MEDICINES CONTROL COUNCIL

Transcription

1 MEDICINES CONTROL COUNCIL REGISTRATION OF AN IN VITRO DIAGNOSTIC (IVD) MEDICAL DEVICE TECHNICAL DOSSIER This guideline is intended to provide recommendations to applicants wishing to submit applications for the registration of an IVD medical device. It represents the Medicines Control Council s current thinking on the safety, quality and performance of medical devices. It is not intended as an exclusive approach. Council reserves the right to request any additional information to establish the safety, quality and performance of a medical device in keeping with the knowledge current at the time of application. Alternative approaches may be used but these should be scientifically and technically justified. The MCC is committed to ensure that all registered medical devices will be of the required safety, quality and performance. It is important that applicants adhere to the administrative requirements to avoid delays in the processing and evaluation of applications. Guidelines and application forms are available from the office of the Registrar of Medicines and the website. First publication released for comment June 2017 Due date for comment 31 October 2017 Use the Guideline Comments Form 1 available on the MCC website when submitting comments. Submit comments in hard copy to the Registrar of Medicines, Civitas Building, Thabo Sehume Street, Pretoria. Alternatively, to Ms Andrea Keyter Julsing at Andrea.Julsing@health.gov.za DR JC GOUWS REGISTRAR Guideline Comments Form Dec08 v1.doc 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 1 of 68

2 TABLE OF CONTENTS Page 1 INTRODUCTION SCOPE DEFINITIONS NUMBERING OF HEADINGS QUALITY MANAGEMENT SYSTEM CHAPTERS (6A & 6B) CONFORMITY ASSESSMENT AND CRITERIA FOR REGISTRATION LANGUAGE REQUIREMENTS ORGANISING DOCUMENTS VOLUME IDENTIFICATION PAGINATION PAPER SIZE FONTS ELECTRONIC DOCUMENTS Submission media OTHER GENERAL NOTES ACRONYMS HIERARCHY PRESENTATION... 8 CHAPTER 1 ADMINISTRATIVE... 9 CHAPTER 2 SUBMISSION CONTEXT CHAPTER 3 NON-CLINICAL EVIDENCE CHAPTER 4 CLINICAL EVIDENCE CHAPTER 5 LABELLING AND PROMOTIONAL MATERIAL CHAPTER 6A QUALITY MANAGEMENT SYSTEM PROCEDURES CHAPTER 6B QUALITY MANAGEMENT SYSTEM DEVICE SPECIFIC INFORMATION UPDATE HISTORY _Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 2 of 68

3 1 INTRODUCTION This guideline provides an internationally harmonized, modular format for use when submitting in vitro diagnostic medical device new applications and applications for amendments to the Medicines Control Council. It is based on the In Vitro Diagnostic Device Market Authorization Table of Contents (IVD MA ToC) dated 30 June 2014 of the International Medical Device Regulators Form (IMDRF). The South African Regulatory authority will monitor the use of these structures and work to continually improve the documents at appropriate intervals based on sufficient use and experience. 2 SCOPE This guideline is for the application for registration of an In Vitro Diagnostic (IVD) medical device. The document is intended to provide guidance for industry for new submissions and applications for amended submissions. 3 DEFINITIONS FULL REPORT - Typically includes a complete, detailed description of the objective of the assessment, the methods and procedures, study endpoint(s), pre-defined pass/fail criteria, deviations, results summary, discussion and conclusions, and may include data. Complete, detailed support of method selection, study endpoint selection, and pass/fail criteria should be included. SUMMARY - Typically includes a brief synopsis of the assessment (1) purpose, (2) methods and (3) results and (4) discussion and conclusions. Outliers and deviations should be reported with the results. The purpose of the assessment and description of methods should address: 1. Why the characteristic being evaluated is of interest; and 2. Why the particular methods are being used to evaluate the characteristic, if applicable including why a South African or harmonized/recognized standard has or has not been complied with. SUBMISSION A regulatory submission can be any type of information related to a medical device regulatory process. This includes but is not limited to a request for registration of a medical device and approval/authorization to market a device, any communications relating to the original submission, and any request for modification to an existing approval. 4 NUMBERING OF HEADINGS Numbering should remain consistent regardless of whether the heading is required or not. For example, if CH1.02 is not required for the submission type or jurisdiction, but s CH1.01 and CH1.03 are, then the numbering would remain CH1.01 followed by CH1.03. Letters should be added to the numbering of custom headings to indicate the sequence of presentation. For example, under stability of samples, CH is a custom heading. It should be presented as shown below. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 3 of 68

