Draft guidance document HIV Simple/Rapid Test Kits
This guidance document is being distributed for comment purposes only.
Published by authority of the Minister of Health
Draft Date: 1997
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- minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and
- promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health. Health Products and Food Branch
Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.
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 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 document, 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 guidance documents.
Table of Contents
- 1. Background
- 2. General information on the evaluation process of hiv device licence applications
- 3. Safety and Effectiveness Studies
- 4. Device label
- Appendix 1
An application for a Medical Device Licence for HIV test kits must be prepared in accordance with Section 32 of the Medical Devices Regulations.
The Guidelines for HIV Simple/Rapid Test Kits are intended to give additional details specific to Class 4 HIV test kits on the requirements of Section 32 (4) (a) to (p). This document is a complement to the guidance document “Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications”Footnote 1 and, therefore, manufacturers must ensure that all subsections found in the guidance document are fully addressed in their application, not only those mentioned in these Guidelines.
These Guidelines were developed by representatives from the Provincial Laboratory B.C. Centre for Disease Control, Alberta's Provincial Laboratory of Public Health, the Laboratoire de Santé Publique du Québec, the Ontario Ministry of Health Central Laboratories, the B.C. Centre for Excellence in HIV/AIDS, the Canadian Red Cross Society, the Laboratory Centre for Disease Control (LCDC) and the Medical Devices Bureau (MDB).
The Medical Devices Bureau reserves the right to ask for more information than is requested in these Guidelines if it is felt that such data are necessary to substantiate the safety and effectiveness of the kit.
2. General Information on the Evaluation Process of HIV Device Licence Applications
In support of their Device Licence Application, all manufacturers of HIV test kits will be required to conduct prospective investigational studies in the intended target population (intended users). Investigational studies can only be undertaken once the Manufacturer has obtained an “Authorization for Investigational Testing” from the Medical Devices Bureau in accordance with Sections 79 to 88 of the Medical Devices Regulations.
Some laboratory studies (e.g. sensitivity studies, panel studies) can be conducted in Canadian laboratories without a prior “Application for Investigational Testing Authorization” from the Medical Devices Bureau, provided these studies are conducted on repository specimens of known HIV status (e.g. repository confirmed HIV positive samples, panels, etc.). In these cases, the kits must be labelled "For Research Use Only".
The following subsections are numbered in accordance with those found in the “Guidance Document: The Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications” Section 7.0 Format of a Class IV Review Document (IVDDs) - They are intended to complement this Guidance Document and, therefore, Manufacturers must ensure that all 8 sections of the Guidance Document, which cover the requirements of Section 32, subsection (4) paragraphs (a) to (p) of the Medical Devices Regulations, are fully addressed in their application, not only those mentioned below.
- 7.4.1 MATERIAL SPECIFICATIONS
As part of the information required in this section, include details regarding the strain of the virus, the cell line for the cultivation of the virus, sequences of relevant nucleic acids and amino acids, etc., used in the manufacturing process of viral lysate, purified proteins, recombinant and synthetic proteins, primers, probes, etc.
- 7.4.2 MANUFACTURING PROCESS SPECIFICATIONS
As part of the information required in this section, include a flow chart of the manufacturing process on which all Quality Control (QC) steps are indicated. Provide detailed information of the QC procedures.
The information should also include details of the manufacturing process and of the Quality Assurance Program in place for the preparation of viral lysate, purified proteins, recombinant and synthetic proteins, primers, probes, immunoglobulin, immunoglobulin-proteins conjugate, positive and negative controls, coated plates, etc.
3. Safety and Effectiveness Studies
Manufacturers are strongly encouraged to contact a designated Canadian laboratory (see attached list) for a pre-investigational evaluation of their kits and to submit this data in support of an “Application for Investigational Testing Authorization”.
In cases where the data are generated in laboratories (Canadian or foreign) other than those mentioned in the attached list, provide a certificate of accreditation, or equivalence, for the said laboratories, attesting that the laboratory meets the requirements of Good Laboratory Practices, or equivalent.
For all studies done on behalf of a Manufacturer, a copy of the laboratory evaluation report, signed and dated by the principal investigator, must be provided.
- A prospective study in the intended Canadian target population on 2,500 individuals, 500 of which must be from a high risk population. The study must be conducted in at least three different cities, two of which should be Montreal, Vancouver or Toronto. Samples should be distributed equally among the different investigational sites. This study can only be undertaken once the Manufacturer has received an Investigational testing authorization from the Medical Devices Bureau in accordance with sections 79 to 88 of the Medical Devices Regulations.
