Guidance Document - Guidance for Manufacturers of Human Immunodeficiency Virus (HIV) Rapid Diagnostic Tests (RDTs) for use at the Point of Care or for Self-Testing

    (PDF Version - 192 K)

Date adopted: 2017/10/20
Effective Date: 2017/11/20

Table of Contents

• 1 Introduction
  • 1.1 Policy Objective
  • 1.2 Scope and Application
  • 1.3 Background
  • 1.4 Definitions
• 2 Guidance for Implementation
  • 2.1 General Requirements
    • 2.1.1 Quality Control
    • 2.1.1.1 External Material
    • 2.1.1.2 Internal Control
    • 2.1.2 Performance Panels
    • 2.1.3 Study Sites outside of Canada
    • 2.1.4 Study Protocol and Study Report
    • 2.1.5 Presentation of Test Results
    • 2.1.6 Minimum Clinical Sensitivity and Specificity
  • 2.2 Human Immunodeficiency Virus (HIV) Point of Care (POC) Tests
    • 2.2.1 Performance Studies
    • 2.2.1.1 Analytical
    • 2.2.1.2 Clinical
    • 2.2.1.2.1 Study Design
    • 2.2.1.2.2 Study Population
    • 2.2.1.2.3 Comparator Assays
    • 2.2.1.2.4 Near Patient Studies (Usability studies)
    • 2.2.1.3 Labelling
  • 2.3 Human Immunodeficiency Virus (HIV) Tests intended for Self-Testing
    • 2.3.1 Performance studies
    • 2.3.1.1 Analytical
    • 2.3.1.2 Clinical
    • 2.3.1.2.1 Study Design
    • 2.3.1.2.2 Study Population
    • 2.3.1.2.3 Comparator Assays
    • 2.3.1.2.4 Near Patient Studies (Usability studies)
    • 2.3.1.3 Labelling
• 3 Customer Support Services
• 4 Appendix A; Recommendations for Analytical, Clinical and Near Patient Studies
• Table 1: Analytical Studies for rapid diagnostic tests (RDTs) intended for use at the Point of Care (POC) and/or for Self-testing
• Table 2: Minimum number of samples for calculation of Sensitivity and Specificity
• Table 3: Near Patient Studies using Untrained Users

1 Introduction

The purpose of this guidance document is to provide manufacturers of Class IV Human Immunodeficiency Virus (HIV) rapid diagnostic tests (RDTs) intended to be used at the point of care (POC) and/or for self-testing (home testing) with specific recommendations on: (1) the analytical and clinical data, and (2) device labelling, required to support a medical device licence application.

1.1 Policy Objective

To facilitate the submission of the analytical (pre-clinical), clinical and labelling content of a licence application filed pursuant to sections 32 and 34 of the Medical Devices Regulations (Regulations) for HIV rapid diagnostic tests intended to be used at the Point of Care and/or for self-testing.

1.2 Scope and Application

This guidance applies to Class IV HIV rapid diagnostic tests (RDTs) intended to be used at the POC and/or for self-testing.

It makes recommendations on the labelling requirements specific to an HIV POC or HIV self-test as per sections 21 to 23 of the Regulations and the analytical, clinical and near patient study design and data required as per sections 32(4) (i)(i) and 32(4)(k). It does not address other elements of safety and effectiveness, such as process validation, software validation and literature studies. Please refer to the guidance Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications and the guidance Labelling of In Vitro Diagnostic Devices for additional data and labelling requirements.

This guidance does not apply to HIV test kits which are used for patient management, donor screening or those intended for laboratory use. A separate guidance, Guidance for Manufacturers of Human Immunodeficiency Virus (HIV) Test Kits Intended to be used in the Laboratory is available for manufacturers of laboratory based kits.

This guidance does not address issues related to investigational testing (clinical trials). Manufacturers of HIV test kits wishing to conduct investigational testing in Canada should refer to the guidance document Preparation of an Application for Investigational Testing - In Vitro Diagnostic Devices (IVDD). It is recommended that you contact Health Canada prior to beginning your studies to discuss protocol and study design.

The cited guidance documents can be found on the Health Canada website.

1.3 Background

The following documents, reviewed in the development of this guidance, may be useful to manufacturers of HIV rapid diagnostic tests as background information on the studies and performance requirements for RDTs used at the POC or for self-testing.

