trials TABLE OF CONTENTS 5.4 Principal Investigatr and site selectin and initiatin Page 6 REFERENCES UPDATE HISTORY _Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 3 f 16

4 Oversight and Mnitring in Clinical Trials 1 INTRODUCTION This guideline assists spnsrs f clinical investigatins in develping mnitring strategies and plans fr investigatinal studies f medical prducts, including human medicine and bilgical prducts, medical devices, and cmbinatins theref. The verarching gal is t enhance human participant prtectin and the quality f clinical trial data by fcusing spnsr versight n the mst imprtant aspects f study cnduct and reprting. While this guideline makes it clear that spnsrs, and clinical research rganisatins (CROs) acting n their behalf, can use a variety f appraches t fulfil their respnsibilities fr mnitring Principal Investigatr (PI) cnduct and perfrmance in investigatinal studies. It must be highlighted that the respnsibility fr adequate versight f the cnduct f a clinical trial, including the justificatin fr and selectin f mnitring methds, remains that f the spnsr slely. The cnsequences f inadequate mnitring are the sle respnsibility f the spnsr r its representative. 2 BACKGROUND Effective mnitring f clinical trials by spnsrs is critical t the prtectin f human participants and the cnduct f high-quality studies. Spnsrs f clinical trials invlving human medicines, bilgical prducts, medical devices, and cmbinatins theref are required t prvide versight t ensure adequate prtectin f the rights, welfare, and safety f human participants and the quality f the clinical trial data submitted t the Medicines Cntrl Cuncil (MCC). The MCC requires spnsrs t mnitr the cnduct and prgress f their clinical trials. During the past decade, the number and cmplexity f clinical trials have grwn dramatically. These changes create new challenges t clinical trial versight, particularly increased variability in clinical investigatr experience, site infrastructure, treatment chices, and standards f health care, as well as challenges related t gegraphic dispersin. At the same time, increasing use f electrnic systems and recrds, as well as imprvements in statistical assessments and pharmacvigilance, present pprtunities fr alternative mnitring appraches that can imprve the quality and efficiency f spnsr versight f clinical trials. The MCC encurages spnsrs t develp mnitring plans that manage imprtant risks t human participants and data quality and address the challenges f versight, in part by taking advantage f the innvatins in mdern clinical trials. This guideline fcuses principally n mnitring, which is ne aspect f the prcesses and prcedures needed t ensure clinical trial quality and participant safety. Mnitring is a quality cntrl tl fr determining whether study activities are being carried ut as required, s that deficiencies can be identified and crrected. Mnitring r versight alne cannt ensure quality. Rather, quality is an verarching bjective that must be built int the clinical trial enterprise. The term mnitring is used in different ways in the clinical trial cntext. It can refer t the assessment f Principal Investigatr (PI) cnduct, versight, and reprting f findings f a clinical trial; t the nging evaluatin f safety data and the emerging benefit-risk prfile f an investigatinal prduct (IP); and t the mnitring f internal spnsr and CRO prcesses and systems integral t prpsing, designing, perfrming, recrding, supervising, reviewing, r reprting clinical investigatins. Fr purpses f this guideline, mnitring refers t the methds used by spnsrs f investigatinal studies, r CRO s delegated respnsibilities fr the cnduct f studies, t versee the cnduct f, and reprting f data frm clinical investigatins, including apprpriate PI supervisin f study site staff and third party 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 4 f 16 Back t TC

5 Oversight and Mnitring in Clinical Trials cntractrs. Mnitring activities include cmmunicatin with the PI and study site staff; review f the study site s prcesses, prcedures, and recrds; and verificatin f the accuracy f data submitted t the spnsr. 2.1 Definitins Risk-based mnitring (RBM) is a mnitring technique that invlves the use f validated tls in the evaluatin and assessment f risk in the versight f the quality f data and using the risk assessment t increase r decrease n site mnitring and/r Surce Data Verificatin (SDV). Remte mnitring is the technique f mnitring sites ffsite by invlving the site in verificatin f surce data fr example asking the site t cnfirm the time f cnsenting. It implies the reliance n the site itself t augment r replace nsite mnitring. This may invlve the use f telephne r faxes t mnitr the site. Remte mnitring is nt acceptable t the MCC. Centralised r central mnitring is the use f data generated n site which is used by the spnsr ffsite t evaluate and assess risk and deviatins frm the prtcl r the median and is nt dependant n the site verifying the data. Centralised mnitring can be used t augment RBM r n-site mnitring. On-site mnitring is an in-persn evaluatin carried ut by spnsr persnnel r representatives at the sites at which the clinical investigatin is being cnducted. On site mnitring is the traditin technique where a mnitr reviews surce n site t ensure cmpliance and data quality. On site mnitring may invlve the use f centralised tls and remte access t facilitate efficiencies and streamline n site visits. Remte access t data and even surce can be facilitated by the advancement in electrnic systems and the increasing use f electrnic recrds. Remte access t surce dcuments which meets all the ethical and legal requirements fr participant prtectin and safety allws fr review and mnitring ffsite but is then essentially equivalent t nsite mnitring in many but nt all aspects. Ideally, remte access shuld be used t augment and fcus n-site mnitring alng with RBM tls. Telephnic mnitring is equivalent t remte mnitring and is f limited value. Telephnic supprt can and must be given t sites but spnsrs must refrain frm asking sites t verify surce which then inadvertently becmes remte mnitring. 