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GUIDANCE FOR INDUSTRY
Guidance for the Interpretation of Significant Change of a Medical Device
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(PDF Version - 80 K)Therapeutic Products Directorate
Medical Devices Bureau
Room 1605
Statistics Canada Main Building
Tunney's Pasture
Address Locator: 0301H1
OTTAWA, Ontario K1A 0L2
March 20, 2003
To: Medical Devices Stakeholders
Subject: Guidance for the Interpretation of Significant Change
The Medical Devices Regulations set out the requirements governing the sale, importation and advertisement of medical devices. The goal of the Regulations is to ensure that medical devices distributed in Canada are safe and effective and meet quality standards. These Regulations were published in Canada Gazette II on May 27, 1998, and implementation began on July 1, 1998.
This document, entitled, Guidance for the Interpretation of Significant Change sets out the Directorate's guidance for Industry on the subject.
Every Class II, III and IV medical device sold in Canada is required to be licensed under Section 26 of the Regulations. An amended licence application is required if a significant change has been made to a licensed Class III or IV medical device. This amended licence must be issued prior to the modified device being offered for sale in Canada.
This guideline is intended to aid manufacturers in determining when a significant change has been made to a medical device. Medical devices undergo almost constant evolution, in response to many factors. Most changes are non-significant and will not trigger the need for an amended licence application.
For more information on the interpretation of significant change please contact:
Manager, Device Evaluation Division
Medical Devices Bureau
1605 Statistics Canada Main Building
Address Locator: 0301H1
Tunney's Pasture
Ottawa, Ontario K1A 0L2
phone: (613) 954-0297
fax: (613) 957-9969
email: ded_manager@hc-sc.gc.ca
original signed by
Roland Rotter, Ph.D.
Director
Medical Devices Bureau
Attachments
Published by authority of the
Minister of Health
Effective Date: 2003/03/20
Health Products and Food Branch
Guidance Document
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© Minister of Public Works and Government Services Canada 2003
Available in Canada through
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Également disponible en français sous le titre : Directive sur l'interprétation d'une modification importante d'un instrument médical
FOREWORD
Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.
Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.
As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.
This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.
| Document Number | GD001/Rev01-MDB | Replaces | GD001/Rev00-MDB |
|---|---|---|---|
| File name | signchn3_e.wpd | Replaces | signchn2_e.wpd |
| Version | V3 | Replaces | V2 |
| Date | March 20, 2003 | Date | November 9, 1998 |
| Change | Location | Nature of Change |
|---|---|---|
| 1 | Title Page, Document Number. | Status of document changed from final (Rev00) to final (Rev01) |
| 2 | Introduction | |
| 1.1 Purpose | All changes are to be recorded in a quality system. Some non-significant changes must be reported to the Bureau, these are identified. | |
| 1.3 Scope | This document also does not address changes to Quality Systems. | |
| 1.4 Definitions | Additional Information definition no longer included Documentable change definition no longer included "Not Significant Change" no longer included Definitions added for control mechanism and operating principles. Definition of recall added. Definition of non-significant change removed. Definition of Additional Information is removed. |
|
| 3 | When to Use This Guidance Document | Examples relating to family and group family have been provided. |
| 4 | How to Use This Guidance Document | Text clarifies: All changes must be documented in the Quality Management System. |
| 3.1 Main Flowchart | Clarification as to which changes must be reported to the Bureau annually. | |
| 3.2 Changes to Manufacturing Process, Facilities or Equipment | Text has been revised and examples provided. A change in the packaging of sterile medical devices is considered a significant change. | |
| 3.3 Changes to Manufacturing Requirements and Procedures | Title has been changed. Text has been revised and examples provided. |
|
| 3.4 Changes in Design Specifications | This section has been redrafted into four subsections, the following three existed in the previous version: control mechanisms, operating principles and performance specifications. A fourth section describing design changes has been added Specific examples have been provided. |
|
| 3.5 Changes in Materials | Text has been revised Changes determined to be not significant do not need to be reported to the Bureau, |
|
| 3.6 Changes in Materials - IVDDs | Text has been revised. | |
| 5 | Process and Procedures | |
| 4.1 Significant Changes | Reference is made to the Management of Applications Policy. | |
| 4.2 Documentable Changes | Reference to additional information is removed. | |
| Text has been revised, process has been clarified. All changes are to be documented in QMS Revised and rename: obligation to inform |
||
| 4.3 Non-Significant Changes | Section has been removed. | |
| 6 | Appendices | |
| Flowchart A | Chart has been revised. Specific questions regarding packaging requirements have been added. Example of changes "expiration date" determination of shelf life move to Flowchart E Example of changes "validating sterilization process" moved to Flowchart B |
