ISO 14155:2020 Clinical Investigation Planning (July 2020)

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ISO 14155:2020Clinical InvestigationPlanning (July 2020)Slides released 04NOV20201 2020 Frestedt Incorporated

DISCLAIMERThese slides are not meant to replace the purchase of theISO 14155:2020 standard from ISO available at YouTube discussions exist, too: WK7X3nrJVyo TG8GTPTDrYk2 2020 Frestedt Incorporated


Major ChangesISO 14155:2020 includes new guidance for: Clinical quality management Risk based monitoring and related monitoring plans Addressing increased statistical requirements bynotified bodies Ethics committees Clinical investigation audits In-vitro diagnostic medical devices (IVDs)4 2020 Frestedt Incorporated

Major Changes Increased emphasis on risk management (ISO 14971) Clinical investigation planning requires inclusion ofpersonnel with relevant medical expertise Alignment with definitions with current updated GCPguidelines Emphasis of clinical evidence in European RegulationsISO 14155:2020 implementation should not result in majorchanges in clinical research operations if already incompliance with ISO 14155:20115 2020 Frestedt Incorporated

ISO 14971:2019 Application of risk management to medical devices Major components include: 6Risk management systemRisk analysisRisk evaluationRisk controlEvaluation of residual riskRisk Management reviewProduction and post-production activities 2020 Frestedt Incorporated

Risk Management in Practice Implementation ISO 14971 involves a system for riskmanagement Risk Management Plan identifies, evaluates, ranks andcontrols risks RMPs can be inclusive of risk from entire product life cycle Risks can be product related or patient related Can be applied to project specific risks (clinical trials) Formal risk management processes is focus of ISO14155:20207 2020 Frestedt Incorporated

Clinical Quality Management Quality Management processes include SOPs,computerized quality systems and personnel training Sponsor is responsible for clinical study quality even ifstudy management is outsourced to third-party Document control process for study files such asprotocol, IB, etc. Complete records maintenance Preparation for audits Identify, justify and document exceptions torequirements8 2020 Frestedt Incorporated

European Regulations European Medical Device Regulation (EU MDR2017/745) implementation is currently ongoing Aim is to increase patient benefit risk ratio byincreasing clinical data requirements ISO 14155:2020 Annex ZC details how “GeneralSafety and Performance Requirements of Regulation(EU) 2017/745” is addressed / implemented indocument9 2020 Frestedt Incorporated

Scope (1)Addresses good clinical practices (design, conduct, recording,reporting) for clinical investigations in human subjects (clinicalperformance or effectiveness and safety) of medical devices. Protection of subjects Ensure scientific conduct Defines responsibilities of principal investigator (PI), sponsor,other parties10 2020 Frestedt Incorporated

Normative References (2)Normative documents are referred to in the text so their content isrequired for this document. ISO 14971, Medical devices – Application of risk management tomedical devices11 2020 Frestedt Incorporated

Terms and Definitions (3)ISO and IEC maintain terminological databases for standardization ISO : IEC: used terms: Adverse Event (AE) Case Report Form (CRF) Medical Device (software, reagent for in vitro use, etc.)* Some jurisdictions have different criteria for medical devices (invitro devices, devices with animal/human tissue)12 2020 Frestedt Incorporated

Summary of Good Clinical Practice (GCP)Principles (4) 13Ethical principlesRisk-benefit ratioRights, safety, well-being of subjectsScientifically soundEthics Committee (EC) approvalExpert advice and careEducation/experiencePrivacy, confidentialitySystems for quality control 2020 Frestedt Incorporated

Ethical Considerations (5)Principles in Clause 4 must be understood, observed and applied inevery step in the clinical investigation. Coercion Compensation Registration and public access Responsibilities (all parties) Communication with EC (use this document and record) Information from EC (approval documents) Informed consent images/coursera/vacctrials.png14 2020 Frestedt Incorporated

EC Responsibility (Annex G)Provides guidance on best practices for operation of EC reviewingclinical investigations of medical devices. Purpose of ECComposed of members who collectively haveexperience/qualification to review/evaluate scientific medical,methodological, statistical and ethical aspects of proposed clinicalinvestigation Members Procedures/records15 2020 Frestedt Incorporated