2.2 Current Mnitring Practices Histrically, a range f practices has been used t mnitr the cnduct f clinical trials. These practices vary in intensity, fcus, and methdlgy and include centralised mnitring f clinical data by statistical and data management persnnel; targeted n-site visits t higher risk sites (e.g. where centralised mnitring suggests prblems at a site), and frequent, cmprehensive n-site visits t all sites by spnsr persnnel r representatives (e.g. clinical mnitrs r clinical research assciates). Peridic, frequent visits t each site t evaluate study cnduct and review data fr each enrlled participant remain the predminant mechanism by which pharmaceutical, bitechnlgy, and medical device cmpanies mnitr the prgress f clinical investigatins. Fr majr efficacy trials, cmpanies typically cnduct n-site mnitring visits at apprximately 4- t 8-week intervals. This type f traditinal frequent nsite mnitring visit mdel, with 100 % verificatin f all data, histrically has been the MCC s preferred way fr spnsrs t meet their mnitring bligatins. The 1996 Internatinal Cnference n Harmnisatin f Technical Requirements fr Registratin f Pharmaceuticals fr Human Use (ICH) guidance n gd clinical practice (ICH E6) and the 2011 Internatinal Standards Organizatin (ISO) Clinical investigatin f medical devices fr human subjects gd clinical practice (ISO 14155:2011) address mnitring. Bth ICH E6 and ISO 14155:2011 specifically prvide fr flexibility in hw trials are mnitred. Bth E6 and ISO 14155:2011 advise spnsrs t cnsider 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 5 f 16 Back t TC

6 Oversight and Mnitring in Clinical Trials the bjective, design, cmplexity, size, and endpints f a trial in determining the extent and nature f mnitring fr a given trial. Althugh the ICH guidance and ISO standard specifically prvide fr the pssibility f reduced r even n, n-site mnitring, they als make clear that it wuld be apprpriate t rely entirely n centralised mnitring nly in exceptinal circumstances. 2.3 Apprach t Risk-Based Mnitring A risk-based apprach t mnitring (RBM) by definitin invlves the use f validated tls in the evaluatin and assessment f risk in the versight in the quality f data. It des nt imply nr is equivalent t remte r ff-site mnitring, and must be distinguished frm this. While it des nt suggest any less vigilance in the versight f clinical investigatins, there is the danger that the risk-based mnitring may ffer less versight than the traditinal mnitring appraches. RBM fcuses spnsr versight activities n preventing r mitigating imprtant and likely risks t data quality and t prcesses critical t human participant prtectin and trial data integrity. Mrever, a risk-based apprach is dynamic, mre readily facilitating cntinual imprvement in trial cnduct and versight. Fr example, mnitring findings shuld be evaluated t determine whether additinal actins (e.g. training f clinical investigatr and site staff, clarificatin f prtcl requirements) are necessary t ensure human participant prtectin and data quality acrss sites. Spnsrs shuld be prepared t augment RBM if necessary as it is an imperative f the cncept f RBM. The MCC believes that RBM culd imprve spnsr versight f clinical investigatins if understd and executed crrectly. RBM and the reliance n technlgical advances (e.g. remte risk and quality management tls and prcesses), can meet statutry and regulatry requirements under apprpriate circumstances. The incrpratin f centralised mnitring practices, where apprpriate, shuld imprve a spnsr s ability t ensure the quality f clinical trial data. While several publicatins suggest that certain data anmalies (e.g. fraud, including fabricatin f data, and ther nn-randm data distributins) may be mre readily detected by centralised mnitring techniques than by n-site mnitring, there is als cnfusin arund bth terminlgy and implementatin. While adequate training may address sme f these issues, it has been suggested that a statistical apprach t central mnitring can help imprve the effectiveness f nsite mnitring by priritising site visits and by guiding site visits with central statistical data checks. The MCC encurages spnsrs t tailr mnitring plans t the needs f the trial. The advancement in electrnic systems and increasing use f electrnic recrds (i.e. electrnic data capture [EDC] systems) facilitate remte access t electrnic data and, increasingly, t sme surce data althugh limited. Additinally, statistical assessments using data submitted n paper case reprt frms (CRFs) r via EDC may permit timely identificatin f clinical sites that require additinal training, mnitring, r bth. The MCC acknwledges that there is limited empirical data t supprt the utility f the varius methds emplyed t mnitr clinical investigatins (e.g. superirity f ne methd versus anther), including data t supprt n-site mnitring. As a result, the recmmendatins are based, in part, n the MCC s experience frm the review f prtcls, data submitted in pre-apprval applicatins, and the results f inspectins cnducted t ensure human participant prtectin and data integrity. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 6 f 16 Back t TC