1. OraSure Technologies. Final Advisory Committee Briefing Materials: Available for Public Release, OraQuick In-Home HIV Test, Food and Drug Administration, Blood Products Advisory Committee, 2012.
2. PATH, Target Product Profile: HIV Self-Test, Version 4.1. White paper on the evaluation of current HIV rapid tests and development of core specifications for next-generation HIV tests. May 2014.
3. TGA. Clinical performance requirements and risk mitigation strategies for HIV tests. Version 1.0. March 2015.
4. Technical Specifications Series for submission to WHO Prequalification - Diagnostic Assessment: Human Immunodeficiency Virus (HIV) rapid diagnostic tests for professional use and/or self-testing. Geneva: World Health Organization; 2016.

In addition, international guidance documents prepared by the Global Harmonization Task Force (GHTF) and the International Medical Devices Regulator Forum (IMDRF) may also be helpful in the preparation of a medical device licence application.

These documents include:

1. The “Summary Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance of In Vitro Diagnostic Medical Devices”
2. “In Vitro Diagnostic Medical Device Market Authorization Table of Contents (IVD MA ToC)”

1.4 Definitions

Near Patient in vitro diagnostic device or near patient IVDD

an in vitro diagnostic device that is intended for use outside a laboratory, for testing at home or at the point of care, such as a pharmacy, a health care professional’s office or the bedside. (Medical Devices Regulations)

Health care professional

a person who is entitled under the laws of a province to provide health services in the province. (Medical Devices Regulations)

Abbreviations and Acronyms

Ab: antibody
Ag: antigen
HCP: Health Care Professional
IVDU: Intravenous drug user
POC: Point of care
RDT: Rapid diagnostic test

2 Guidance for Implementation

2.1 General Recommendations

2.1.1 Quality Control

2.1.1.1 External Material

External quality control (QC) material (both positive and negative) should be available for HIV RDTs intended for use at the POC. If you are the manufacturer of the external QC material, you may wish to consult with Health Canada on licensing requirements. For manufacturers that do not intend to provide external controls, the package insert should clearly include instructions on how to obtain appropriate external controls.

2.1.1.2 Internal Control

An internal or built in control should be included in the design of the kit. The internal control should verify the specimen and buffers/solutions have flowed through the device correctly. A control which appears even if a specimen is not added is not acceptable.

2.1.2 Performance Panels

Commercial or non-commercial panels which are used to establish performance claims should be well characterized. The data sheets or results of testing which confirm the reactivity of the samples should be provided. For non-commercial panels, the tests used to characterize the samples should be identified and the Canadian medical device licence number for these tests should also be provided.

2.1.3 Study Sites outside of Canada

When the data used to support the clinical performance claims of the device is obtained from sites outside Canada, the manufacturer should ensure the quality, integrity and scientific validity of the data. In addition, the studies should be conducted under good clinical practices, be appropriately monitored and protect the rights, safety, and well-being of the subjects providing the specimens used in the clinical performance studies.

Manufacturers should provide evidence that the laboratories in which data are generated meet the requirements of good laboratory practices (GLP) or equivalent. This evidence should be in the form of a certificate of accreditation or equivalent.

2.1.4 Study Protocol and Study Report

The complete study protocol and final study report for each analytical, clinical and near patient (including usability) study should be provided. Each protocol and report should be properly identified with a document reference number, version number and date.

The study protocol should include the objectives, study population, description of test method(s) and interpretation of results, specimen type, specimen collection, preparation, handling and storage, inclusion and exclusion criteria, limitations, warning and precautions, data collection/management, data analysis, required materials, number of study sites and if applicable, clinical endpoints/outcomes, and requirements for patient follow-up. It should also identify the key factors which may impact the completeness and significance of results, such as intended participant follow-up procedures, decision algorithms, discrepancy resolution process, masking/blinding, approaches to statistical analyses, and methods for recording endpoints/outcomes and, where appropriate, communication of test results.

The study report should include, as appropriate, any protocol amendments or deviations, and data exclusions with the appropriate rationale; explanations for any discrepant results and how they were resolved, test result summaries (for analytical data) with acceptance criteria and formatted raw data (individual data points) for clinical studies. Study conclusions should be stated. A summary of each study should also be provided.

For all studies done on behalf of a Manufacturer, a copy of the laboratory evaluation report, signed and dated by the principal investigator, should be provided. If the laboratory evaluation report is not prepared in English or French, a certified and notarized translation should be provided (i.e. an exact translation signed by the translator and verified by a notary public with the official notary seal affixed).

2.1.5 Presentation of Test Results

When feasible, it is recommended that photographs of the completed tests be provided. Reactive results should be graded according to the intensity of the observed reaction. The grading scale with photographs should be provided. Reactive results should not be reported as “+”, “pos”, or “positive” as these results cannot be properly evaluated.