Clinical Development Stages (Annex I)Provides possible types of clinical investigations in different clinicaldevelopment stages and from a regulatory status applies to both preand post-market clinical investigations. Pre-market clinical investigation Post-market clinical investigation Clinical development stages (pilot, pivotal and post-marketstage) Types of clinical investigation design (Exploratory, confirmatoryand observational)16 2020 Frestedt Incorporated

Clinical Development Stages (Annex I) Description of clinical investigations First in human clinical investigation Early feasibility clinical investigation Traditional feasibility clinical investigations Pivotal clinical investigation Registry17 2020 Frestedt Incorporated

Clinical Development Stages (Annex I)APPLICABILITY OF THIS DOCUMENT’S PRINCIPLESThe principles of this document are expected to protect humansubject’s rights, safety and well-being, scientific outcome andcredibility of clinical data and overall risk management of clinicalinvestigation of medical /18 2020 Frestedt Incorporated

Clinical Investigation Planning (6)General (6.1) All involved with trial design and conduct must bequalified by education, training or experience. Qualifications must be documented The sponsor must have access to medical expertiserelevant to the 19 2020 Frestedt Incorporated

Risk Management (6.2)Balance risks associated with device and related clinicalprocedure (including follow-up) against anticipatedbenefits to subjectsThe sponsor should predefine risk acceptability thresholds If threshold is reached or exceeded, risk assessment todetermine whether/what actions are needed20 2020 Frestedt Incorporated

Application of ISO 14971 (6.2, Annex H)ISO14971 about risk managementfor medical devicesISO14971activitiesRisk control effectivenessevaluated through devicelifecycle, including during trialsTrials provide data tosupport/refute acceptability ofbenefit-risk ratio21 2020 Frestedt IncorporatedISO 14155Activities

Design of Clinical Investigation (6.3)Design trial to evaluate if device suitable forintended purpose and population.Design based on pre-clinical data and clinicalevaluation, aligned with risk assessment Clinical evaluation includes analysis ofclinical performance, effectiveness andsafety data of investigational device orsimilar device Use to justify endpoints, confoundingfactors, choice of control group(s), biasminimization, subject selection22 2020 Frestedt Incorporated

Clinical Investigation Plan (CIP) (6.4,Annex A) 23Identification of CIP, Sponsor, principle investigator, coordinating investigator andinvestigation sites Objectives and hypothesis of clinical investigationSynopsis of investigationIdentification and description of investigational device Design of clinical investigation including: Investigation device(s) and comparator(s) Subjects (e.g. inclusion/exclusion criteria) Procedures Monitoring Plan Justification of designStatistical design and analysis Data management (e.g. methods for data entry and collection, procedures for databasecleaning)Benefits and risks of investigational device,clinical procedure and clinical investigationDescription of procedures to amend CIPDeviations from CIP (e.g. Statement sayingcannot deviate except as specified, proceduresof recording and reporting deviations)Device accountabilityStatements of ComplianceInformed Consent ProcessAdverse events, adverse device effects, devicedeficienciesVulnerable Populations (if applicable)Suspension or premature termination ofinvestigationPublication PolicyBibliography 2020 Frestedt Incorporated

Investigator’s Brochure (IB) (6.5, AnnexB)Purpose: To provide principal investigator andinvestigation site team with sufficient safety andperformance data to justify human exposure toinvestigational device Principal investigator(s) acknowledge receipt in writing andkeep confidentialUpdate throughout investigation as new data becomesavailableUpdate if investigational device design changes24 2020 Frestedt Incorporated

IB Components (Annex B)Identification of IBSponsor/ManufacturerInvestigational deviceinformationPreclinical TestingExisting Clinical DataRisk Management ofinvestigational deviceRegulatory and otherreferences25 2020 Frestedt Incorporated

Case Report Form (CRF) (6.6, Annex C)Captures data for each enrolled subject Condition of each subject at beginning and throughout investigation Exposure to investigational device and other therapiesFormat should minimize errors e.g. To avoid repeat entries, pre-print or pre-program elements such as name ofclinical investigation, CRF version #, investigator identification numberCRF completion guidelines provide instructions for accuratecompletion, correction and signature of CRFsIf CIP amended, CRFs should be reviewed to determine if needrevised26 2020 Frestedt Incorporated

