EN ISO 14155-1:2009

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.Klinische Prüfung von Medizinprodukten an Menschen - Teil 1: Allgemeine Anforderungen (ISO 14155-1:2003)Investigation clinique des dispositifs médicaux pour sujets humains - Partie 1: Exigences générales (ISO 14155-1:2003)Clinical investigation of medical devices for human subjects - Part 1: General requirements (ISO 14155-1:2003)11.040.01Medicinska oprema na splošnoMedical equipment in generalICS:Ta slovenski standard je istoveten z:EN ISO 14155-1:2009SIST EN ISO 14155-1:2009en01-december-2009SIST EN ISO 14155-1:2009SLOVENSKI
STANDARDSIST EN ISO 14155-1:20031DGRPHãþD

EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMEN ISO 14155-1July 2009ICS 11.100.20Supersedes EN ISO 14155-1:2003
English VersionClinical investigation of medical devices for human subjects -Part 1: General requirements (ISO 14155-1:2003)Investigation clinique des dispositifs médicaux pour sujetshumains - Partie 1: Exigences générales (ISO 14155-1:2003)Klinische Prüfung von Medizinprodukten an Menschen -Teil 1: Allgemeine Anforderungen (ISO 14155-1:2003)This European Standard was approved by CEN on 27 June 2009.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this EuropeanStandard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such nationalstandards may be obtained on application to the CEN Management Centre or to any CEN member.This European Standard exists in three official versions (English, French, German). A version in any other language made by translationunder the responsibility of a CEN member into its own language and notified to the CEN Management Centre has the same status as theofficial versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre:
Avenue Marnix 17,
B-1000 Brussels© 2009 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. EN ISO 14155-1:2009: ESIST EN ISO 14155-1:2009

Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 SIST EN ISO 14155-1:2009

Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices
This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 93/42/EEC on medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZA confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/NotesA.2.5 Annex X:
1.1.1 This requirement is also addressed in 4.5.1 of EN 14155-2:2003 11 Annex X: 1.1.2 This requirement is also addressed in 4.5.3 of EN 14155-2:2003
Annex X: 1.1.a) This requirement is not addressed in this standard 7 Annex X: 1.1.b) This requirement is partly addressed in this standard
Annex X: 1.1.c) This requirement is not addressed in this standard
Annex X: 1.1.d) This requirement is not addressed in this standard 5 Annex X: 2.2
6.3 Annex X: 2.3.1 Entire EN 14155-2 6.4 Annex X: 2.3.2 This requirement is also addressed in 4.7 of EN 14155-2:2003 6.4 Annex X: 2.3.3 This requirement is also addressed in 4.7 of EN 14155-2:2003
Annex X: 2.3.4 This requirement is not addressed in this standard
This requirement is addressed in 4.5.4 of EN 14155-2:2003 8.2 i) Annex X: 2.3.5 This requirement is also addressed in 4.11 of EN 14155-2:2003 10.2 a) Annex X: 2.3.6
11.2 Annex X: 2.3.7
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 90/385/EEC on active implantable medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZB confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/NotesA.2.5 Annex 7:
1.1.1 This requirement is also addressed in 4.5.1 of EN 14155-2:2003 11 Annex 7: 1.1.2 This requirement is also addressed in 4.5.3 of EN 14155-2:2003 A.2.5 Annex 7: 1.2
7 Annex 7: 1.3
Annex 7: 1.4 This requirement is not addressed in this standard