2.1.6 Minimum Clinical Sensitivity and Specificity

Evidence that the RDT intended for use at the POC or for self-testing has a minimum sensitivity and specificity of ≥99% for HIV antibody detection should be provided and the 95% confidence intervals should be calculated.

2.2 Human Immunodeficiency Virus (HIV) Point of Care (POC) Tests

An HIV test that is intended to be used at the POC is considered a near patient in vitro diagnostic device (near patient IVDD). POC refers to a variety of settings which are outside a laboratory such as a pharmacy, a health care professional’s office, sexual health clinics, or mobile outreach clinics. In the POC setting, it is a Health Care Professional (HCP) who administers the test.

2.2.1 Performance studies

The analytical, clinical and near patient studies used to establish the performance characteristics of an HIV test kit used at the POC should be designed to support all claims made by the manufacturer with respect to the device.

2.2.1.1 Analytical

The studies that are necessary to validate the analytical performance of the device will depend on whether it is a qualitative or quantitative test. However, in most cases, the following studies will be needed:

• Specimen type studies;
• Precision (repeatability and reproducibility);
• Analytical sensitivity (when claims for p24 antigen are made);
• Analytical specificity (interference and cross reactivity);
• Robustness;
• Stability

Please refer to Table 1 in Appendix A which provides additional details and recommendations regarding the analytical studies.

2.2.1.2 Clinical

Prospective clinical studies should be conducted to establish the clinical sensitivity and clinical specificity of the device.

2.2.1.2.1 Study Design

Clinical sensitivity and specificity studies should be designed as follows:

• Testing should be done using a minimum of three production lots;
• Testing should be done at a minimum of three geographically distinct POC sites (e.g. sexual health clinic, doctor’s office) by the intended operators;
• The results from the POC device should be compared to serological results obtained on a sample collected at the time the POC test is administered. Serological testing should be done using, at a minimum, a 4^th generation EIA test that is licensed in Canada. All reactive EIA tests should be confirmed by more specific methods. The test algorithm used by the collaborating laboratory should be provided to Health Canada and should be representative of the HIV test algorithms implemented in Canada.
• The number of samples that give indeterminate or invalid results should be provided;
• All discrepant results between the test under investigation and the test of reference should be clearly indicated and resolved using supplemental, specific assays, definitive clinical data, or clinical follow up; and,
• Sensitivity, specificity and their 95% confidence intervals should be calculated.

The clinical sensitivity and clinical specificity of a RDT intended to be used at the POC should be established using the sample numbers and sample types (e.g. confirmed HIV positive samples, low titer and seroconversion panels, HIV subtypes, clinical samples) described in Table 2 of Appendix A.

2.2.1.2.2 Study Population

Clinical studies should be performed using samples that represent an ethnically and genetically diverse population so as to be representative of the Canadian population. In addition, the performance of the tests should be established in a population with similar HIV prevalence rates to those seen in Canada.

2.2.1.2.3 Comparator Assays

For all clinical studies, the comparator assay should be licensed in Canada. A database listing of licensed medical devices is available on the Health Canada website (Medical Devices Active Licence Listing (MDALL)).

If the comparator test used is not licensed in Canada, the manufacturer should contact Health Canada for further guidance.

2.2.1.2.4 Near Patient Studies (Usability studies)

Near patient studies which establish the performance of the device when used by the intended user, in the intended setting, without assistance and following the instructions provided in the labelling should be provided. Near patient studies include usability studies which establish whether untrained users can understand the key messages in the labelling and whether these users can correctly perform the test and interpret the test results.

If clinical sensitivity and clinical specificity are established using trained HCPs, near patient studies which establish diagnostic accuracy using untrained HCP should be provided along with studies that demonstrate the ability of the untrained HCP to interpret a variety of test results. The results from a questionnaire which assesses how well the untrained HCP understood how to use the device should also be provided. Additional details on these studies are provided in Table 3 of Appendix A.

2.2.1.3 Labelling

The version of the instructions for use (IFU) and Quick Reference Guide used for the clinical and near patient studies should be provided. In addition the final version of the labelling with the history and the reasons for all changes made (if applicable) should be provided.

2.3 Human Immunodeficiency Virus (HIV) Tests intended for Self-Testing

An HIV test that is intended to be used for self-testing is considered a near patient in vitro diagnostic device (near patient IVDD). The intended user of a self-test is a layperson.

2.3.1 Performance studies

The analytical, clinical and near patient studies used to establish the performance characteristics of an HIV test kit for self-testing should be designed to support all claims made by the manufacturer with respect to the device.