- At this time, the results obtained from simple/rapid test kits must be compared to conventional serological testing done in designated laboratories.
- The study must be performed on three (3) master lots, one of which should be close to its expiry date.
- Results must be expressed in terms of: # of non-reactive samples, # of reactive samples, # of indeterminates for both the rapid test kit and the test of reference. Calculate specificity and 95% confidence intervals.
- All discrepant results between the kit under investigation and the test of reference must be clearly indicated and resolved using supplemental, specific assays, or definitive clinical data or clinical follow up.
- If applicable, studies must be conducted to determine if the users understand the purpose of the test, the conditions for its use, the tests limitations, the meaning of the result (positive, negative or indeterminate) and the appropriate follow-up.
|Intended use of the kit||confirmed HIV positive||Commercial sero-conversion panelsFootnote T2||panels of the various cladesFootnote T3||recent Canadian seroconverted samplesFootnote T4|
|Rapid Test Kits (serum or whole blood)|
|Rapid Test Kits (saliva or urine)|
|HIV-1||1,000||NR||as available||Yes||as available|
|HIV-1/HIV-2||1,000||30||as available||yes||as available|
Note: Deficiencies in the evaluation of the kit due to the unavailability of panels or samples will need to be addressed in the package insert, .e.g. under “limitations of the assay”.
3.1.2 Additional Instructions for Specificity and Sensitivity Studies
For all studies conducted in laboratories other than the designated Canadian Laboratories, data presentation should include a summary of the data in the form of Tables, as well as the detailed results (actual OD values, WB bands, other read-out values) of individual specimens obtained with both the investigational kit and the kits of reference. For photographs of gels and blots, only originals are acceptable.
For studies conducted in designated Canadian Laboratories, summaries of the data, in the form of Tables and Figures, is sufficient.
For all studies done on behalf of a Manufacturer, a copy of the laboratory evaluation report, signed and dated by the principal investigator, must be provided.
3.1.3 Criteria of Acceptability for Sensitivity and Specificity of HIV Rapid Test Kits
- OTC HIV Home Test Kits: to be considered for receiving a Medical Device Licence, the predictive values in the intended target population will need to be equivalent to those obtained by the testing algorithm in practice in Canadian Provincial Laboratories. A built-in (internal) control must be included in the design of the kit.
- For other rapid test kits, such as those used in Health Care settings, the manufacturers will have to demonstrate that the performance characteristics of the kits agree with their intended use (objective). A built-in (internal) control should be included in the design of the kit.
Any potentially cross-reacting or interfering substances or conditions potentially encountered in specific specimen types should be tested using the assay system. For example:
- if the antigen utilized in the device is a recombinant, test sera containing antibodies against the organism in which vectors were induced
- if the antisera utilized in the devices were produced by using recombinant(s) as the immunogen(s), test sera containing antibodies against the organism in which the vectors were induced.
- verify that recommended specimen storage conditions are compatible with the assay, i.e. can the specimen be frozen and thawed one or more times without affecting the qualitative detection of the analyte? Both the possibility of false positivity or false negativity due to storage conditions of the specimens should be evaluated.
- samples from individuals with non-HIV viral infections (Hepatitis C virus, Hepatis B virus, Hepatitis A virus, Epstein-Barr virus, Herpes simplex virus, Rubella, Cytomegalovirus, etc.), other retroviral infections (Human T-cell Lymphotropic virus type I/II), bacterial/parasitic diseases (syphilis, toxoplasmosis), autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), other miscellaneous medical conditions (cancer, cirrhosis, etc.), polyclonal and monoclonal gammopathies (IgG or IgM hypergammaglobulinemia), recipients of multiple blood transfusions, lipemia, haemolysis, etc.
Intra - and inter-assay variations must be determined with a panel consisting of:
- dilutions of an HIV-1 positive specimen (4 above end point with one near cutoff value and 2 below end point and one near cutoff value).
- dilutions of an HIV-2 positive specimen (4 above end point with one near cutoff value and 2 below end point and one near cutoff value).
- 2 negative specimens
- positive control
The specimens should be tested in triplicate on 3 different days (runs) in at least 3 sites on 3 lots (total number of replicates of each member = 3 × 3 × 3 × 3 = 81).
Using a panel similar to the one described in the Reproducibility studies, provide data for each of the three (3) master production lots:
- the recommended shelf life of the unopened kit, reagents, controls, etc., under the recommended storage conditions.
- the recommended product life of the opened kit, reagents, controls, etc.
- the stability of on-board reagents, where applicable.