Annex 7: 1.5 This requirement is not addressed in this standard 6.3 Annex 7: 2.3.1 Entire EN 14155 6.4 Annex 7: 2.3.2 This requirement is also addressed in 4.7 of EN 14155-2:2003 6.4 Annex 7: 2.3.3 This requirement is also addressed in 4.7 of EN 14155-2:2003 6.5 Annex 7: 1.6
Annex 7: 2.3.4 This requirement is not addressed in this standard
This requirement is addressed in 4.5.4 of EN 14155-2:2003 8.2 i) Annex 7: 2.3.5 This requirement is also addressed in 4.11 of EN 14155-2:2003 10.2 a) Annex 7: 2.3.6
11.2 Annex 7: 2.3.7
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard. SIST EN ISO 14155-1:2009

Reference numberISO 14155-1:2003(E)© ISO 2003
INTERNATIONAL STANDARD ISO14155-1First edition2003-02-15Clinical investigation of medical devices for human subjects —
Part 1: General requirements Investigation clinique des dispositifs médicaux pour sujets humains —
Partie 1: Exigences générales
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ii © ISO 2003 — All rights reserved
ISO 14155-1:2003(E) © ISO 2003 — All rights reserved iii Contents Page Foreword.v Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.2 4 Justification for a clinical investigation.5 5 Ethical considerations.5 5.1 Declaration of Helsinki.5 5.2 Improper influence or inducement.5 5.3 Compensation and additional health care.5 5.4 Responsibilities.5 6 General requirements.5 6.1 Formal agreement(s).5 6.2 Qualifications.5 6.3 Clinical investigation plan.6 6.4 Design of the clinical investigation.6 6.5 Confidentiality.6 6.6 Start of clinical investigation.6 6.7 Informed consent.6 6.8 Suspension or early termination of the clinical investigation.8 6.9 Document and data control.8 6.10 Accounting for subjects.9 6.11 Access to preclinical and clinical information.9 6.12 Auditing.9 7 Documentation.9 7.1 General.9 7.2 Clinical investigator's brochure.9 7.3 Other documents.10 8 Sponsor.10 8.1 General.10 8.2 Responsibilities of sponsor.10 9 Monitor.11 9.1 Responsibilities of monitor.11 10 Clinical investigator.12 10.1 General.12 10.2 Qualification of clinical investigator.12 10.3 Responsibilities of clinical investigator.12 11 Final report.14 11.1 Presentation of results.14 11.2 Contents of the final report.14 SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) iv © ISO 2003 — All rights reserved Annex A (informative)
Suggested procedure for literature review.15 Annex B (informative)
Information for the ethics committees.17 Annex C (informative)
Final reports of clinical investigations with medical devices.18 Bibliography.21
ISO 14155-1:2003(E) © ISO 2003 — All rights reserved v Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2. The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 14155-1 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This first edition of ISO 14155-1, together with ISO 14155-2, cancels and replace ISO 14155:1996, which has been technically revised. ISO 14155 consists of the following parts, under the general title Clinical investigation of medical devices for human subjects:  Part 1: General requirements  Part 2: Clinical investigation plans SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) vi © ISO 2003 — All rights reserved Introduction This part of ISO 14155 is intended to be applied worldwide to clinical investigations of medical devices in order to fulfil the technical aspects of the various national, regional and international regulatory requirements. As the legal regulatory requirements presently differ throughout the world, regulatory specifics have been excluded from the scope of this part of ISO 14155. They are part of national or regional legislative texts and can be referenced in the national or regional forewords, as appropriate.