7 Oversight and Mnitring in Clinical Trials 3 OVERVIEW OF MONITORING METHODS 3.1 On-site and Centralised Mnitring This sectin is intended t assist spnsrs in identifying and designing mnitring practices apprpriate t a given clinical trial. It describes sme f the capabilities f n-site and centralised mnitring prcesses and factrs t cnsider in determining which mnitring practices may be apprpriate fr a given clinical trial On-site Mnitring On-site mnitring is an in-persn evaluatin carried ut by spnsr persnnel r representatives at the sites at which the clinical investigatin is being cnducted. On-site mnitring can identify data entry errrs (e.g. discrepancies between surce recrds and CRFs) and missing data in surce recrds r CRFs; prvide assurance that study dcumentatin exists; assess the familiarity f the site s study staff with the prtcl and required prcedures; and assess cmpliance with the prtcl and investigatinal prduct accuntability. On-site mnitring can als prvide a sense f the quality f the verall cnduct f the trial at a site (e.g. attentin t detail, thrughness f study dcumentatin, apprpriate delegatin f study tasks, and apprpriate PI supervisin f site staff perfrming critical study functins). On-site mnitring can therefre be particularly helpful early in a study, especially if the prtcl is cmplex and includes nvel prcedures with which PIs may be unfamiliar. Findings at the site may lead t training effrts at bth the site visited and elsewhere Centralised Mnitring Centralised mnitring is a remte evaluatin carried ut by spnsr persnnel r representatives (e.g. clinical mnitrs, data management persnnel, r statisticians) at a lcatin ther than the sites at which the clinical investigatin is being cnducted. Centralised mnitring prcesses can prvide sme f the capabilities f n-site mnitring as well as additinal capabilities. The types f mnitring activities and the extent t which centralised mnitring practices can be emplyed depend n varius factrs, including the spnsr s use f electrnic systems; the spnsr s access t participants electrnic recrds, if applicable; the timeliness f data entry frm paper CRF, if applicable; and cmmunicatin tls available t the spnsr and study site. These may vary by study and by site. Spnsrs wh plan t use centralised mnitring prcesses shuld ensure that the prcesses and expectatins fr site recrd keeping, data entry, and reprting are well-defined and ensure timely access t clinical trial data and supprting dcumentatin If spnsrs intend t rely heavily n centralised mnitring practices, they shuld identify, in the mnitring plan, the limitatins f this plan, and when mre n-site mnitring visits wuld be indicated, nting that mnitring remains a sle respnsibility f the spnsr. 3.2 Examples f mnitring practices and activities Mnitring activities bradly include cmmunicatin with the PI and study site staff; review f the study site s prcesses, prcedures, and recrds; and verificatin f the accuracy f data submitted t the spnsr. Centralised mnitring techniques shuld be used t the extent apprpriate and feasible t: Supplement r reduce the frequency and extent f n-site mnitring with mnitring activities that can be dne as well r better remtely r with mnitring activities that can be accmplished using centralised prcesses nly. Examples include: Mnitr data quality thrugh rutine review f submitted data t identify and fllw-up n missing data, incnsistent data, data utliers, and ptential prtcl deviatins that may be indicative f systemic r significant errrs in data cllectin and reprting at a site; 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 7 f 16 Back t TC

8 Oversight and Mnitring in Clinical Trials Cnduct statistical analyses t identify data trends nt easily detected by n-site mnitring, such as: Standard checks f the ranges, cnsistency, and cmpleteness f data Checks fr unusual distributin f data within and between study sites, such as data with t little variance Analyse site characteristics, perfrmance metrics (e.g. high screen failure r withdrawal rates, high frequency f eligibility vilatins, delays in reprting data), and clinical data t identify trial sites with characteristics crrelated with pr perfrmance r nncmpliance; Verify critical surce data remtely as described in the mnitring plan, in cases where such surce data are accessible, r where CRF data are, accrding t the prtcl, surce data; Cmplete administrative and regulatry tasks. Such tasks include, fr example, verifying cntinuus institutinal review bard (IRB) apprval by reviewing electrnic IRB crrespndence, if available; perfrming prtins f investigatinal prduct accuntability, such as cmparisn f randmisatin and CRF data, t preliminarily assess whether the participant was administered r dispensed the assigned prduct and t evaluate cnsistency between investigatinal prduct receipt, use, and dispsitin recrds; and verifying whether previusly