4 Figure 1 - Numbering of Custom s 5 QUALITY MANAGEMENT SYSTEM CHAPTERS (6A & 6B) Chapter 6A & B of the Table of Contents (ToC) is written in terms of the quality management system language employed in ISO Chapter 6A is where the company places the standard operating procedures (SOPs) the company utilizes to implement its overall high level quality management system. Chapter 6B is where the company places the documents and records the company utilizes to implement the quality management system SOPs described in Chapter 6A. 6 CONFORMITY ASSESSMENT AND CRITERIA FOR REGISTRATION Refer to the current version of the Conformity Assessment Procedures for Medical Devices and IVDs Guideline issued by the MCC / SAHPRA for details of requirements by class of medical device. Details of the required South African Declaration of Conformity are noted therein. For registration of Class C and Class D medical devices which were not on the market prior to 9 December 2016, and until this guideline is amended by MCC or SAHPRA, documentation to confirm fulfillment of the following minimum international market authorisation criteria is required: Class D medical device: Evidence of market authorisation from at least two (2) of the following regulatory authorities: European Union s European Commission; Health Canada; Medicines Health Regulatory Authority of the United Kingdom - MHRA UK; National Health Surveillance Agency Brazil ANVISA Brazil; Pharmaceutical and Medical Devices Agency - PMDA Japan Therapeutic Goods Administration TGA Australia; United States Food and Drug Administration -USFDA; World Health Organisation (WHO) IVD Pre Qualification Unit. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 4 of 68

5 Class C medical device: Evidence of market authorisation from at least one (1) of the following regulatory authorities: European Union s European Commission; Health Canada; Medicines Health Regulatory Authority of the United Kingdom - MHRA UK; National Health Surveillance Agency Brazil ANVISA Brazil; Pharmaceutical and Medical Devices Agency - PMDA Japan Therapeutic Goods Administration TGA Australia; United States Food and Drug Administration -USFDA; World Health Organisation (WHO) IVD Pre Qualification Unit. This information must be provided in CH 2.7 in the technical dossier as noted in section 13 below. 7 LANGUAGE REQUIREMENTS The submission must be in English. Any translated material submitted should be verified for accuracy. 8 ORGANISING DOCUMENTS Documents can be combined in volumes as long as they are separated by appropriately named tab identifiers. In general, documents from different chapters should not be included in the same volume. Documents from different chapters may be combined in the same volume for amendments consisting of a small number of short documents. Administrative documents (e.g. Application letter) are included in Chapter 1. The organisation of such documents should be consistent with the structure described in this guideline. These administrative documents should ideally be placed in the same volume, separated by tab identifiers. 9 VOLUME IDENTIFICATION Volumes must be numbered by chapter, resulting in a separate set of numbers for each chapter. The labelling of each volume should include: Name of applicant Name of medical device Chapter and Volume number. The volumes in each chapter should be numbered separately and sequentially using the format: x of y volumes, where x is the number for the specific volume and y is the total number of volumes submitted for the respective chapter, e.g. Chapter 3, Vol.1 of 6. Copy number: The copies of the submission should be numbered as copies x of y. Contents: Each volume must also be labelled according to the chapter(s) which it contains. 10 PAGINATION A document is a set of pages, numbered sequentially and divided from other documents by a tab. Page numbering should be at the document level and not at the volume or chapter level. (The entire submission should never be numbered consecutively by page.) In general, all documents should have page numbers. Since the page numbering is at the document level, there should only be one set of page numbers for each document. Cross-referencing to documents should be made by referring to the relevant chapter volume, tab identifier, and page number 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 5 of 68

6 Documents must be printed on both sides of a page, legibility must not be impaired and margin space must be sufficient on both the left and right side, so that information is not obscured when the page is placed in a binder. However, the cover letter and any labelling and package must be copied singlesided. Copying of each document must start on a new page and must be separated from the next document by a tab. 11 PAPER SIZE Standard A4 paper should be used for all submissions. Text and tables should be prepared using margins that allow the document to be printed on A4 paper. The left-hand margin should be sufficiently large that information is not obscured through binding. 12 FONTS Font sizes for text and tables should be of a style and size that are large enough to be easily legible, even after photocopying or when provided electronically. Arial 12 point font is preferred for narrative text, but printing in a font size with a legibility equivalent to at least Arial 10 point black on white could be used. The copies, including figures, tables, photo s should be clearly legible. Shading and/or coloured filling/background and/or print, e.g. in tables and headers, or across pages, is unacceptable and should be avoided. 13 ELECTRONIC DOCUMENTS Currently the only information to be submitted in electronic format is the Statistical Data required in Chapters 3 and 4. An electronic copy declaration should be submitted in Annex to confirm that the electronic versions are identical to the PDF included in the dossier. As it is a declaration, it must be signed and dated Submission media Hard media (e.g. CD-ROMs, DVD-ROMs) must be used for the submission of all the statistical data. CD (CD-ROM) conforming to ISO 9660 or ISO can be accepted. The use of re-writable disks is not encouraged. When using re-writable disks, all open sessions must be closed before submitting the CDs/DVDs. The following statement must be included in the letter of application: We confirm that the CD/DVD-burning session is closed and the submission is checked with an up-to-date and state-of-the art virus checker: [name of the antivirus software and version of the virus checker] and is virus-free". Each CD or DVD submitted with the dossier should include the following label information, clearly presented and printed on the media: The applicant s name The medical device name(s) The submission date (MM-YYYY) The relevant chapter numbers The number of CDs or DVDs per full set and an indication of the place of the individual CD/DVD within this set 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 6 of 68