INTERNATIONAL STANDARD ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 1 Clinical investigation of medical devices for human subjects — Part 1: General requirements 1 Scope This part of ISO 14155 defines procedures for the conduct and performance of clinical investigations of medical devices. It specifies general requirements intended to  protect human subjects,  ensure the scientific conduct of the clinical investigation,  assist sponsors, monitors, investigators, ethics committees, regulatory authorities and bodies involved in the conformity assessment of medical devices. This part of ISO 14155 a) specifies requirements for the conduct of a clinical investigation such that it establishes the performance of the medical device during the clinical investigation intended to mimic normal clinical use, reveals adverse events under normal conditions of use, and permits assessment of the acceptable risks having regard to the intended performance of the medical device, b) specifies requirements for the organization, conduct, monitoring, data collection and documentation of the clinical investigation of a medical device, c) is applicable to all clinical investigation(s) of medical devices whose clinical performance and safety is being assessed in human subjects. This part of ISO 14155 is not applicable to in vitro diagnostic medical devices. 2 Normative references The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 14155-2, Clinical investigation of medical devices for human subjects — Part 2: Clinical investigation plans SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) 2 © ISO 2003 — All rights reserved 3 Terms and definitions For the purposes of this document, the following terms and definitions apply. 3.1 adverse device effect any untoward and unintended response to a medical device NOTE 1 This definition includes any event resulting from insufficiencies or inadequacies in the instructions for use or the deployment of the device. NOTE 2 This definition includes any event that is a result of a user error. 3.2 adverse event any untoward medical occurrence in a subject NOTE This definition does not imply that there is a relationship between the adverse event and the device under investigation. 3.3 case report form document designed to record all information to be reported to the sponsor on each subject as required by the clinical investigation plan 3.4 clinical investigation any designed and planned systematic study in human subjects undertaken to verify the safety and/or performance of a specific device 3.5 clinical investigation plan CIP document that states the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct and record-keeping of the clinical investigation NOTE The word “protocol” is often used synonymously with the term “clinical investigation plan”. However, it has many different meanings, some not related to clinical investigations, and these may differ from country to country. Therefore, it is not used in this part of ISO 14155. 3.6 clinical investigator individual and/or institution responsible for the conduct of a clinical investigation who and/or which takes the clinical responsibility for the well-being of the subjects involved NOTE Whether this is an individual or an institutional responsibility may depend on national legislation. 3.7 clinical investigator's brochure compilation of the clinical and non-clinical information on the device(s) under investigation, that is relevant to the investigation in human subjects 3.8 clinical performance behaviour of a specific medical device and/or its performance in relation to its intended use when correctly applied to appropriate subjects 3.9 coordinating clinical investigator clinical investigator who is appointed by the sponsor to coordinate work in a multicentre clinical investigation SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 3 3.10 ethics committee independent and properly constituted competent body whose responsibility is to ensure that the safety, well-being and human rights of the subjects participating in a clinical investigation are protected NOTE For the purposes of this part of ISO 14155, “ethics committee” is synonymous with “research ethics committee” or “institutional review board”. The regulatory requirements pertaining to ethics committees or similar institutions may differ from country to country. 3.11 final report description, results and evaluation of the clinical investigation after its completion 3.12 informed consent legally effective, documented confirmation of a subject's (or his/her legal guardian or representative) voluntary agreement to participate in a particular clinical investigation after information has been given to the subject on all aspects of the clinical investigation that are relevant to the subject's decision to participate 3.13 investigation centre investigation site institution or site where the clinical investigation is carried out 3.14 medical device any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application, intended by the manufacturer to be used on human beings for the purpose of  diagnosis, prevention, monitoring, treatment or alleviation of disease,  diagnosis, monitoring, treatment, alleviation or compensation for an injury or handicap,  investigation, replacement or modification of the anatomy or of a physiological process,  control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. NOTE The term “medical device” is usually defined by national law. In order to inform the user of this part of ISO 14155, the definition from reference [1] is listed (see Bibliography). More information is given in reference [3]. 3.15 monitor individual appointed by the sponsor responsible for assessing the investigator's compliance with the clinical investigation plan and for performing source-data verification NOTE The monitor is also responsible for reporting to the sponsor on the progress of the clinical investigation, including the compliance of the investigators. 