requested CRF crrectins were made. Centralised techniques, including rutine review f submitted data and statistical and ther analyses, may als be used t identify significant cncerns (e.g. need fr clarificatin f a prtcl prcedure, indicatins f data fabricatin) with nn-critical data that may nt have therwise been a fcus f mnitring. Target n-site mnitring by identifying higher risk clinical sites (e.g. sites with data anmalies r a higher frequency f errrs, prtcl vilatins, r drputs relative t ther sites), thrugh the activities described abve. Such findings, whether related t critical r nn-critical data, may warrant n-site visits r mre intensive and cnsideratin f further n-site mnitring. The fllwing sectins prvide additinal descriptins f varius mnitring appraches Cmmunicatin with study site staff Cmmunicatin between the mnitr and the study site staff is an essential cmpnent f the clinical trial. Varius mdes f cmmunicatin (e.g. telecnferences, videcnferencing, ) culd be cnsidered fr specific study time pints (e.g. study initiatin) and activities (e.g. t discuss findings f a mnitr s ecrf review, training f new site staff). Cmmunicatin with sites des nt invlve evaluatin r review f data by spnsr persnnel r representatives Review f site s prcesses, prcedures, and recrds Techniques fr mnitring infrmed cnsent and site recrds are included here as examples f appraches t mnitring site s prcesses, prcedures, and recrds. a) Infrmed cnsent Verificatin f participants infrmed cnsent is a critical activity that shuld be mnitred. Alternatives t the traditinal apprach (mnitrs verifying the riginal signature n the cnsent frm fr each participant at the site) may be effective in identifying inadequacies in the cnsent prcess. The study site sending dcuments electrnically (e.g. fax, ) t the mnitr ff-site may nt be apprpriate. The mnitr may perfrm remte cmparisn f dates f study prcedures and dcumentatin f infrmed cnsent n CRFs. A secure internet prtal that enables the site staff t uplad signed cnsent frms and enables access by designated mnitrs is a tl that can be cnsidered. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 8 f 16 Back t TC

9 Oversight and Mnitring in Clinical Trials Use f electrnic infrmed cnsent may als facilitate spnsr versight f human participant prtectin. Spnsrs must attend t privacy and cnfidentiality cncerns when cnsidering techniques fr mnitring infrmed cnsent. b) Site s recrds A grwing prtin f surce dcuments (e.g. labratry and radilgy reprts, surce dcuments submitted by the PI fr ther purpses such as health recrds dcumenting serius adverse events r adjudicated events) are electrnic and may be available t the spnsr remtely. Spnsrs may nt have remte access t electrnic health recrds maintained by hspitals, universities, and ther institutins because f data privacy and security cncerns as well as technlgical challenges Surce data verificatin and crrbratin The spnsr shuld cnsider the quantity and types f surce data that need t be verified against CRFs r crrbrated against ther recrds (e.g. review f medical recrd t crrbrate a participant s respnse f n hspitalisatins since the previus visit n a CRF) during the spnsr s identificatin f critical data and prcesses r in the risk assessment, r bth. The spnsr shuld include a descriptin f the quantity and types f surce recrds t verify r crrbrate in the mnitring plan. The spnsr shuld cnsider which surce recrds are likely t prvide the mst meaningful infrmatin abut a participant s participatin and the PI s cnduct and versight. Fr example, fr a particular study, there may be minimal benefit in cmparing 100 % f the surce data fr each participant t the CRFs fr each study visit. Rather, it may be sufficient t cmpare the mst critical data pints fr a sample f participants and study visits as an indicatr f data accuracy. Similarly, fr a particular study, althugh cllectin f all cncmitant medicatins, bdy temperature, and bdy weight are required by the prtcl and are dcumented in the medical recrd and transcribed t a CRF, they may nt be identified by the spnsr as critical data, because a small errr rate in thse variables wuld nt affect the utcme f the trial. In the absence f infrmatin indicating ptential cncerns with the data (e.g. sites with data anmalies, incnsistent data), surce dcument verificatin r crrbratin f these nn-critical data may nt prvide significantly useful infrmatin t the spnsr. 4 RISK-BASED MONITORING N single apprach t mnitring is apprpriate fr every clinical trial. The MCC recmmends that each spnsr design a mnitring plan that is tailred t the specific human participant prtectin and data integrity risks f the trial. Ordinarily, such a risk-based plan wuld include a mix f centralised and n-site mnitring practices. The mnitring plan shuld identify the varius methds intended t be used and the ratinale fr their use. Mnitring activities shuld fcus n preventing r mitigating imprtant and likely surces f errr in the cnduct, cllectin, and reprting f critical data and prcesses necessary fr human participant prtectin and trial integrity. Spnsrs shuld prspectively identify critical data and prcesses, then perfrm a risk assessment t identify and understand the risks that culd affect the cllectin f critical data r the perfrmance f critical prcesses, and then develp a mnitring plan that fcuses n the imprtant and likely risks t critical data and prcesses. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 9 f 16 Back t TC