7 14 OTHER GENERAL NOTES This outline of documentation is to support a smooth documentation process. It remains the applicant s responsibility to ensure all regulatory requirements are met, and that clear and transparent evidence of conformity to these requirements are provided. The latest version of the MCC Guidelines for the Essential Principles of Safety and Performance; Classification of Medical Devices and IVDs and Conformity Assessment of Medical Devices and IVDs and the latest ISO13485 version should be taken as reference to verify the correct presumption of conformity with the requirements of the regulations for Medical Devices and IVDs. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 7 of 68

8 15 ACRONYMS ANVISA CAPA EU GMDN HC IMDRF JP MCC MHRA UK NB PMDA PHCR RCT SANAS SAHPRA SA SUD TGA ToC USFDA National Health Surveillance Agency - Brazil Corrective Action and Preventive Action European Union Global Medical Device Nomenclature Health Canada International Medical Device Regulators Forum Japan Medicines Control Council Medical Health Regulatory Association United Kingdom Notified Body Pharmaceuticals and Medical Devices Agency, Japan Prospective Holder Certificate of Registration Randomized Controlled Trial South African National Accreditation System South African Health Products Regulatory Authority South Africa / South African Single Use Device Therapeutic Goods Administration - Australia Table of Contents United States Food and Drug Administration 16 HIERARCHY PRESENTATION The hierarchical presentation of the submission structure is detailed in the Application for Registration of a Medical Device. Detailed guidance regarding where elements belong is provided in the following table: 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 8 of 68

9 CHAPTER 1 ADMINISTRATIVE Level Content Content Note CH Cover Letter a) The cover letter should state applicant name and/or their authorized representative, the type of submission, the common name of the device (if applicable), device trade name or proprietary name (both of the base device and a new name if one is given to the new version/model of the device) and include the purpose of the application, including any changes being made to existing approvals. b) If applicable and accepted by the regulator, it should include information pertaining to any Master Files referenced by the submission. c) If applicable, acknowledgement that a device sample has been submitted or offered alternatives to allow the regulator to view or access the device (when the regulator requests a sample). d) If the submission is requesting approval of a change that is the result of CAPA due to a recall, this should be stated. e) If the submission is in response to a request for information from the regulator this should be stated and the date of that letter should be included as well as any reference number(s). f) If the submission is unsolicited information (where accepted), this should be stated and any related reference number(s) provided. The cover letter must be on the company letterhead and include Postal address, official correspondent(s), phone/fax number(s), address(s) Device class or if the device has not been classified with rationale for that conclusion The cover letter must be signed and dated by the Authorised Representative for the company NOTE: The cover letter should not contain any detailed scientific information. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 9 of 68

10 Level Content Content Note CH Submission Table of Contents CH List of Terms / Acronyms CH Application Form / Administrative Information a) Includes at least level 1 & 2 headings for the entire submission. b) Specifies the page number for each item referred to in the table. NOTE: Refer to the Pagination Section of this document for information about submission pagination. Terms or acronyms used in the submission that require definition, should be defined here Annexes CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL Letter of authorisation for communication on behalf of the applicant/phcr CV of person responsible for vigilance Electronic copy declaration Application form Medical Device Registration Application Form CH1.04 and Fee required by MCC - The application must be signed by the Authorised Representative responsible for the compilation of the application. This should be an original signature (scanned signature not acceptable). Attach an individualised, person specific letter of authorisation for the signatory, issued by the Person responsible for the overall management and control of the business (CEO). Include a curriculum vitae of the qualified person responsible for vigilance. Both paper and electronic submissions must comply fully with the Medical Device Technical Dossier as regards presentation and content of the dossier. Any documents submitted on CD-ROM/DVD must be declared identical to that in the paper submission (currently only the statistical data). 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 10 of 68