3.16 multicentre investigation clinical investigation which is conducted according to a single clinical investigation plan and which takes place at two or more sites 3.17 principal clinical investigator clinical investigator responsible for the organization of the clinical investigation at one site SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) 4 © ISO 2003 — All rights reserved 3.18 serious adverse device effect adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event or that might have led to any of these consequences if suitable action had not been taken or intervention had not been made or if circumstances had been less opportune 3.19 serious adverse event adverse event that a) led to a death, b) led to a serious deterioration in the health of the subject that 1) resulted in a life-threatening illness or injury, 2) resulted in a permanent impairment of a body structure or a body function, 3) required in-patient hospitalization or prolongation of existing hospitalization, 4) resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function. c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 3.20 source data all information in original and identified records and certified copies of original records of clinical findings, observations, or other activities in a clinical investigation, necessary for the reconstruction and evaluation of the clinical investigation 3.21 source documents original documents, data and records NOTE This may be for example, hospital records, laboratory notes, pharmacy dispensing records, copies or transcriptions certified after verification as being accurate copies, photographic negatives, radiographs, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical investigation. 3.22 sponsor individual or organization who or which takes responsibility for the initiation and/or implementation of a clinical investigation NOTE 1 For the purposes of this part of ISO 14155 the word “sponsor” is synonymous with the word “promoter”. NOTE 2 When a clinical investigator independently initiates, implements and takes full responsibility for the clinical investigation, the clinical investigator also assumes the role of the sponsor. 3.23 subject individual who participates in a clinical investigation, either as a recipient of the device under investigation or as a control SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 5 4 Justification for a clinical investigation In order to determine the justification and optimal design for a clinical investigation, an objective review of published and available unpublished medical and scientific data and information shall be conducted and documented. NOTE 1 Guidance for such a literature review is given in Annex A. The decision to embark upon a clinical investigation of a medical device requires inter alia the residual risks to be balanced against the anticipated benefits of the clinical investigation. NOTE 2 For further information, see ISO 14971[6]. 5 Ethical considerations 5.1 Declaration of Helsinki
The rights, safety and wellbeing of clinical investigation subjects shall be protected consistent with the ethical principles laid down in the Declaration of Helsinki. This shall be understood, observed and applied at every step in the clinical investigation. 5.2 Improper influence or inducement The sponsor and the clinical investigator(s) shall avoid improper influence or inducement of the subject, monitor, the clinical investigator(s) or other parties participating in or contributing to the clinical investigation. 5.3 Compensation and additional health care The sponsor shall state what provision will be made for compensation of subjects in the event of injury arising from participation in the clinical investigation and this shall be documented. Arrangements for additional health care for subjects required as a result of an adverse device effect shall be made and documented. NOTE This may be the subject of national legislation. 5.4 Responsibilities All parties involved in the conduct of the clinical investigation shall share the responsibility for its ethical conduct in accordance with their respective roles in the investigation. 6 General requirements 6.1 Formal agreement(s) There shall be agreement(s) between the sponsor, the clinical investigator(s) and other relevant parties which define(s) their responsibilities. All formal agreements shall be recorded in writing and signed by all parties involved. 6.2 Qualifications All parties participating in the conduct of the clinical investigation shall be appropriately qualified by education and/or experience to perform their tasks. SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) 6 © ISO 2003 — All rights reserved 6.3 Clinical investigation plan A clinical investigation plan shall be compiled in accordance with ISO 14155-2. 6.4 Design of the clinical investigation The clinical investigation shall be designed to evaluate whether the device is suitable for the purpose(s) and the population(s) for which it is intended. It shall be designed in such a way as to ensure that the results obtained have clinical relevance and scientific validity and will support the clinical investigation objectives. 6.5 Confidentiality At all times throughout the clinical investigation confidentiality shall be observed by all parties involved. All data shall be secured against unauthorized access. Privacy and confidentiality of information about each subject shall be preserved in the reports and any publication of the clinical investigation data. Lists of subjects' names and identifying information should, wherever possible, be maintained separately from case report forms. 6.6 Start of clinical investigation No clinical investigation shall start until a) a clinical investigation plan has been written and signed, b) the opinion and/or approval of the ethic(s) committee(s) has been obtained, c) regulatory clearance or approval, if applicable, has been obtained. 