10 Oversight and Mnitring in Clinical Trials 4.1 Identify critical data and prcesses t be mnitred Spnsrs shuld prspectively identify critical data and prcesses that if inaccurate, nt perfrmed, r perfrmed incrrectly, wuld threaten the prtectin f human participants r the integrity f the study results. As examples, the fllwing types f data and prcesses shuld rdinarily be identified as critical: Verificatin that infrmed cnsent was btained apprpriately; Adherence t prtcl eligibility criteria designed t exclude individuals fr whm the investigatinal prduct may be less safe than the prtcl intended and t include nly participants frm the targeted study ppulatin fr whm the test article is mst apprpriate; Prcedures fr dcumenting apprpriate accuntability and administratin f the investigatinal prduct (e.g. ensuring the integrity f randmisatin at the site level, where apprpriate). Cnduct and dcumentatin f prcedures and assessments related t: Study endpints; Prtcl-required safety assessments; Evaluating, dcumenting, and reprting serius adverse events and unanticipated adverse device effects, participant deaths, and withdrawals, especially when a withdrawal may be related t an adverse event. Cnduct and dcumentatin f prcedures essential t trial integrity, such as ensuring the study blind is maintained, bth at the site level and at the spnsr level, as apprpriate, referring specified events fr adjudicatin, and allcatin cncealment. Other types f data (e.g. cvariates such as cncmitant treatments r demgraphic characteristics, rutine labratry tests perfrmed as part f participant mnitring that d nt address prtcl specified safety r efficacy endpints) and prcesses (e.g. a hspital pharmacy s strage f an investigatinal prduct with n specific critical handling instructins) identified by the spnsr as nn-critical ften may be mnitred less intensively. There is increasing recgnitin that sme types f errrs in a clinical trial are mre imprtant than thers. Fr example, a lw, but nn-zer rate f errrs in capturing certain baseline characteristics f enrlled participants (e.g. age, cncmitant treatment, r cncmitant illness) will nt, in general, have a significant effect n study results if the errrs are distributed randmly. In cntrast, a small number f errrs related t study endpints (e.g. nt fllwing prtcl-specified definitins) can prfundly affect study results, as culd failure t reprt rare but imprtant adverse events. 4.2 Risk assessment This guideline als discusses risk assessment, a cmpnent f risk management, as applied in the cntext f clinical mnitring. Risk assessment generally invlves identifying risks, analysing risks, and then determining whether risks need t be mdified by implementing cntrls (e.g. prcesses, plicies, r practices). The risk assessment recmmended in this guideline t infrm develpment f a mnitring plan may als supprt effrts t manage risks acrss a clinical trial (e.g. thrugh mdifying the prtcl design r implementatin) r develpment prgram. This guideline des nt prvide cmprehensive detail n hw t perfrm a risk assessment. There are many risk assessment methdlgies and tls frm a variety f industries that can be applied t clinical trials. These shuld be validated. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 10 f 16 Back t TC

11 Oversight and Mnitring in Clinical Trials Fllwing the identificatin f critical data and prcesses, spnsrs shuld perfrm a risk assessment t identify and understand the nature, surces, and ptential causes f risks that culd affect the cllectin f critical data r the perfrmance f critical prcesses. Risks t critical data and prcesses merit cnsideratin during risk assessment, t ensure that mnitring effrts are fcused n preventing r mitigating imprtant and likely surces f errr in their cnduct, cllectin and reprting. Risk identificatin fr mnitring purpses shuld generally cnsider the types f data t be cllected, the specific activities required t cllect these data, and the range f ptential safety and ther human participant prtectin cncerns that are inherent t the clinical investigatin (e.g. based n trial design r investigatinal prduct). The identified risks shuld be assessed and priritised by cnsidering the likelihd f errrs ccurring and the impact f such errrs n human participant prtectin and trial integrity the extent t which such errrs wuld be detectable. Spnsrs shuld use the results f the risk assessment in develping the mnitring plan (e.g. determining which risks may be addressed thrugh mnitring, determining the types and intensity f mnitring activities best suited t addressing these risks). Spnsrs may als determine that sme risks are better managed thrugh activities ther than mnitring, fr example, mdifying the prtcl t remve the surce f the risk. Spnsrs shuld peridically evaluate emerging risks and whether mnitring activities require mdificatin t effectively versee the risks. 