Risk DisclosureBenefit-risk summary should be disclosed in relevant trialdocuments. For example: Residual risk in Investigator’s Brochure (IB) andInstructions for Use (IFU) All anticipated AE device effects in ClinicalInvestigation Plan (CIP) and Informed Consent Form(ICF) Rationale for benefit-risk ratio in CIP27 2020 Frestedt Incorporated

Monitoring Plan (6.7)Determine appropriate monitoring based on riskassessment.oMonitoring methods can differ between countries and should complywith national or regional regulations regarding personal data protectionMonitoring Plan describes:28Risks and riskcontrol measuresMonitoringmethods [e.g. onsite, centralized(off-site)]Methods fordocumenting andcommunicatingmonitoring resultsEscalation processif continuous oregregious noncomplianceAspects ofinvestigationneeding specialattentionProcesses to bemonitored and datato be verified insource documents 2020 Frestedt Incorporated

Investigation Site Selection (6.8)Identify criteria necessary for successful conduct of clinicalinvestigation prior to start of site qualification, e.g.: Facilities requiredPrincipal investigator’s qualificationsType of environment (e.g. home-based vs hospital)Principal investigator(s) qualifications and investigation site(s)adequacy verified and documented in investigation siteselection report29 2020 Frestedt Incorporated

Agreements (6.9)Written agreement between sponsor and principalinvestigator(s)/investigation site(s) and other relevantparties (e.g. laboratories, CROs) should be signed anddated by all partiesAgreement should detail responsibilities of each partyAgreement should identify instances where parties shareregulatory responsibilities with sponsor30 2020 Frestedt Incorporated

Labeling (6.10)The device, IFU and packaging should state device isexclusively for use in a clinical investigation. In US,investigational label as per 21 CFR 812.5:"CAUTION-Investigational device.Limited by Federal (orUnited States) law toinvestigational use."31 2020 Frestedt Incorporated

Clinical Investigation Conduct (7)General (7.1) Conducted in accordance with CIP Not to commence until EC and/or regulatory approvalsare /800288529232 2020 Frestedt Incorporated

Investigation Site Initiation (7.2)Initiation visit for each investigation site or an investigatormeeting shall be conducted and documented by sponsor ormonitor at start of the clinical investigation. Log with names, initials, signatures, functions anddesignated authorizations for principal investigatorand members of investigation site team This may be done by telephone or other means33 2020 Frestedt Incorporated

Investigation Site Monitoring (7.3) Conduct of clinical investigation monitored accordingto monitoring plan All monitoring activities documented34 2020 Frestedt Incorporated

Adverse Events and Device Deficiencies(7.4)7.4.1 AE or device deficiencies potentially indicating aserious health threat are evaluated by sponsor. Mayrequire a specific reporting process according toregulatory requirements.7.4.2 All AE and any new information are documented ina timely manner and reported as specified (see AECategorization). All AE are reported in interim andfinal reports.35 2020 Frestedt Incorporated

Adverse Events and Device Deficiencies(7.4)- continued7.4.3 Device deficiencies documented throughout clinicalinvestigation and managed by sponsor as specifiedfor control of non-conforming product. All deficientdevices are returned for evaluation and reportssubmitted even if deficiency did not cause AE butcould have caused serious AE36 2020 Frestedt Incorporated

Adverse Events and Device Deficiencies(7.4)- continued7.4.4 Arising risks during clinical investigationa) Any person identifying risk potentially impacting safety informsprincipal investigator and sponsorb) Sponsor shall perform risk analysis with principal investigator todetermine if information is reflected in current risk assessment andrisks remain acceptable. If unacceptable, and serious health threatidentified, sponsor shall suspend trial immediately.c) If a possible unacceptable risk, sponsor shall conduct risk assessmentin compliance with ISO 14971 with possibility of 1) risks remainacceptable, 2) corrective actions found not affecting validity ofinvestigation with revised benefit-risk may continue investigation, 3)if corrective actions affect validity of trial, trial is to be terminated, 4)if no corrective actions may be applied, investigation is to beterminated.37 2020 Frestedt Incorporated