6.7 Informed consent 6.7.1 General Informed consent shall be obtained in writing and documented before a subject is enrolled into the clinical investigation. NOTE The consent form usually consists of an information part and an approval/signature part. These two parts can either be combined in one document (patient information and consent form) or separated into a patient information sheet and a patient consent form. 6.7.2 Process of obtaining informed consent The process of obtaining informed consent shall a) avoid any coercion of or undue influence of subjects to participate, b) not waive or appear to waive subject’s legal rights, c) use language that is non-technical and understandable to the subject or his/her legal representative, d) provide ample time for the subject to consider participation, e) include dated signatures of the subject or the subject's legal representative and of the clinical investigator, SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 7 f) show how informed consent will be obtained and recorded in circumstances in which the subject is unable to give it, NOTE A subject intended for the participation in a clinical investigation may be unable to make the necessary decisions (foetus, infant, child and juvenile, the seriously ill or unconscious, mentally ill, mentally handicapped). In such circumstances, informed consent can only be given by the legal guardian or representative. g) be documented in the clinical investigation plan. 6.7.3 Information to be provided to the subject for the purpose of obtaining informed consent At least the following information shall be provided in writing and in non-technical language that is understandable to the subject (or the subject's legal representative): a) description/purpose: 1) the investigation involves research; 2) the objective of the investigation; 3) the anticipated duration and involvement of subject participation in the investigation; 4) description of the device under investigation ; 5) description of procedures, emphasising any that are experimental. b) foreseeable risks: 1) description of any foreseeable risks and inconveniences; 2) possible side effects. c) potential benefits: 1) description of potential benefits to the subjects; 2) description of potential benefits to others. d) alternative therapy: 1) information on alternative treatments or procedures available. e) confidentiality: 1) statement that subject participation is confidential; 2) statement that subject allows access to medical records by regulatory authorities and sponsor’s delegates; 3) statement that investigation results may be published without disclosing the subject’s identity. f) compensation (medical/financial): 1) information about provisions for compensation in the event of injury arising from participation in the clinical investigation and additional health care to be provided to subjects as a result of an adverse device effect; 2) information on financial compensation for participation, if applicable. SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) 8 © ISO 2003 — All rights reserved g) questions and/or termination: 1) whom to contact with questions about the investigation; 2) whom to contact in the event of injury; 3) circumstances under which subject’s participation may be terminated by the investigator, if applicable. h) new findings: 1) statement that new findings relevant to the subject’s confirmed participation shall be made available. 6.7.4 Informed consent statement The statement of informed consent shall contain the following in writing: a) statement that subject's participation is voluntary; b) statement that refusal of participation incurs no penalty for the subject; c) statement that discontinuation at any time incurs no penalty for the subject; d) statement on possible consequences of withdrawal; e) acknowledgement of the information provided. 6.7.5 Informed consent agreement In signing the consent form, the subject or his/her legal representative shall a) agree to participate in and comply with the clinical investigation, b) agree to his/her personal physician being informed of his/her participation, or state his/her disagreement to the release of this information, c) agree to the use of his/her relevant personal data for the purpose of
the clinical investigation. 6.8 Suspension or early termination of the clinical investigation If an investigation is terminated prematurely or suspended, the sponsor shall promptly inform the clinical investigators/investigation centres of the termination or suspension and the reason(s) for this. The ethics committee shall also be informed promptly and provided with the reason(s) for the termination or suspension by the sponsor or by the clinical investigator/investigation centres. NOTE Depending on the type of investigation, regulatory authorities and the personal physicians of the subjects may also need to be informed. 6.9 Document and data control All documents and data shall be produced and maintained in such a way as to assure control of documents and data and to protect the subject's privacy as far as reasonably practicable. A case report form shall be developed to capture the data for the individual subject required by the clinical investigation plan. SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 9 6.10 Accounting for subjects All subjects enrolled in the clinical investigation (including those withdrawn from the investigation or lost to follow-up) shall be accounted for and documented. 6.11 Access to preclinical and clinical information Each clinical investigator taking part in the clinical investigation shall have the right of access to the relevant preclinical and safety information. All information given shall be kept confidential. The monitor shall have access to the source documents and other information needed to ensure investigator compliance with the clinical investigation plan and applicable rules and regulations, and to assess the progress of the clinical investigation. 6.12 Auditing The clinical investigator(s) shall allow auditing of their clinical investigation procedures. 