4.3 Factrs t cnsider when develping a mnitring plan A mnitring plan rdinarily shuld fcus n preventing r mitigating imprtant and likely risks, identified by the risk assessment, t critical data and prcesses. The types (e.g. n-site, centralised), frequency (e.g. early, fr initial assessment and training versus thrughut the study), and extent (e.g. cmprehensive [100 % data verificatin] versus targeted r randm review f certain data [less than 100 % data verificatin]) f mnitring activities will depend t sme degree n a range f factrs, cnsidered during the risk assessment, including the fllwing: Cmplexity f the study design Mre intensive mnitring (e.g. increased frequency and extent f review) may be necessary as study design cmplexity increases. Types f study endpints Endpints that are mre interpretative r participative may require n-site visits t assess the ttality f participant recrds and t review applicatin f prtcl definitins with the PI. Mre bjective endpints (e.g. death, hspitalisatin, r clinical labratry values and standard measurements) may be mre suitable fr remte verificatin. Endpints fr which inapprpriate participant withdrawal r lack f fllw-up may impede study evaluatin are likely t need mre intensive mnitring t identify the reasn(s) participants are withdrawing and t determine whether fllw-up can be imprved. Clinical cmplexity f the study ppulatin A study that invlves a ppulatin that is seriusly ill r vulnerable may require mre intensive mnitring and cnsideratin f n-site mnitring visits t be sure apprpriate prtectin is being prvided. Gegraphy Sites in gegraphic areas where there are differences in standards f medical practice r participant demgraphics, r where there is a less established clinical trial infrastructure may require mre intensive mnitring and cnsideratin f n-site mnitring visits. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 11 f 16 Back t TC

12 Oversight and Mnitring in Clinical Trials Relative experience f the PI and f the spnsr with the PI PIs wh lack significant experience in cnducting and verseeing investigatins, using a nvel r innvative medical device, r with the surgical prcedure assciated with medical device use may benefit frm mre intensive mnitring and frequent cmmunicatin t ensure PI understanding f respnsibilities. In additin, the relative experience f a spnsr with the PI may be a factr in determining an apprpriate mnitring plan. Electrnic data capture Use f EDC systems with the capability t assess quality metrics (e.g. missing data, data errr rates, prtcl vilatins) in real-time culd help identify ptentially higher risk sites fr the purpse f targeting sites in need f mre intensive mnitring. Relative safety f the investigatinal prduct A study f a prduct that has significant safety cncerns r fr which there is n prir experience in human clinical trials (e.g. a phase 1 pharmaceutical investigatin r a device feasibility study) may require mre intensive mnitring and cnsideratin f n-site mnitring visits t ensure apprpriate PI versight f participant safety. Stage f the study A tapered apprach t mnitring may be used where apprpriate, with mre intensive mnitring at initiatin and during early stages f a trial. Fr example, a tapered apprach culd be used fr a cmplex study where mre intensive and n-site mnitring might be required early, but where, nce prcedures are established, less intensive mnitring might suffice. Similarly, a tapered apprach culd be used fr relatively inexperienced PIs. Quantity f data Sme centralised mnitring tls may be mre useful as the quantity f data (e.g. size r duratin f trial, number f sites) cllected increases. 4.4 Mnitring plan Fr each clinical trial, the spnsr shuld develp a mnitring plan that describes the mnitring methds, respnsibilities, and requirements fr the trial. The mnitring plan shuld include a brief descriptin f the study, its bjectives, and the critical data and study prcedures, with particular attentin t data and prcedures that are unusual in relatin t clinical rutine and require training f study site staff. The plan shuld als cmmunicate the specific risks t be addressed by mnitring and shuld prvide thse invlved in mnitring with adequate infrmatin t effectively carry ut their duties. A mnitring plan may reference existing plicies and prcedures (e.g. standard perating prcedure describing general mnitring prcesses r issue investigatin and reslutin). All spnsr and CRO persnnel invlved with mnitring, including thse wh review r determine apprpriate actin regarding ptential issues identified thrugh mnitring, shuld review the mnitring plan and assciated dcuments and apprpriately trained in the cnduct f the study (e.g. standard perating prcedures r ther dcuments referenced in the mnitring plan). The cmpnents f a mnitring plan might include the fllwing: Descriptin f Mnitring Appraches A descriptin f each mnitring methd t be emplyed during the study and hw it will be used t address imprtant risks and ensure the validity f critical data. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 12 f 16 Back t TC