11 Level Content Content Note CH Listing of Device(s) A table listing each variant / model / configuration / component / accessory that is the subject of the submission and the following information for each variant/model: a) the identifier (e.g. bar code, catalogue, model or part number, UDI) b) a statement of its name/description that provides (e.g. Trade name, size, material) NOTES: i) A model/variant/configuration/component/accessory of a device has common specifications, performance and composition, within limits set by the applicant. ii) Typically, each item listed should be available for sale. For example, if everything is sold as part of a kit, then this list would only include the kit. You do not need to list all components that may be sold within a kit/set, unless the component is available for sale independently of the kit. CH Quality Management System, Full Quality System or Other Regulatory Certificates The grouping (family, set and systems) of medical devices must be in compliance with South Africa s requirements which specify the conditions to establish grouping of medical devices. For all classes of devices a) the relevant Global Medical Device Nomenclature (GMDN) Code, Term definition and name b) the classification and the applicable South African classification rule This subsection includes a copy of the quality management system certificate certifying that the quality management system under which the device is designed and manufactured satisfies the latest version of ISO Medical devices - Quality management systems - Requirements for regulatory purposes. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 11 of 68

12 Level Content Content Note MCC / SAHPRA will only accept quality system certificates that have been issued by special third party auditing organizations called Conformity Assessment Bodies which are accredited by the South African National Accreditation System (SANAS) or Conformity Assessment Bodies formally accredited and recognised by the following medical device regulatory authorities: HEALTH CANADA; TGA; EU; ANVISA, JAPAN or USFDA or MHRA UK or certificates issued by the same afore-mentioned regulatory authorities. CH Free Sale Certificate Document/certificate issued by the Regulatory Authority where the medical device is marketable, attesting that the device is marketed without any restriction at their jurisdiction. CH Fees Proof of payment of fee. Information about fees payable available at: CH Pre-Submission Correspondence and Previous Regulator Interactions a) During the product lifecycle, pre-submission correspondence, including teleconferences or meetings, may be held between the regulator and the applicant. Further, the specific subject device may have been subject to previous regulatory submissions to the regulator. The contents should be limited to the subject device as similar devices are addressed in other areas of the submission. If applicable, the following elements should be provided: i. List prior submission or pre-submissions where regulator feedback was provided ii. Prior submissions should include identification of submission # 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 12 of 68

13 Level Content Content Note iii. For any pre-submission activities that have not previously been assigned any tracking/reference number, include the information package that is submitted prior to pre-submission meetings, the meeting agenda, any presentation slides, final meeting minutes, responses to any action items arising from the meetings, and any correspondence related to specific aspects of the application. iv. Issues identified by the regulator in prior submissions (i.e. clinical study applications, withdrawn/ deleted/ denied marketing submission) for the subject device v. Issues identified and advice provided by the regulator in pre-submission interactions between the regulator and the applicant. vi. Explain how and where the prior advice was addressed within the submission. OR b) Affirmatively state there has been no prior submissions and/or pre-submission interactions for the specific device that is the subject of the current submission NOTE: The scope of this section is limited to the particular regulator to which the submission is being submitted i.e. MCC / SAHPRA. CH Acceptance for Review Checklist [to be supplied] Complete the checklist and provide section and pages numbers indicating where every item on the check is addressed in the submission. Complete the checklist by answering the preliminary questions and providing the page numbers indicating the locations of each item on the checklist is addressed in the submission. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 13 of 68

14 Level Content Content Note CH Statements/ Certifications/ Declarations of Conformity CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL CH Performance and Voluntary Standard CH Environmental Assessment CH Clinical Trial Certifications a) If claiming categorical exclusion, information to justify the exclusion OR b) Provide the environmental assessment (only required for devices that present new environmental concerns) Certification of Compliance with Requirements of Clinical Trials CH Indications for Use Statement with Order /Rx and/or OTC designation Enclosure CH Truthful and Accurate Statement A declaration (per text below), dated and signed by the Authorised Representative of the company: We declare that the information provided at this submission is truthful and accurate, and can be proven by documental evidence and that no material fact has been omitted. We also declare that: i. The device will be marketed observing all requirements established by the South African regulatory authority; 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 14 of 68