|
| Flowchart B | Example of changes "validating sterilization process" moved here. | |
| Flowchart C | The chart has been revised. Specific questions regarding design changes added. Example of changes to "device packaging" added here |
|
| Flowchart E | Flowchart E removed | |
| Flowchart F | Renamed Flowchart E Example of changes "expiration date" moved here |
|
| 7 | Appendix 7 added | Table of examples added |
Table of Contents
2 When to Use This Guidance Document
3 How to Use This Guidance Document
3.2 Flowchart A - Changes to Manufacturing Processes, Facility or Equipment
3.3 Flowchart B - Changes to the Manufacturing Quality Control Procedures
3.4 Flowchart C - Changes in Design or Performance Specifications
3.4.4 Performance Specifications
3.5 Flowchart D - Changes in Materials
3.5.1 Changes in Materials in in vitro diagnostic devices (IVDD)
3.6 Flowchart E - Changes in Materials in in vitro diagnostic devices (IVDD)
4.2 Obligation to Inform - Other Changes
1 Introduction
1.1 Purpose
Medical devices are classified into one of four risk classes (I to IV) by means of classification rules set out in Schedule I of the Medical Devices Regulations 1998 (Regulations), where Class I is the class representing the lowest risk and Class IV is the class representing the highest risk.
All Class II, III and IV medical devices sold in Canada are required to be licensed under Section 26 of the Regulations. An amended licence application is required if a SIGNIFICANT CHANGE has been made to a licensed Class III or IV medical device. This amended licence is required to be issued prior to the modified device being offered for sale in Canada.
This guideline is intended to aid manufacturers in determining when a SIGNIFICANT CHANGE has been made to a medical device. Medical devices undergo almost constant evolution, in response to many factors. Most changes are not significant and will not trigger the need for an amended licence application.
1.2 Background
The concept of SIGNIFICANT CHANGE is linked to the principles of safety and effectiveness and the ability of a risk-based regulatory system to control the risk of medical devices offered for sale in Canada. Effective regulatory management of medical devices is based on a balance of premarket review, postmarket surveillance and quality systems. An accurate device licensing process is fundamental to all these processes.
SIGNIFICANT CHANGE is defined in the Regulations, and the definition is repeated in section 1.4 of this document.
The concept of SIGNIFICANT CHANGE has been harmonized with other regulatory organizations, including those of the United States, Australia and the European Union. It also builds on the historic concept of Supplementary Notices of Compliance under Part V of the Medical Devices Regulations of 1982.
1.3 Scope
This document sets out some points for consideration by the device manufacturer and the Therapeutic Products Directorate (TPD) staff when a Class III or IV device is being modified. An exact discussion of all changes is not possible within the scope of this document. If additional questions or concerns remain about a particular change, the manufacturer and/or device sponsor is urged to contact the Manager, Device Evaluation Division, Medical Devices Bureau.
A SIGNIFICANT CHANGE includes any change that could reasonably be expected to affect the safety or effectiveness of a Class III or IV medical device. This guidance document addresses manufacturing processes and procedures, labelling changes, technology or performance specification changes and material changes. This document is also applicable to any SIGNIFICANT CHANGE to a licensed device that results from a recall.
This document does not address the reasons listed in Section 34 of the Medical Devices Regulations for submitting an application for an amended medical device licence for Class II, III and IV medical devices.
This document also does not address changes to Quality Systems. Please refer to our website for other MDB guidances on Quality Systems:
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/
1.4 Definitions
CONTRAINDICATIONS describe situations where the device should not be used because the risk of use clearly outweighs any reasonably foreseeable benefits.
CONTROL MECHANISM is a means of verifying or checking that the specifications or outputs of the device meet a standard or predetermined result. They are mechanisms put in place to maintain on-going control or regulate the output of a device.
INDICATIONS FOR USE is the general description of the disease(s) or condition(s) the device will diagnose, treat, prevent or mitigate, including where applicable a description of the patient population for which the device is intended. The indications include all the labelled patient uses of the device, such as: the condition(s) or disease(s) to be prevented, mitigated, treated or diagnosed, part of the body or type of tissue applied to or interacted with, frequency of use, physiological purpose and patient population. Indications for use are generally found in the indications section of the labelling, but indications may also be inferred from other parts of the labelling such as the precautions, warnings, bibliography or directions for use sections. In some instances, intended use is determined by a manufacturer's and/or distributor's statements or may be shown by the circumstances surrounding the distribution of the article.