13 Oversight and Mnitring in Clinical Trials Criteria fr determining the timing, frequency, and extent f planned mnitring activities: Specific activities required fr each mnitring methd emplyed during the study, including reference t required tls, lgs, r templates; Definitins f events r results (e.g. findings frm central mnitring activities) that wuld trigger changes in planned mnitring activities fr a particular PI. Fr example, if it is determined that a PI differs markedly frm ther PIs in making safety-related findings r ther key safety metrics, in rate f enrlment, in the number f prtcl deviatins, r in the rate f missing CRFs, the PI s site shuld be cnsidered fr targeted n-site visits. The establishment f acceptable variatin fr particular critical data and prcesses wuld facilitate identificatin f significant deviatins. Identificatin f pssible deviatins r failures that wuld be critical t study integrity and hw these are t be recrded and reprted. Fr example, spnsrs may wish t establish a specific mechanism fr tracking and ntifying key study persnnel f deviatins related t cllectin r reprting f data necessary t interpret the primary endpint, regardless f which mnitring methd identified a cncern. The study mnitring plan shuld als describe hw varius mnitring activities will be dcumented, regardless f whether they are cnducted n-site r centrally Cmmunicatin f Mnitring Results Frmat, cntent, timing, and archiving requirements fr reprts and ther dcumentatin f mnitring activities. Prcess fr apprpriate cmmunicatin: Of rutine mnitring results t management and ther stakehlders (e.g. CRO, data management) Of immediate reprting f significant mnitring issues t apprpriate parties (e.g. spnsr management, PI and site staff, IRB, FDA), as necessary; Frm study management and ther stakehlders t mnitrs. Fr example, data management persnnel may prvide mnitrs with rutine reprts f utstanding CRFs r f cmmn data queries at r acrss sites that may enable effective targeting f mnitring activities Management f Nncmpliance Prcesses fr addressing unreslved r significant issues (e.g. significant nn-cmpliance with the investigatinal plan, suspected r cnfirmed data falsificatin) identified by mnitring, whether at a particular site r acrss study sites. Prcesses t ensure that rt cause analyses are cnducted where imprtant deviatins are discvered and that apprpriate crrective and preventive actins (e.g. additinal training n a study r site level) are implemented t address issues identified by mnitring. Other quality management practices applicable t the clinical investigatin (e.g. reference t any ther written dcuments describing apprpriate actins regarding nn-cmpliance) Ensuring Quality Mnitring It is the spnsr s respnsibility t ensure that the mnitr is bth trained and qualified t undertake the mnitring f a specific trial. Descriptin f any specific training required fr persnnel carrying ut mnitring activities, including persnnel cnducting internal data mnitring, statistical mnitring, r ther centralised review activities shuld be prvided. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 13 f 16 Back t TC

14 Oversight and Mnitring in Clinical Trials Training shuld include Gd Clinical Practice, principles f clinical investigatins and human participant prtectin. In additin, study-specific training shuld include training n the disease under study, study trial design, prtcl requirements, study mnitring plan, applicable standard perating prcedures (SOPs), apprpriate mnitring techniques, and applicable electrnic systems. Planned audits f mnitring t ensure that spnsr and CRO staff cnduct mnitring activities in accrdance with the mnitring plan, applicable regulatins, guidance, and spnsr plicies, prcedures, templates, and ther study plans. Auditing is a quality assurance tl that can be used t evaluate the effectiveness f mnitring t ensure human participant prtectin and data integrity. Many spnsrs have successfully implemented n-site c-mnitring visits (i.e. mnitring visits perfrmed by bth a study mnitr and the mnitr s supervisr r anther evaluatr designated by the spnsr r CRO) t evaluate whether mnitrs are effectively carrying ut visit activities, in cmpliance with the study mnitring plan. These visits may be cnducted either fr randmly selected mnitrs r may be targeted t specific mnitrs, based upn questins arising frm review f mnitring visit dcumentatin, centralised data review r PI feedback Mnitring Plan Amendments Spnsrs shuld cnsider what events wuld indicate a need fr review and revisin f the mnitring plan and establish prcesses t permit timely updates where necessary. Fr example, a prtcl amendment, change in the definitin f significant prtcl deviatins, r identificatin f new risks t study integrity culd result in a change t the mnitring plan. 4.5 Dcumenting mnitring activities Dcumentatin f mnitring activities shuld generally include the fllwing: The date f the activity and the individual(s) cnducting and participating in it; A summary f the data r activities reviewed; A descriptin f any nncmpliance, ptential nncmpliance, data irregularities, r ther deficiencies identified; A descriptin f any actins taken, t be taken, r recmmended, including the persn respnsible fr cmpleting actins and the anticipated date f cmpletin. Dcumentatin f mnitring shuld include sufficient detail t allw verificatin that the mnitring plan was fllwed. Mnitring dcumentatin shuld be prvided t apprpriate management in a timely manner fr review and fllw-up, as indicated. 5 ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY Althugh the fcus f this guideline is n mnitring the versight and cnduct f, and reprting f data frm, clinical investigatins, MCC cnsiders mnitring t be just ne cmpnent f a multi-factr apprach t ensuring the quality f clinical investigatins. Many ther factrs cntribute t the quality f a clinical investigatin. This sectin highlights additinal areas that cmplement mnitring and can affect study quality. A fundamental cmpnent f ensuring quality mnitring is a spnsr s cmpliance with mnitring plans and any accmpanying prcedures. 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 14 f 16 Back t TC