15 Level Content Content Note CH Nil Nil CH Declaration of Conformity As part of the conformity assessment procedures, the manufacturer of a medical device is required to make a Declaration of Conformity that declares that the device complies with: a) the applicable provisions of the Essential Principles/Requirements b) the classification rules c) an appropriate conformity assessment procedure ii. The labelling (e.g. labels, instructions of use, promotional material) of the device complies with the South African regulatory requirements, and will be maintained up to date during all the period that it will be available on the South African market; iii. The device and accessories that accompany the device were designed and are manufactured attending the Essential Requirements of Safety and Efficacy and the Quality Assurance principles required by the MCC/ SAHPRA; iv. All the reasonably foreseeable risks were identified and mitigated. The residual risk is acceptable in relation to the benefits obtained by the use of the devices; v. The devices delivered to the market will be continuously monitored in order to identify new risks that have not been already addressed, according to the Risk Management Plan established by the manufacturer and the licensed South African manufacturer or distributor. The wording of the Declaration of Conformity by the South African Authorised Representative will depend on the conformity assessment procedure chosen by the manufacturer. Directives for each of the types of Declarations of Conformity are available in the MCC / SAHPRA Guideline for Conformity Assessment. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 15 of 68

16 Level Content Content Note CH Letters of Reference for Master Files Letter from any Master File owner granting access to the information in the master file. The letter should specify the scope of access granted. CH Letter of Authorization When applicable, an authorization letter issued by the device manufacturer allowing the South African licensed importer / authorized legal agent to market the device in South Africa. Only a person licensed by the MCC / SAHPRA to import, manufacture and / or distribute medical devices may register a device for sale in South Africa. CH SA Administrative Information for other information that may be important to the submission but that does not fit in any of the other headings of this chapter. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 16 of 68

17 CHAPTER 2 SUBMISSION CONTEXT Level Content Content Note CH2.1 1 Chapter Table of Contents CH2.2 1 General Summary of Submission CH2.3 1 Summary and Certifications for Premarket Submissions a) Includes all headings and sub-headings for the chapter. b) Specifies the page number for each item referred to in the table. a) Statement of the device type (e.g. Tacrolimus test system, blood specimen collection device, calibrator) and name (e.g. trade name, proprietary name), its general purpose, and a high-level summary of key supporting evidence (i.e. studies that are unique to the risks of this device type). b) Summary of submission, including i) The type of submission (e.g. new, amendment, change of existing application, renewal); ii) if amendment/supplement, the reason of the amendment/supplement; iii) if a change to existing approval, description of the change requested (e.g., changes in design, performance, indications, changes to manufacturing processes, manufacturing facilities, suppliers); iv) any high-level background information or unusual details that the manufacturer wishes to highlight in relation to the device, its history or relation to other approved devices or previous submissions (provides context to submission). If renewal, amendment or change, identification of the registration/notification number issued by MCC /SAHPRA for the device, family, group, system or set of devices and the number of the original application must be informed. If recertification or change to a conformity assessment certificate, identification of the affected MCC / SAHPRA certificate numbers must be detailed. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 17 of 68

18 Level Content Content Note CH2.4 1 Device Description CH Comprehensive Device Description and Principle of Operation CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL a) A general description of the device, including: i. A statement of the device name. ii. What does it detect? iii. Who uses it and for what? (high level statement) iv. Where to use it? (places/environment where the device is intended to be used) v. General description of the principle of the assay method or instrument principles of operation. vi. Description of the components (e.g. reagents, assay controls and calibrators) and where appropriate, a description of the reactive ingredients of relevant components (such as antibodies, antigens, nucleic acid primers). vii. If applicable, labelled pictorial representation (diagrams, photos, drawings). viii. If system, how the components relate? ix. If applicable, identify if the device incorporates software/firmware and its role. b) Product specification, including: i. Physical characteristics of relevance to the end user (dimensions, weight) ii. If applicable, technical features and operating modes iii. If applicable, operating specifications and performance characteristics (e.g. electrical power requirements, settings and associated allowable ranges/limits, temperature and humidity limits, number of tests per hour, sensitivity/specificity) iv. If applicable, a complete list of the configurations/models of the devices and a summary of the differences in specifications (comparison table and/or pictures/diagrams with supporting text). a) Some accessories may require independent submission at MCC /SAHPRA, especially when it is considered a medical device by itself and is not of exclusive use of the medical device to be used in combination. For this accessories shall be identified and their registration/notification number in MCC/SAHPRA provided. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 18 of 68

19 Level Content Content Note c) If applicable, engineering diagrams/prints/schematics of the device. d) Describe the different sample types that can be used for this device (e.g. serum, plasma, urine, cerebrospinal fluid), including any additives that are required (e.g. anticoagulant). e) Describe the use of controls. If applicable, a list of compatible control materials or control material specifications. f) Description of the accessories, other IVD or non-ivd medical devices and other products, which are intended to be used in combination with the IVD medical device. g) If approved by the regulator, provide the approval number and identification for each of the accessories, other IVD or non-ivd medical devices and other products, which are intended to be used in combination with the IVD medical device. h) If applicable, indication of biological material or derivate used in the medical device, including: origin (human, animal, recombinant or fermentation products or any other biological material) and source (e.g. blood, bone, heart, any other tissue or cells). Where a significant risk is identified, a brief summary of evaluations performed to minimize biological risks, in particular, with regard to viruses and other transmissible agents. i) If the device contains an active pharmaceutical ingredient (API) or drug, an indication of the substance, should be provided. This should include its identity and source, and the intended reason for its presence and its primary mode of action. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 19 of 68