Clinical Investigation Documents (7.5) Amendments are made as needed throughoutinvestigation following written procedures withdocumentation reviewed and approved as specified. Subject identification log maintained at eachinvestigation site with an identification code linked totheir private information Source documents are maintained by investigation siteteam throughout clinical investigation38 2020 Frestedt Incorporated

Additional Members of the InvestigationSite Team (7.6)New members added to investigational site teams willonly start their assignment after receiving adequatetraining and training is %20Buyer.png39 2020 Frestedt Incorporated

Subject Privacy and Confidentiality ofData (7.7) Confidentiality observed by all involved parties anddata is secured against unauthorized access. Privacy of subjects is preserved in all reports andpublications.40 2020 Frestedt Incorporated

Document and Data Control (7.8)Traceability of Documents and DataAll documents produced and maintained ensuring reliability,integrity, control and traceability including all versions ofdocuments. Source documents are verified and signed.Recording of DataData on CRFs from source documents and discrepanciesexplained in writing. All CRFs are signed and dated.Electronic Clinical Data SystemsWritten procedures are used to describe system validation,data collection, security, backup and recovery. Ensure nodeletion of entered data and changes can be followed via anaudit trail.41 2020 Frestedt Incorporated

Investigational Device Accountability (7.9) a)b)c)d)e)f)g)42Access to devices is controlled and only used in the clinicalinvestigation following the CIP.Physical location of all devices documentedRecords shall be kept on:name of person received, used, returned or disposed of devicedate of receipt, identification and quantity of devicesexpiry date if applicabledate(s) of usesubject identificationdate device returned or explanted from subjectreturn date of unused, expired or malfunctioning devices 2020 Frestedt Incorporated

Accounting for Subjects (7.10) All subjects accounted for and documented If subject discontinues, the reason(s) shall be recorded Investigator may use existing data on the subject andmay ask for permission to obtain [email protected]/3377207497243 2020 Frestedt Incorporated

Auditing (7.11, Annex J) Audits may be conducted to evaluate compliance toCIP, written procedures, ISO 14155 and applicableregulatory requirements Audits may cover all involved parties and are separatefrom quality control or routine monitoring functions Auditors shall be independent of the clinicalinvestigation Audit results are documented and communicated torelevant parties.44 2020 Frestedt Incorporated

Suspension, Termination, and Close-Outof the Clinical Investigation (Section 8)8.1 Completion of clinical investigation may be prespecified by the plan or terminated earlyCompletion coincides with: Last visit of the last subject When follow up is complete45 2020 Frestedt Incorporated

Suspension or Premature Termination (8.2)May suspend entire investigation or single site May be suspended or terminated by: sponsor, principalinvestigator, EC or regulatory authority Justify in writing and inform all parties Reasons for suspension or termination: Suspicion of unacceptable risko Suspend for risk assessment, terminate if risk is unacceptableSerious or repeated deviations by investigator Sponsor is responsible for obligations to participants46 2020 Frestedt Incorporated

Resuming After Temporary Suspension (8.2.2)After problem analysis and corrective actions in place: Inform principal investigators (PI), ECs and regulatoryauthorities (when applicable) Provide with reasoning and supporting data ECs and regulatory authorities (when applicable) mustconcur BEFORE clinical investigation -approved.gif47 2020 Frestedt Incorporated

Routine Close-Out (8.3)Close-out activities: PI records and sponsor’s file complete and up to date Case Report Forms (CRF) complete, Adverse Event (AE)status documentedRecord retention and archival arrangements in place Remaining materials disposed of Devices, samples, other materials All identified issues resolved All parties notified 48EC, regulatory body (if applicable), study database 2020 Frestedt Incorporated

Clinical Investigation Report (8.4)Report for all clinical investigations should follow Annex D Include:

ISO 14971:2019 Application of risk management to medical devices Major components include: Risk management system Risk analysis Risk evaluation Risk control Evaluation of residual risk Risk Ma