15 Oversight and Mnitring in Clinical Trials 5.1 Prtcl and Case Reprt Frm design The mst imprtant tl fr ensuring human participant prtectin and high-quality data is a well-designed and articulated prtcl. A prly designed r ambiguus prtcl may intrduce systemic errrs that can render a clinical investigatin unreliable despite rigrus mnitring. Additinally, the cmplexity f the trial design and the type and amunt f data cllected may influence data quality. The CRF, which captures the data required by the prtcl, is anther critical tl fr which design directly affects the quality f trial data. Care shuld be taken t ensure that the CRF captures data accurately (e.g. as required by the prtcl) and that the CRF design and instructins facilitate cnsistent data cllectin acrss PI sites. 5.2 Principal Investigatr training and cmmunicatin Clinical trial mnitrs cnducting n-site visits have histrically played an imprtant rle in training the PI and site staff during a study. On-site visits als have served as a primary means f prviding feedback t PIs and study persnnel n study cnduct. Withut meaningful training prir t the cnduct f a study and f apprpriate instructin during the study (e.g. when changes are made t the prtcl), PIs and their staff may have difficulty carrying ut a trial crrectly. Spnsrs wh plan less frequent r limited n-site mnitring shuld cnsider the fllwing: Mnitring activities shuld include sufficient time fr discussin f PI s and site staff s respnsibilities, feedback, and additinal training, if needed, during the cnduct f the study. It may be necessary t implement alternative training (e.g. telecnferences, webcasts, n-line training mdules) and cmmunicatin methds fr prviding and dcumenting nging, timely training and feedback, as well as t prvide ntificatin f significant changes t study cnduct r ther imprtant infrmatin. It must be cnsidered that many f the factrs that necessitate nsite mnitring may be relevant and this shuld be cnsidered. 5.3 Delegatin f mnitring respnsibilities t a CRO If a spnsr f a study delegates the respnsibility fr ensuring prper mnitring t a CRO, the MCC wuld require the written transfer f any bligatins frm a spnsr t a CRO and require the CRO t cmply with the regulatins. Althugh spnsrs can transfer respnsibilities fr mnitring t a CRO(s), they retain respnsibility fr versight f the wrk cmpleted by the CRO(s) that assume this respnsibility. Spnsrs shuld evaluate CRO cmpliance with regulatry requirements and cntractual bligatins in an nging manner. Fr example, spnsr versight f mnitring perfrmed by a CRO may include the spnsr s peridic review f mnitring reprts and vendr perfrmance r quality metrics and dcumented cmmunicatin between the spnsr and CRO regarding mnitring prgress and findings. Spnsrs and CROs shuld cnsider additinal factrs when a spnsr transfers respnsibilities fr mnitring t a CRO. Spnsrs and CROs shuld prspectively establish a clear understanding f bth parties respnsibilities and f the expectatins fr the cnduct f the transferred bligatins. Spnsrs shuld share infrmatin with a CRO that may infrm decisins a CRO may make regarding the mnitring practices fr a trial (e.g. findings f a risk assessment). Spnsrs shuld prspectively evaluate mnitring prcedures and mnitring plans develped by a CRO t ensure the mnitring apprach is cnsistent with applicable aspects f the trial. In additin, spnsrs and CROs shuld have prcesses in place fr timely exchange f relevant infrmatin (e.g. significant mnitring findings, significant changes in risk fr a trial). 2.43_Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 15 f 16 Back t TC

16 Oversight and Mnitring in Clinical Trials 5.4 Principal Investigatr and site selectin and initiatin In additin t regulatry requirements fr PI selectin, spnsrs shuld cnsider factrs such as spnsr s previus experience with the PI r site, wrklad f the PI and study staff, and resurce availability at the study site during PI and site selectin. Site training and initiatin is a critical study activity that ften invlves spnsr persnnel frm a range f disciplines, including mnitrs. Key cmpnents f site initiatin include ensuring the PIs and site staff understands their respnsibilities, including applicable regulatry requirements as well as study prcesses and prcedures, including the spnsr s prcesses fr mnitring the investigatin. Cmmunicatin and dcumentatin tls fr mnitring discussed in this guideline can als be used fr site selectin and initiatin activities. 6 REFERENCES Guidance fr Industry Oversight f Clinical Investigatins - A Risk-Based Apprach t Mnitring. FDA. August. Internatinal Standard Clinical investigatin f medical devices fr human subjects-gd Clinical Practice. ISO nd editin. Internatinal Cuncil fr Harmnisatin f Technical Requirements fr Registratin f Pharmaceuticals fr Human Use. (1996) ICH Harmnised Tripartite Guideline. Guideline fr Gd Clinical Practice. Current Step 4 versin dated 10 June 1996 (including the Pst Step 4 crrectins). 7 UPDATE HISTORY Date Reasn fr Update Versin & Publicatin April 2016 First versin fr External Stakehlder cmment Published fr cmment Versin 1, May June 2016 Due date fr cmment Sept 2016 Dcument title and number changed New sectin 2.1 Amendments t sectins 1, 2, 2.2, , 3.1.2, 3.2, 3.2.1, a), , 4.3, 4.4.4, 5.1, 6 Published fr implementatin Versin 1, Nv _Oversight_Mnitring_Clinical_Trials_Sept16_v1.dc Nv 2016 Page 16 f 16 Back t TC