20 Level Content Content Note j) Description of the collection and/or transport container(s) provided with the IVD medical device or a description of specifications or recommended collection and/or transport container(s). k) If applicable, a listing of assays that are compatible with the instrument. l) If applicable, a listing of compatible instruments. m) A list of any software to be used with the IVD medical device and a description of its role in the delivery of the intended purpose. NOTE: The applicant should explicitly address any existing regulatory guidance related to the comprehensive device description and principles of operations provided in this section regarding the subject device. CH Material Specifications CH Description of Device Packaging a) Details of relevant material identifications and specifications, including critical raw materials and components should be provided. Information should include complete chemical and physical characterization of all component materials. NOTE: If applicable, chemicals should be identified using either the IUPAC (International Union of Pure and Applied Chemistry) or the CAS (Chemical Abstract Service) Registry number. Reference to applicable material standards may also be useful in this description. a) A brief description of the packaging of the devices, including the packaging configuration and materials involved. This is not intended to include shipping/transport packaging. b) Specific packaging of accessories marketed together with the IVD medical devices shall also be described. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 20 of 68

21 Level Content Content Note CH History of Development CH Reference and Comparison to Similar and/or Previous Generations of the Device CH Substantial Equivalence Discussion For any device versions/prototypes referenced in the evidence presented in the submission, a table describing the version/name, with 4 columns (Device Name and/or Version; Description of changes from previous row; motivation for the change; list of verification/validation activities, including clinical studies, conducted using this version). For any design verification or validation activities presented in this submission (including clinical studies) performed on any earlier versions of the subject device, include a justification for why the changes do not impact the validity of the data collected under those activities in supporting the safety and effectiveness of the final device design. a) A list of the similar devices (available on local and international market) and/or previous generation of the devices (if existent) relevant to the submission. This should include any similar/previous generation devices that were previously reviewed and refused by the subject regulator. b) Description of why they were selected. c) A key specification comparison, preferably in a table, between the references (similar and/or previous generation) considered and the device. a) If the application is an amendment to a licenced device or is based on a modification of a licensed device, a description of the modifications is required (e.g., changes in design, performance, and indications). b) Comparisons can be used to support the safety and effectiveness of the device if they are made to a currently registered device in South Africa. If this method is used, ensure the SA Medical Device Registration Number of the comparator is stated. The comparison device does not need to be manufactured by the same manufacturer. a) Identify the predicate device(s) i. Registration number, trade name and model number ii. Ensure the identified predicate device(s) is consistent throughout the submission (i.e., Substantial Equivalence discussion are the same as registered and the same as those used in comparative performance testing). 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 21 of 68

22 Level Content Content Note CH2.5 1 Indications for Use and/or Intended Use CH Intended Use; Intended Purpose; Intended User; Indications for Use CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL This section should include, as appropriate: a) Intended Use: The statement of intended use should specify what is detected and the function provided by the device (e.g. screening, monitoring, diagnosis or aid to diagnosis). It should identify i. Instruments on which the device can be used, ii. if the assay is automated or not, iii. is the diagnostic qualitative or quantitative, iv. and the sample types (e.g. serum, plasma, urine, cerebrospinal fluid), including any additives that are required (e.g. anticoagulant) b) Intended Purpose: What is the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate? c) Intended user: Lay person or professional? d) Identify if the device is intended for single or multiple use b) Include a comparison of indications for use and the technology (including features materials and principles of operation) between the predicate device(s) and subject device(s). c) Include an analysis of why any differences between the subject device(s) and the predicate device(s) do not render the subject device(s) Not Substantially Equivalent, affect safety or effectiveness or raise different questions of safety and effectiveness. The content of this section should be contained in a single body of text. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 22 of 68