OPERATING PRINCIPLES are the means by which a device produces or brings about a desired or appropriate effect. They are the means whereby a device is able to have a certain influence on a person or its surroundings.
RECALL in respect of a medical device that has been sold, means any action taken by the manufacturer, importer or distributor of the device to recall or correct the device, or to notify its owners and users of its defectiveness or potential defectiveness, after becoming aware that the device:
- may be hazardous to health;
- may fail to conform to any claim made by the manufacturer or importer relating to its effectiveness, benefits, performance characteristics or safety, or;
- may not meet the requirements of the Food and Drugs Act or the Medical Devices Regulations.
SIGNIFICANT CHANGE means a change that could reasonably be expected to affect the safety or effectiveness of a medical device. It includes a change to any of the following:
- the manufacturing process, facility or equipment;
- the manufacturing quality control procedures, including the methods, tests or procedures used to control the quality, purity and sterility of the device or of the materials used its manufacture;
- the design of the device, including its performance characteristics, principles of operation and specifications of materials, energy source, software or accessories; and
- the intended use of the device, including any new or extended use, any addition or deletion of a CONTRAINDICATION for the device, and any change to the period used to establish its expiry date.
SURGICALLY INVASIVE DEVICE means an invasive device that is intended to enter the body through an artificially created opening that provides access to body structures and fluids.
PRECAUTIONS describe any special care to be exercised by a practitioner or patient for the safe and effective use of a device. This definition includes limitations stated for in vitro diagnostic devices (IVDDs).
WARNINGS describe serious adverse reactions and potential safety hazards that can occur in the proper use, or the misuse, of a device, along with consequent restrictions in use and mitigating steps to take if problems occur.
2 When to Use this Guidance Document
Section 34 of the Regulations requires a manufacturer to apply for and obtain an amended device licence if a SIGNIFICANT CHANGE has been made to a licensed Class III or IV medical device. This guidance document will aid in determining whether the Therapeutic Products Directorate (TPD) would reasonably expect a particular change to affect the safety and effectiveness of the device.
The use of this document pertains only to medical devices with an established reference to a predicate device that has a licence in good standing with the TPD. Manufacturers are requested to state whether predicate devices should be added to or removed from a licence.
The SIGNIFICANT CHANGE of one member of a medical device family or a medical device group family would require a new licence application for the single device or device group and an amended licence application to modify the medical device family licences appropriately.
For example, a manufacturer holds a licence for a family of in-dwelling catheters made of silicone elastomer. The manufacturer also holds a group family licence for the same silicone catheters sold as a group with the necessary devices for insertion of the catheters. The manufacturer proposes to modify one of the existing catheter designs, so that it is manufactured from a polyurethane material. It is not possible for this modified catheter to be part of the existing family or group family licences, so two new licence applications are required. Additionally, the silicone family and group family licences may need to be modified to remove the medical device identifier associated with the new polyurethane catheter.
A medical device family or group family licence can be amended when the significant change only affects the number of devices in the original family. An amended device licence is required to add a smaller or larger sized family member provided the indications for use of the device are not concurrently altered.
In some instances the applicant may choose to file for a new medical device licence rather than for a SIGNIFICANT CHANGE amendment to the predicate medical device licence.
3 How to Use This Guidance Document
When several simultaneous changes are being considered in the evolution of a licensed device, this guidance document should be used to assess each change separately. If the manufacturer decides to submit an amended licence application for any one of the changes made, the application should describe how the modified device differs from the last licensed device (or device type).
This guidance document presents two options in detailing a decision making process. The first is a generalized discussion of broad principles and issues that can be used to determine if a change can reasonably be expected to affect the safety and effectiveness of a medical device. The second method involves the use of a flowchart model. The model uses specific questions and answers that may not be applicable to all manufacturers or all devices in all instances.
The majority of questions regarding the significance of a change will fall somewhere between the two extremes of broad principles and detailed enumeration.
The following seven sections discuss the broad principles relating to particular types of changes, and each section is illustrated with a flowchart of specific examples. Flowcharts A to E detail the most common types of changes made to medical devices. The main flowchart provides assistance in locating which individual charts will be helpful.