2.3.1.1 Analytical

The studies that are necessary to validate the analytical performance of the device will depend on whether it is a qualitative or quantitative test. However, in most cases, the following studies will be needed:

• Specimen type studies;
• Precision (repeatability and reproducibility);
• Analytical sensitivity (when claims for p24 antigen are made);
• Analytical specificity (interference and cross reactivity);
• Robustness;
• Stability

Please refer to Table 1 in Appendix A which provides additional details and recommendations regarding the analytical studies.

In cases where a manufacturer of a Health Canada licensed HIV POC test wishes to make a claim for self-testing; the analytical studies for the POC device may be used to support performance of the self-test device. If, however, the manufacturer has modified the POC device such that the device intended for POC use and the device intended for self-testing are not identical, additional studies will be needed to demonstrate that the analytical performance is unchanged. Additional studies may also be identified by the risk analysis conducted by the manufacturer for the self-test device.

2.3.1.2 Clinical

Prospective clinical studies should be performed to establish the clinical sensitivity and clinical specificity of the device. Manufacturers of HIV self-tests devices may establish clinical performance using trained users in a controlled setting (e.g. point of care) however near patient studies which establish the accuracy of the test using untrained lay users will be necessary (see section 2.3.1.2.4 below).

In cases where a manufacturer of a Health Canada licensed HIV POC test wishes to make a claim for self-testing; the clinical studies for the POC device may be used to support performance of the self-test device. However, near patient studies will still be required (see section 2.3.1.2.4 below).

2.3.1.2.1 Study Design

Clinical sensitivity and specificity studies should be designed as follows:

• Testing should be done using a minimum of three production lots;
• Testing should be done at a minimum of three geographically distinct sites using the intended operators;
• The results from the self-test device should be compared to serological results obtained on a sample collected at the time the self-test is administered. Serological testing should be done using, at a minimum, a 4th generation EIA test that is licensed in Canada. All reactive EIA tests should be confirmed by more specific methods. The test algorithm used by the collaborating laboratory should be provided to Health Canada and should be representative of the HIV test algorithms implemented in Canada.
• The number of samples that give indeterminate or invalid results should be provided;
• All discrepant results between the kit under investigation and the test of reference should be clearly indicated and resolved using supplemental, specific assays, definitive clinical data, or clinical follow up; and,
• Sensitivity, specificity and their 95% confidence intervals should be calculated.

The clinical sensitivity and clinical specificity of an HIV self-test should be established using the sample numbers and sample types (e.g. confirmed HIV positive samples, low titer and seroconversion panels, HIV subtypes, clinical samples) described in Table 2 of Appendix A.

2.3.1.2.2 Study Population

Clinical studies should be performed using samples that represent an ethnically and genetically diverse population so as to be representative of the Canadian population. In addition, the performance of the tests should be established in a population with similar HIV prevalence rates to that seen in Canada.

2.3.1.2.3 Comparator Assays

For all clinical studies, the comparator assay should be licensed in Canada. A database listing of licensed medical devices is available on the Health Canada website (Medical Devices Active Licence Listing (MDALL)).

If the comparator test used is not licensed in Canada, the manufacturer should contact Health Canada for further guidance.

2.3.1.2.4 Near Patient Studies (Usability studies)

Near patient studies which establish the performance of the device when used by the intended user, in the intended setting, without assistance and following the instructions provided in the labelling should be provided. Near patient studies include usability studies which verify whether untrained users can understand the key messages in the labelling (label comprehension study) and whether these users can correctly perform the test (accuracy study) and interpret the test results (test result interpretations study).

Additional details on these studies are provided in Table 3 of Appendix A.

2.3.1.3 Labelling

The instructions for use (IFU) and Quick Reference Guide used for the clinical and near patient studies should be provided. In addition the final version of the labelling with the history and the reasons for all changes made (if applicable) should be provided.

The IFU should make use of pictures or diagrams as much as possible with text targeted to a Grade 6 reading level. The intended use should be simple and clear. All components and steps for performing the assay should be clearly and simply described. Examples of positive, negative and invalid test results should be included.

Links to local support services must be provided.

It is strongly recommended that an on-line video be available to assist lay users in the correct performance of the test.

3 Customer Support Services

Manufacturers should provide evidence that procedures are in place to ensure that self-testers have access to appropriate support and counselling services. Pre and post-test counselling is a critical component of HIV testing and functions to ensure that individuals are informed about their risk and are provided information on how to protect themselves and others from exposure to HIV. For individuals who test positive, they need to be connected with and have access to support services.

Manufactures should ensure the links and contact phone numbers that will provide local and national support and counselling services are valid and kept up to date.

4 Appendix A: Recommendations For Analytical, Clinical and Near Patient Studies