23 Level Content Content Note e) Indications for Use: i. Disease or medical condition that the device will diagnose, treat, prevent, mitigate, or cure, parameters to be monitored and other considerations related to indication for use. ii. If applicable, information about patient selection criteria. iii. If applicable, when/where the use of the medical device should be avoided. iv. If applicable, information about intended patient population (e.g. adults, pediatrics or newborn) or a statement that no subpopulations exist for the disease or condition for which the device is intended. NOTES: i. The statements of intended use and indications for use must be as presented in the labelling. ii. If more than one device is included, the information should be provided for each device. CH Intended Environment/ Setting for use a) The setting where the device is intended to be used (e.g. domestic use, self-testing, near-patient/point of care). Multiple options can be indicated. b) If applicable, environmental conditions that can affect the device s safety and/or performance (e.g. temperature, humidity, power, pressure, movement). CH Paediatric Use a) Description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose or cure. b) The number of affected pediatric patients, as a whole and within each pediatric subpopulation. OR c) Statement that no pediatric subpopulation exists for the disease or condition for which the device is intended. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 23 of 68

24 Level Content Content Note CH Contraindications for Use CH2.6 1 Global Market History CH Global Market History If applicable, specify the disease or medical conditions that would make use of the device inadvisable due to unfavourable risk/benefit profile. NOTE: The statement re contraindications for the device must be as presented in the labelling. CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL a) Up to date indication of the markets (all countries or jurisdictions) where the device is approved for marketing, including any marketing under compassionate use regulations. b) Should include history of the marketing of the device by any other entity in as much detail as possible, acknowledging that detailed information may not be available in all cases. c) If the subject device is different in any way (e.g. design, labelling, specifications) from those approved or marketed in other jurisdiction, the differences should be described. d) The month and year of market approval in each country or jurisdiction where the device is marketed. If the device has been marketed for greater than 10 years, a statement of greater than 10 years can be made. e) For each of the markets listed in (a) above, and statement of the commercial names used in those markets OR a clear statement that the commercial names are the same in all jurisdictions. f) State the date of data capture for the market history data. g) If the subject device has been the subject of any previous compassionate use and/or clinical trials this should be identified and, if applicable, relevant reference numbers provided. If there is any approval reference number, given to the device by the regulator authority of the markets (country or jurisdictions) where the device is already marketed, this identification must be informed. Any notifications to foreign regulators of substantial change to the device must be included. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 24 of 68

25 Level Content Content Note CH Global Incident Reports and Recalls CH Sales, Incident and Recall Rates a) List adverse events/incidents associated with the device and a statement of the period associated with this data. b) If the number of adverse events is voluminous, provide a summary by event type that state the number of reported events for each event type. c) List of the IVD medical device recalls and/or advisory notice, and a discussion of the handling and solution given by the manufacturer in each case. d) A description of any analysis and/or corrective actions undertaken in response to items listed above. NOTES: It is acknowledged that the definition of recall may vary from one jurisdiction to another. Refer to the MCC / SAHPRA adverse event guideline a) A summary of the number of units sold in each country/region and a statement of the period associated with this data. b) Provide the rates calculated for each country/region, for example: i. Incident rate = # adverse events/incidents divided by # units sold x 100 ii. Recall rate = # recalls divided by # units sold x 100 Rates may be presented in other appropriate units such as per patient year of use or per use. In this case, methods for determining these rates should be presented and any assumptions supported. c) Critical analyses of the rates calculated (e.g. Why are they acceptable? How do they break down in terms of incidents? Is there some outlier data that has driven the rates up? Are there any trends associated with any sub-groups of the devices that are subject of the submission (e.g. size, version)? Include when submitting an application to implement a design change to address a recall of a device. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 25 of 68

26 Level Content Content Note CH Evaluation/ Inspection Reports CH2.7 1 Other Submission Context Information NOTES: i. Sales in this context should be reported as the number of units sold. ii. The summary of sales should be broken down by components when appropriate. To inform special/additional data that does not fit on previous headings. NOTE: To ensure all elements of your submission are adequately reviewed, please be sure that any content placed here does not belong under any heading described above. Copies of Evaluation/Inspection Reports from other parties (e.g. Notified Body / Conformity Assessment body inspection reports). For registration of Class C and Class D medical devices which were not on the market prior to 9 December 2016, documentation to confirm fulfillment of the following minimum international market authorisation criteria is required: Class D medical device: Evidence of market authorisation from at least two (2) of the following regulatory authorities: USFDA; PMDA Japan; HC; ANVISA; TGA; MHRA UK; EU or WHO. Class C medical device: Evidence of market authorisation from at least one (1) of the following regulatory authorities: USFDA; PMDA Japan; HC; ANVISA; TGA; MHRA UK; EU or WHO. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 26 of 68