Main Flowchart - General changes made to devices
Flowchart A - Changes in manufacturing processes, facility or equipment
Flowchart B - Changes in manufacturing quality control procedures
Flowchart C - Changes in design or performance specifications
Flowchart D - Changes in materials
Flowchart E - Changes to labelling
The discussions and flowcharts are intended to define the processes used to answer the question: Is this a SIGNIFICANT CHANGE? If the change is significant, then an amended licence application must be submitted.
All changes, regardless if they are SIGNIFICANT CHANGE or not, must be documented in the Quality Management System. The manufacturer should contact their Quality System registrar before implementing these changes. Refer to our website for other MDB guidances on Quality Systems.
In addition to the above discussions, an extensive table of examples reviewed by the Medical Devices Bureau has been added to this document in Appendix 7.
3.1 Main Flowchart
This flowchart describes the general types of changes that can be made to a medical device. It leads the manufacturer to more detailed information contained in flowcharts A to E. All changes made to a device or the processes used in its manufacture must be recorded in the manufacturer's quality system. Any of these changes that might reasonably be expected to affect the safety and effectiveness of the device will require that an amended device licence application be submitted. These are SIGNIFICANT CHANGES. For changes not specifically mentioned in this document, the manufacturer must determine whether the change might reasonably affect the safety and effectiveness of the device. If the determination is not straightforward, consult with the Medical Devices Bureau.
Some changes are made to devices which are not significant, but do affect the information that was used to make a decision regarding the safety and effectiveness of the device. These changes to the information or documents supplied by the manufacturer with respect to the device must be reported to the Bureau in a tabular format annually with renewal. (Section 43(1)(b)).
Changes made as a result of a RECALL that are intended only to bring the device back to its original specifications and that can be validated according to the applicable procedures records in a quality system do not require an amended licence application. Additional changes made to a device as the result of the recall must be evaluated individually to determine if they are SIGNIFICANT CHANGES.
3.2 Flowchart A - Changes to Manufacturing Processes, Facility or Equipment
In most instances, changes to the manufacturing process, facility or equipment that are determined not to be significant can be documented in the quality system. However, if changes impact on the safety and effectiveness of a device (sections 10 to 20) then they are SIGNIFICANT CHANGES. A change to the device specifications that impacts on the manufacturing processes, facility or equipment is significant and therefore an amendment is required while a change to the manufacturing process, facility or equipment that does not impact on device specifications is not considered significant and therefore no amendment is required.
For example, changes to the manufacturer's requirements for packaging are to be considered a SIGNIFICANT CHANGE if these changes alter the performance specifications of the device.
Some packaging changes made to sterile medical devices are significant. For example, if these changes are made to the inner sterile wrapper or if the sterilization process must be revalidated. These changes can be supported by a device description, with no additional studies, provided validation processes and procedures have not changed.
Changes in the method of sterilization have the potential for changing performance characteristics of a device. This is particularly true of the properties of polymeric materials.
When manufacturers make changes in sterilization methods, they must specify that the important properties and specifications of the device remain unaffected. Manufacturers should refer to Flowchart C for further guidance.
3.3 Flowchart B - Changes to the Manufacturing Quality Control Procedures
Changes to the manufacturing quality control procedures, like the methods, tests or procedures used to control the quality, purity and sterility of the materials or the device, are considered significant if they alter the performance specifications of the device. In these cases an amended licence application is required, and the manufacturer is referred to Flowchart C for further guidance.
For example, changes to the manufacturer's requirements for material acceptance criteria can be considered a SIGNIFICANT CHANGE if these changes alter the performance specifications of the device. Changes in packaging material specifications for implanted medical devices, such as intra ocular lenses, must be carefully evaluated and proven not to affect the performance of the finished product.
Changing or adding a new test acceptance criteria or test methods to provide equivalent or better assurances of sterility, reliability or similar safety aspects are not considered to be a SIGNIFICANT CHANGE.
Changes in the methods used for validating the sterilization process are significant. Changing contract sterilizers would not be significant, if the method of validating the process remained the same.
3.4 Flowchart C - Changes in Design or Performance Specifications
Changes in design characteristics or performance specifications span the full spectrum from minor engineering changes to major changes in operating principles. All design changes must be evaluated and validated according to the accepted procedures recorded in the quality system. The results of this validation process for each proposed change are then used to determine if an amended licence application is required.