7 Documentation 7.1 General Documentation in 7.2 and 7.3 shall be prepared before commencement of the clinical investigation. The information supplied to the clinical investigator shall be documented. 7.2 Clinical investigator's brochure The clinical investigator's brochure shall contain a) a summary of the literature and an evaluation supporting the rationale for the intended use of the device and the design of the clinical investigation, b) a general description of the device and its components in accordance with ISO 14155-2, c) a description of the mechanism of action of the device, along with supporting scientific literature including, if relevant, the manufacturer's instructions for use and installation, This should include possible risks, contra-indications, warnings, etc. for the device. d) a description of the intended clinical performance, e) a description of the materials used in the device, f) a summary and evaluation of the in vitro and/or ex vivo and/or in vivo data relevant to the device, including preclinical data such as biological studies, non-clinical laboratory studies and any animal studies, g) a summary of relevant previous clinical experience with the device and with other devices with similar features, h) a list of International Standards, if any, complied with in full or in part, i) results of the risk analysis. The clinical investigator's brochure shall be updated throughout the course of the clinical investigation as significant new information becomes available, and shall be communicated to the investigators. SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) 10 © ISO 2003 — All rights reserved 7.3 Other documents As a minimum, the following documents shall be maintained in investigator and/or sponsor files: a) the clinical investigation plan; b) a current, signed and dated curriculum vitae of each of the clinical investigators; c) the name(s) of the institution(s) in which the clinical investigation will be conducted; d) the ethics committee opinion and/or approval, in writing, and relevant correspondence; e) correspondence with authorities as required by national legislation; f) the agreement between the principal and coordinating investigator(s) and the sponsor; g) appropriate insurance certificates, if applicable; h) informed consent forms and other information provided to the subjects; i) case report forms; j) forms for reporting adverse events and adverse device effects; k) names/contact addresses of monitor(s). 8 Sponsor 8.1 General Prior to initiating a clinical investigation, the sponsor shall define, establish, allocate and communicate all investigation-related duties and functions. The sponsor shall ensure documentation of the compliance of the investigator, sponsor and monitor with this part of ISO 14155, the applicable clinical investigation plan and subsequent amendments and with all applicable regulatory requirements through a quality system. 8.2 Responsibilities of sponsor The sponsor shall a) select the clinical investigator(s) and investigation centre(s) for the particular investigation, and if appropriate a coordinating clinical investigator, b) select and appoint a monitor for the clinical investigation or otherwise assume the responsibilities of the monitor, The ultimate responsibility for monitoring remains with the sponsor even if those activities are outsourced or delegated. Instructions should be available from the sponsor to the monitor on how to handle non-compliances and missing data. c) prepare, and keep up to date, the clinical investigator's brochure, d) provide the clinical investigator with the clinical investigation plan and subsequent approved amendments, and with the clinical investigator's brochure, e) sign the approved clinical investigation plan, SIST EN ISO 14155-1:2009

ISO 14155-1:2003(E) © ISO 2003 — All rights reserved 11 f) supply fully characterized devices which are the subject of the clinical investigation, g) ensure that appropriate information and/or training is given to the clinical investigator, if necessary, in the use of the device in accordance with the clinical investigation plan, h) ensure that all deviations from the clinical investigation plan are reviewed with the appropriate clinical investigator(s) and reported in the case report forms and the final report for the clinical investigation, i) ensure that all adverse events and all adverse device effects are reported and reviewed with the clinical investigator(s) and, where appropriate, that all serious adverse events and all serious adverse device effects are reported to the relevant authorities and ethics committee(s) and/or safety monitoring committee(s), j) during the course of the clinical investigation, inform in writing all principal clinical investigators about all serious adverse events and all serious adverse device effects occurring in (multicentre) clinical investigations, that have been reported to the sponsor. This information shall be sent to the clinical investigator(s) based on perceived risk, k) promptly inform the clinical investigator(s), when a clinical investigation is prematurely terminated or suspended, and, where applicable, inform the regulatory authority(ies) and ethics committee(s) of the termination or suspension and the reason(s) for the termination or suspension, l) inform the clinical investigator(s) of the developmental status of the device and the requirements necessary to verify the performance and the safety of the device, m) review and approve any deviation from the clinical investigation plan and take any appropriate corrective or preventive actions, n) collect, store, keep secured and ensure completion by the relevant parties of the following documents: 1) all documents listed in Clause 7 (documentation); 2) copies of signed and dated case report form(s); 3) records of any adverse events and adverse device effects reported to the sponsor during the clinical investigation; 4) any statistical analyses and underlying supporting data; 5) final report of the clinical investigation. o) ensure accurate device accountab
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