27 CHAPTER 3 NON-CLINICAL EVIDENCE Level Content Content Note CH3.1 1 Chapter Table of Contents a) Includes major headings for the chapter, to the level of the custom headings. b) Specifies the page number for each item referred to in the table. CH3.2 1 Risk Management a) A summary of the risks identified during the risk analysis process and how these risks have been controlled to an acceptable level. The summary should address i. Possible hazards for the IVD medical device for example, the risk from false positive or false negative results and the risk of delays in availability of results ii. Indirect risks which may result from IVD medical device-associated hazards, for example, risk associated with instability, which could lead to erroneous results or user-related hazards, such as reagents containing infectious agents. b) The results of the risk analysis should provide a conclusion with evidence that remaining risks are acceptable when compared to the benefits. c) Where a standard is followed, identify the standard. A formal signed statement accepting the residual risk upon completing the risk-benefit analysis before placing product on the market. CH3.3 1 Essential Principles (EP) Checklist a) An EP checklist established for the IVD medical devices, information about method(s) used to demonstrate conformity with each EP that applies, references for the method adopted and identification of the controlled document with evidence of conformity with each method used. b) For the controlled documents indicated which are required for inclusion in the submission: a crossreference of the location of such evidence within the submission. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 27 of 68

28 Level Content Content Note c) If any EP indicated in the checklist does not apply to the device: a documented rationale of the non-application of each EP that does not apply. NOTE: Methods used to demonstrate conformity may include one or more of the following: a) conformity with recognised or other standards; b) conformity with a commonly accepted industry test method(s); c) conformity with an in-house test method(s); d) the evaluation of pre-clinical and clinical evidence; e) comparison to a similar device already available on the market. CH3.4 1 Standards CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL CH List of Standards a) List the standards that have been complied with in full or in part in the design and manufacture of the device. b) At a minimum should include the standard organization, standard number, standard title, year/version, and if full or partial compliance. CH Declaration and/or Certification of Conformity c) If partial compliance, a list the sections of standard that i. Are not applicable to the device, and/or ii. have been adapted, and/or iii. were deviated from for other reasons discussion to accompany This list should include any medical device standard or conformity assessment standard that has been applied to the device; and, if no medical device standard or conformity assessment standard, or part only of such a standard, has been applied to the device the solutions adopted to ensure that each device complies with the applicable provisions of the essential principles. The information in this section may be presented in the Essential Principle Checklist and, if so, needs only to be presented once in the application. The applicant is advised to prepare the South African Declaration of Conformity to recognized standards and to the South African regulations. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 28 of 68

29 Level Content Content Note CH3.5 1 Analytical Performance CH Stability of Sample(s) CH [Study description, study identifier, date of initiation, date of completion] CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL Information regarding and studies to support the stability of all of the sample type(s) identified in the labelling, including any and all recommended additives (e.g. anticoagulants) is to be provided in this section. This should include: a) For each sample type identified in the labelling, a description of the recommended storage parameters and when applicable, transport conditions (e.g. duration, temperatures and freeze/thaw cycles). b) A justification on the selection of the studies performed. c) Provide summary of the evidence that falls within this category d) A discussion and a conclusion to support why the evidence presented is sufficient to support the application. OR e) A discussion of why this category of study is not applicable to this case. NOTE: The applicant should explicitly address any existing SA regulatory guidance related to the study results provided in this section regarding the subject device CONTENT TO BE SUBMITTED AT SUB-CHAPTER LEVEL This heading should be CUSTOM and BASED ON STUDY DETAILS and created for each study under the parent heading. The sub-headings below would be for this study alone. For example, the structure will look something like this: Level 3: Storage of serum samples for 7 days at 2-8 ºC or 4 days at -20 ºC. Level 4: Summary 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 29 of 68

30 Level Content Content Note Level 4: Full Report Level 3: Validation of 3 freeze/thaw cycles for serum samples Level 4: Summary Level 4: Full Report CH Summary A summary of the specific study described in the custom heading above. CH Full Report The test report for the test described in the custom heading above. CH Statistical Data This is the location for statistical data associated with the test described in the custom heading above. This includes metadata and data line listings in their native formats, such as ASCII and Excel. CH Validation of Samples Studies to support the validity of sample type(s) used in the analytical studies as representative of all of the sample type(s) identified in the labelling, including any and all recommended additives (e.g. anticoagulants), are to be included in this section. This should include: a) A list of the sample type(s) used, including any additives (e.g. anticoagulants), in each of the analytical performance studies. If the same samples are used for all analytical studies this can be stated and the sample type identified. b) For any or all of the analytical studies, if a particular sample type(s) including additives (e.g. anticoagulants), has been chosen as representative of other sample types identified in the labelling, this should be described and supported. NOTE: Do not place PDFs here. 8.08_Medical_Device_IVD_Technical_Dossier_Jun17_v1_for_comment.doc Aug 2017 Page 30 of 68