For example, a change in design is made to currently marketed acetabular cups to offer additional flexibility to implanting surgeons. Additional holes are added to the liners, this is considered a significant change, but it can be supported by a device description only. The removal of screw holes is not considered significant.
The addition of new features or software applications to an interpretive ECG monitor represents a significant change to the design of the device. Changes to wire lead length or diameter are not significant.
In response to an adverse event, an additional polymer support clip was added to an endocardial lead. This clip was intended to prevent the dislodging of the electrical connection and to increase the axial retention forces. This is considered a significant change to the design specifications and details of the manufacturing process and testing must be provided to support the amended licence application.
In addition to changes that might have an adverse effect on the medical device, it is also important to note that changes that are intended to improve the performance of the device are also significant changes.
Changes in the sterilization process have the potential for affecting the safety or effectiveness of the devices and thus must be carefully assessed. For example, changes that reduce the sterility assurance level (SAL) to less than 10-6 would routinely need an amended licence application, as would those that ordinarily affect the integrity of device materials.
In general, all changes to the design or performance specifications of a device, not leading to an amended licence application for the addition of new device identifiers (catalogue numbers) must be reported to the Medical Devices Bureau at the time of device licence renewal.
3.4.1 Control Mechanism
Changes in the CONTROL MECHANISM of a device raise questions of safety and efficacy. Therefore, in most circumstances, these changes require an amended licence application. For example, medical devices are often controlled by software programs through complicated sampling and feed back reporting. A software change which results in a change in the algorithm used to control a device in most cases would be a SIGNIFICANT CHANGE.
Similarly, a change in the sensor controlling the fresh air proportions in an anaesthesia machine would also be a SIGNIFICANT CHANGE. These changes most often will be supported by pre-clinical testing of the new CONTROL MECHANISM.
3.4.2 Operating Principles
Changes to the operating principles, including a change in the source of energy used by the device, usually require amended licence applications. These changes are often accompanied by SIGNIFICANT CHANGES to device labelling, and may need both preclinical and clinical testing to substantiate the safety and effectiveness of the altered device.
For example, the internal components of an automatic implanted cardiac defibrillator, including the capacitors, telemetry coils, batteries and transformers were altered with the aim of improving efficiencies in the device operations. These changes are significant, and require an amended licence. However, the application would require only pre-clinical evidence supporting the change, including performance criteria and release specifications. These changes do not require clinical evidence of safety and effectiveness.
A change from an internal DC power source to an external AC source is however considered a significant change in the operating principles of a device. Similarly, the addition of a new foot switch to an electrosurgical generator or other device, addition of "hot keys" and corresponding software to the operating console are significant changes. These changes are supported by preclinical testing and in the absence of new indications for use, clinical data is not required.
3.4.3 Design Characteristics
For some devices, notably non-active surgically invasive devices, such as orthopaedic implants, it is their design characteristics that define their safety and effectiveness, in contrast to control mechanisms or operating principles for active medical devices.
Changes in design characteristics for these devices are significant if they allow for additional or broader indications for use. Thus, a smaller sized hip prosthesis or fracture fixation screw are significantly different from their predicate designs. These amended device licence applications are supported either by a description of the new device and/or objective evidence of safety and effectiveness. Clinical evidence may be required to support new indications for use of the modified design.
3.4.4 Performance Specifications
Collectively, changes to the performance specifications, physical description, patient or user interface, software or firmware may be significant if they affect the indications for use of the device. If these changes collectively result in a change to the indications for use, they are significant and require an amended licence application.
If the response to any of the following three questions is yes, then it is likely that the design change is significant and an amended licence application should be submitted:
- Does the change affect the INDICATIONS FOR USE, i.e. does it create a new indication for use?
- Are clinical data necessary to support the safety and effectiveness of the altered device?
- Do the results of a risk analysis, undertaken during the design validation process, raise new issues of safety and effectiveness?
For example, the change in substrate for an IVDD test kit from a venous blood sample to a dried blood spot is a significant change in performance characteristics, leading to enhanced performance claims. This change will need to be supported by both pre-clinical and clinical test results.
Changes in performance specifications can result from design changes made to cardiac pacing leads. The addition of two or more electrodes, or a new anchoring mechanism can result in new indications for use, as well as enhanced performance claims. In this instance the significant change must be supported by both pre-clinical and clinical results.