- the effects of freezing temperature and of extreme heat (≥37°C) on the performance characteristics and the shelf life of the kit. This is to assess the effects of temperature fluctuation during shipment. If the kits are shipped under special conditions (e.g. dry ice) and there is evidence that the kits are not exposed to temperature outside the recommended range, even during summer days, the studies at the higher temperature are not required.
3.5 Other Studies
Prozone effect, robustness of the kit, etc.
4. Device label
The final package insert must clearly describe the performance characteristics of the test kit, i.e. specificity, sensitivity, reproducibility, stability, earliest clinical detection in comparison with tests of reference, etc., and how these were determined.
In accordance with Sections 86(c), 86(d) and 86(e) of the Medical Devices Regulations, all labels to be used in connection with a device that is sold for investigational testing must include the statements “Investigational Device”, “To Be Used By Qualified Investigators Only” and “The performance specifications of this product have not been established”.
Labelling may be an option to address deficiencies in the evaluation of the performance characteristics of kits due to the unavailability of panels or samples, depending on the nature of the deficiency.
The following complements the guidance document, "Preparation of an Application for Investigational Testing In Vitro Diagnostic Devices (IVDD).
Manufacturers must provide the information described in Sections 79-88 of Part 3 of the Medical Devices Regulations in order to obtain an Authorization for Investigational Testing.
The investigational protocol must clearly indicate that the results obtained with the investigational kit are not to be used for clinical patient management since its performance characteristics have not yet been established.
In accordance with the Medical Devices Regulations, all labels to be used in connection with a device that is sold for investigational testing must include the statements “Investigational Device” and “To Be Used By Qualified Investigators Only” and “The performance specifications of this product have not been established”.
|Contact Person and Address||Contact Person and Address|
|LCDC||Dr. J. Kim
A/Chief, National Lab for HIV Reference Services
Laboratory Centre for Disease Control
Virus Building, Tunnel's Pasture, Postal Locator 1002A1
Tel: (613) 957-9666
Fax: (613) 957-7258
|CBS||Dr. Wesley Rees
VP of Safety and Performance Management
1800 Alta Vista Drive
Tel: (613) 739-2300
Fax: (613) 731-1411
|Nfld||Dr. S. Ratnam
Newfoundland & Labrador Public Health Laboratories
PO Box 8800
St. Johns, Newfoundland
Tel: (709) 737-6568
Fax: (709) 737-7070
|SASK||Dr. E. Chan/Mr. F. Sidaway
Microbiology and Communicable Diseases Provincial Laboratory
3211 Albert Street
Tel: (306) 787-3135
Fax: (306) 787-1525
|PEI||Dr. L. P. Abbott
Provincial Health Laboratory
Queen Elizabeth Hospital
PO Box 6600, Riverside Drive
Tel: (902) 894-2309
Fax: (902) 566-6385
|ALB1||Dr. K. Fonseca
Provincial Laboratory of Public Health
3030 Hospital Drive, NW
PO Box 2490
Tel: (403) 670-1200
Fax: (403) 270-2216
|NS||Dr. S. Lee
Department of Virology and Immunology
Victoria General Hospital
D.J. Mackenzie Building
5788 University Avenue
Halifax, Nova Scotia
Tel: (902) 473-6885
Fax: (902) 473-7971
|ALB2||Dr. J. Preiksaitis
University of Alberta
Walter Mackenzie Health Sciences Centre
Tel: (403) 492-4134
Fax: (403) 492-3684
|BC1||Mr. D. Cook
Provincial Laboratory B.C. Centre for Disease Control
828 West 10th Avenue
Vancouver, British Columbia
Tel: (604) 660-6045
Fax: (604) 660-6073
|BC2||Dr. C. Sherlock
Diagnostic Virology & Reference Laboratory
6th floor, Burrard Building
631-1081 Burrard St., St. Pauls Hospital
Vancouver, British Columbia V6Z 1Y6
tel: (604) 631-5426
Fax: (604) 631-5421
|ON||Ms. C. Major
Ontario Ministry of Health Central Laboratories
PO Box 9000, Terminal "A"
Tel: (416) 235-6096
Fax: (416) 235-6194
|QC||Ms. M. Fauvel
Laboratoire de Santé Publique du Québec
20045, chemin Ste-Marie
Tel: (514) 457-2070
Fax: (514) 457-6346
|MAN||Dr. T. Williams
Cadham Provincial Laboratory
PO Box 8450
750 William Avenue
Tel: (204) 945-6123
Fax: (204) 786-4770
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