3.5 Flowchart D - Changes in Materials
Changes to the materials of a device may lead to subsequent changes, such as manufacturing processes, equipment, labelling or changes to the device performance specifications. The following changes should be considered before applying the logic scheme presented in Flowchart D for material changes.
- All changes to the sourcing or processing of materials of human or animal origin are considered significant and must result in an amended licence application.
- Changes within a single generic material type or changes in formulation can affect the chemistry, metallurgy or other property, such as stability, of the device. These changes must be reviewed in the same manner as changes made to the type of material. Initially, manufacturing processes and equipment, labelling and performance specifications should be reviewed to determine if significant changes have occurred.
In each of the above instances, it must be determined if the device is a surgically invasive device intended to be absorbed by the body or to remain in the body for at least thirty consecutive days. If this is the case, and the altered material would be in contact with body tissues or fluids, then an amended licence application is required. Even when the material would not be in contact with body tissues and fluids, the question of performance specifications arises. If changes to the performance specifications are required, they should be reviewed with the guidance of Flowchart C.
In cases where devices are not intended to be absorbed by the body or to remain in the body for at least 30 consecutive days, but where the altered material is in contact with body tissues or fluids an amended licence application is required if additional biocompatability testing must be done, or referenced. The amended licence application must contain the biocompatability data. As in other cases, changes to performance specifications must be considered with the aid of Flowchart C.
If the supplier or vendor of the material changes, but the material meets the manufacturer's previously reviewed acceptance criteria, then that change is not significant and should only be documented under the quality system.
3.5.1 Changes in Materials in in vitro diagnostic devices (IVDD)
There is a distinction between in vitro diagnostic devices and other devices with regard to material changes. For in vitro diagnostic devices, changes in materials must be carefully judged using Flowcharts B to E.
Changes to materials in an IVDD often affect its performance characteristics, specificity or sensitivity and must be assessed as to their impact on the safety and effectiveness of the device.
Changes that necessitate the testing of additional clinical samples to determine the performance characteristics of the IVDD would be considered significant, and an amended licence application must be submitted. If the additional clinical testing only confirms that the altered IVDD still conforms to the licensed performance specifications and no labelling changes are necessary, then the change simply needs to be documented in the quality management system.
Changes to the materials of an IVDD may result in a change to the operating principle of the product, for example: change from a liquid to solid reagent; change from an RIA to a non-RIA; changes in the source or type of antibody that are likely to produce a change in antibody specificity, affinity, or purity; change from immunofluorescence to ELISA; or change in the conjugates. Such changes are considered significant and require the submission of an amended licence application.
Changes to materials that potentially affect the performance characteristics of an IVDD include changes in reaction components or materials such as calibration materials, or changes in methods of specimen pretreatment, incubation times and temperatures. If these changes result in altered performance characteristics that must be reflected in the labelling, then an amended licence application is required. If changes in the preservatives or the formulations of existing materials do not affect the performance characteristics or lead to labelling changes, no amended application is necessary.
3.6 Flowchart E - Changes to Labelling
Changes to a device, including changes to performance specifications and materials often lead to labelling changes. Labelling changes also occur in response to changing user requirements. Each labelling change must be considered separately and the manufacturer should refer to the logic scheme presented in Flowchart E.
Changes to the indications for use will require an amended licence application, unless the changes are within an approved set of indications, e.g. three indications for use have been previously licensed and the labelling is changed to reflect only two.
Changes to the existing warnings and precautions for a device may not trigger the need for an amended licence application. However, in the case where these changes add a new contraindication, warning or precaution, an amended licence application is required.
Note: Where this new contraindication is vital to public health and safety the change should be implemented immediately, with simultaneous application to the Bureau for an amended licence application.
Precautions describe any special care to be exercised by a practitioner or patient for the safe and effective use of a device, including an IVDD. Warnings describe serious adverse reactions and potential safety hazards that can occur in the proper use or misuse of a device, along with consequent limitations in use and mitigating steps to take if problems occur.
The deletion of a contraindication, such as "single use only," is considered a significant change and requires an amended licence application.
For example, a manufacturer of a dental implant proposes to remove the contraindication against the use of the device in patients who smoke. This is considered a significant change, and must be supported by evidence of safety and effectiveness and the new labelling.
Changes made to device labelling solely for the purposes of clarifying instructions in order to make the device easier, safer or more effective to use will not require an amended application. For example, device labelling often requires modifications in language and structure to be used by a lay person. Provided no changes are made in the indications for use, these changes are not significant.
Changes to labelling to include additional languages, other than French or English required in other regulatory jurisdictions are not significant.
Generally, changes in the expiration date for use of a device will not result in the need for an amended application. For example, an expiration date may be increased due to additional validation data being available. These changes are not significant, provided validation processes and procedures have not been changed from those in place at the time of the original licence application, or latest amendment. Changes in the methods used for determining shelf life of the product are significant.
4 Process and Procedures
4.1 Significant Changes
If a significant change is made to a Class III or IV device, an application for an amended licence must be made using the Application for Licence Amendment. This application will be processed in accordance with the Management of Applications for Medical Device Licences and Investigational Testing Authorizations Policy.
In addition to the application form, a premarket review document applicable to the risk classification of the device must be submitted. Identical changes made to Class III and IV devices may result in different review components being submitted. The review components submitted must contain information and documents that are relevant to the change (refer to the guidance document Preparation of a Premarket Review Document for Class III and IV Device Licence Applications GD008).
4.2 Obligation to Inform - Other Changes
If changes have been found not to be significant by applying the principles of this guidance document and these changes are related to the information and/or documents supplied by the manufacturer with respect to the device, then the changes must be reported to the Bureau at the time of licence renewal (Section 43(1)(b) of the Regulations). These changes should be briefly itemized, in a tabular form with appropriate dates and with any necessary attachments.
Some of these changes may have been the subject of amended device licence applications under Section 34(e) of the Regulations.
5 Bibliography
"Deciding When to Submit a 510(k) for a Change to an Existing Device." U.S. FDA ODE 510(k) Memorandum # K97-1, 10 January 1997.
Official Journal of the European Communities, No. L169/1. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices.
Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications V.2, October 23, 1998.
"The New 510k Paradigm - Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications." U.S. FDA ODE, 20 March 1998.
6 Appendices 1 to 7
Appendix 1 - Main Flowchart
Click to enlarge
Appendix 2 - Flowchart A - Changes in Manufacturing Process, Facility or Equipment
Click to enlarge
Appendix 3 - Flowchart B - Changes in Manufacturing Quality Control Procedures
Click to enlarge
Appendix 4 - Flowchart C - Changes in Design or Performance Specifications
Click to enlarge
Appendix 5 - Flowchart D - Changes in Materials (Medical Devices)
Click to enlarge
Appendix 6 - Flowchart E - Changes in Labelling
Click to enlarge
Appendix 7 - Table of Examples
| Device | Proposed Change | Significant or not | Supporting Data |
|---|---|---|---|
| Dental Implants | Deletion of a contraindication | Yes, this is a significant labelling change, including concurrent changes to the warnings. | Complete amendment, including meta-analysis of clinical results. |
| Hemofiltration System, including software controls. | Addition of a new component, a combined filter and disposable cartridge for convenience. | Yes, significant change in the design of the system. | Complete amendment, including data to support the safety and effectiveness of the new component. |
| Transurethral Thermal System for the treatment of benign prostatic hyperplasia. | Change in software, to provide automatic control of ramping power, respond to elevated rectal temperatures automatically and adjust power. | Yes, significant change to the design, operating principles and performance specifications | Complete amendment, including details of software validation. |
| Metallic Biliary Stent for treating malignant strictures. | A change in the delivery system, addition of two new stent lengths. | Yes, a significant change to the delivery system. New stent lengths are intermediate between previously licensed stent lengths, and these changes are not significant. | Complete amendment, including preclinical evidence of safety and effectiveness. Clinical data is not required for this indication for use. |
| Total Knee System | Addition of longer femoral augments. | Yes, a significant change to the design and performance specifications for the system. | Device description of the new components, attestation that addition testing is not required. |
| Total Hip System | Addition of a new bearing surface. | Yes, a significant change to the design and performance specifications for the system. | Complete amendment, including clinical evidence supporting the new components. |
| Acetabular Cup System | Changes to the design of the acetabular shell, the addition and deletion of placement holes. The addition of a larger shell and liner. | Yes, the additions of a new liner and additional holes are significant changes in the design and performance of the system. The removal of holes in the acetabular shell is not considered a significant change. |
Device description of the new components. Evidence that the larger liner is safe and effective. |
| Bone Void Fillers and Putty | An increase in the amount of cancellous bone material in the filler. | Yes, a significant change to the materials, leading to changes in performance specifications. | Device description and material specifications, including physical strength and characteristics. |
