February 9, 2015
ADMINISTRATIVE ORDER
No. 2015 – 0005
GUIDELINES ON THE PERFORMANCE EVALUATION OF IN–VITRO
DIAGNOSTIC REAGENTS (HIV, HBV, HCV, AND SYPHILIS SCREENING, CONFIRMATORY AND
DISEASE MONITORING TEST KITS)
I. RATIONALE
The
use of the best and quality kits is imperative in providing proper diagnosis
and in ensuring blood products are safe from blood–borne transmissible
infections. In order to support proper diagnosis and blood safety accurate and
reliable laboratory results should be released by the different clinical
laboratory testing center in the country of which this regulation purposely
aims to improve. Certain test kits perform differently in specific geographic
locations and differences in test performance have been reported depending upon
the origin of the samples. Thus, there is a need for assessment and evaluation
by an independent organization to determine the appropriateness of these test
kits in our local setting. Assay evaluations indicate a “point–in–time”
assessment of assay performance, therefore, continued monitoring of the assay’s
ongoing performance should also be implemented.
Pursuant
to the provisions of Republic Act No. 3720 as amended by Republic Act No.
9711, test kits and in–vitro diagnostic reagents must be registered with
the Food and Drug Administration (FDA) of the Department of Health before
release into the Philippine Market.
In
accordance to Department Order No. 393E series 2000 (Designation of
National Reference Laboratories and Transfer of Corresponding Equipment,
Instruments, Supplies, Specimens, Records from the Bureau of Research and
Laboratories), the National Reference Laboratory – STD AIDS Cooperative Central
Laboratory (NRL – SLH/SACCL) of San Lazaro Hospital has been mandated to
perform evaluation, validation and continuous monitoring of test kits in the
diagnosis of HIV and other STIs to endure their quality and good performance in
local setting.
II. SCOPE AND
COVERAGE
These
guidelines shall apply to all manufacturers, traders and distributors
(importers/exporters/wholesalers) of all test kits and in vitro reagents used
to screen, confirm and monitor HIV (antibody and/or antigen), HBV (HBsAg and
other markers), HCV (antibody and antigen) and syphilis (Treponemal and non–
treponemal) infections using serum, plasma or whole blood and other body fluid
samples.
III. DEFINITION
OF TERMS
The
following definitions shall apply:
1. Applicant – refers to a natural or juridical person that seeks
to distribute HIV, HBV, HCV and Syphilis test kits/in–vitro reagents.
2. Center for
Device Regulation, Radiation Health and Research (CDRRHR) – refers to one of the four centers of the Food and
Drug Administration (FDA), mandated to regulate the manufacture, importation, exportation,
distribution, sale, offer to sale, transfer, promotion, advertisement,
sponsorship of and/or, where appropriate, the use and testing of medical
devices including in–vitro diagnostic kits and reagents.
3. Confirmatory
test – refers to tests performed on
samples that are reactive by screening tests to ensure that the screening test
results were accurate.
4. Distributor–Exporter – refers to any establishment that exports raw
materials, active ingredients and/or finished products of screening test kits/reagents
to another country.
5. Distributor–Importer – refers to any establishment that imports raw
materials, active ingredients and/or finished products screening test
kits/reagents for its own use or for wholesale distribution to other
establishments or outlets within the country.
6. Initial
registration – refers to company’s
application to register test kits that has never been registered locally.
7. Point–in–time
assessment – an assessment done for a
test system at that particular point in time when evaluation was performed,
done by a technologist, using a pre–determined set of panel sera and reagent
lot for testing. As such, result of succeeding evaluation done at different
time on the same or different panel may not necessarily produce identical results.
8. Manufacturer – refers to any establishment involved in the
production of an in– vitro diagnostic medical device including processing,
formulating, packing, re– packing, finishing and labeling with the ends in view
of its storage, sale or distribution.
9. Renewal
registration – refers to company’s
application to renew their registration on or before the expiration of their
certificate of product registration.
10. Reactive –
refers to the reported test result from a screening test that indicates
presumptive evidence of infection.
11. Sensitivity
– means the ability of a test to detect very small amounts of analyte, or the
ability of a test to detect infected individuals.
12. Seroconversion
– the point at which specific antigen/antibody can first be detected in an
infected individual who was previously found negative of HBV, HCV, HIV and
Syphilis
13. Specificity
– means the ability of the test to identify negative samples.
14. Trader – any
establishment which is a registered owner of a health product and procures the
raw materials and packing components, and provides the production monographs,
quality control standards and procedures, but subcontracts the manufacture of
such product to a licensed manufacturer. In addition, a trader may also engage
in the distribution and or marketing of its products.
15. Validation –
a process done to monitor the performance of previously approved screening test
kits and verifies performance of other special test systems.
16. Screening test system – an initial test used in a population to identify a
disease in individuals with or without signs or symptoms.
17. Other test systems – test other than screening test, used to monitor/stage infection
a. Confirmatory/Supplemental tests
b. Nucleic Amplification test systems for in vitro
diagnostic use
c. Test to monitor disease activity (e.g. viral load
tests, other serologic markers for Hepatitis B).
IV. GENERAL
GUIDELINES
1. Only applicant company whose application has been
reviewed by the CHRRHR and endorsed to NRL–SLH/SACCL shall be considered for
performance evaluation.
2. NRL–SLH/SACCL reserves the right to ask any other
requirements not indicated in this order but deemed necessary to support the
reliability and authenticity of the submitted documents.
3. The validity of the initial performance evaluation of
all screening test systems shall be two years and it shall undergo validation
every two years upon approval of the initial certificate of product
registration.
4. The validity of the initial performance evaluation of
all other test systems shall be five (5) years and it shall undergo validation
every five years upon approval of the initial certificate of product
registration.
5. The application for the validation shall be applied at
the CDRRHR and the CDRRHR shall endorse the application to NRL–SLH/SACCL.
6. A copy of the Assay Evaluation report shall be issued
directly to FDA by NRL– SLH/SACCL. The NRL–SLH/SACCL shall neither be obliged
to convey statements nor entertain follow–ups of test results by applicant
companies prior to completion of evaluation.
7. Donated reagents from International Donor that are not
included in the list of FDA registered kits cannot be used for diagnostic
testing of patients.
8. If a test kit fails 1% below of the passing criteria,
re–evaluation maybe done depending upon the discretion of applicant company and
must submit requirements within a month to NRL–SLH/SACCL.
9. If a test kit fails >1% below of the passing
criteria, evaluation result will be submitted to FDA without re–evaluation.
Applicant company may re–apply for initial registration to FDA after
improvement on the kit has been made.
V. POLICIES
AND PROCEDURES
A. Documentary
Requirements
The
applicant company shall submit the following documents:
1. Initial
Evaluation – Screening Test Systems
a. Preliminary
Evaluation Requirements
(1) All or any of the following (certified true copy):
· US FDA Approval
· Europe EC Design
Examination Certificate
· Australian
Register of Therapeutic Goods recommendation
· Canada HPFB
recommendation
· Japan NIID
evaluation
· WHO
Prequalification evaluation
· Certificate of
Registration issued by the Health authority of the country where the product is
being sold
(2) Assay Package Inserts
(3) Good Manufacturer Practice Certificate, certified true
copy
(4) Certificate of distributorship from manufacturer
source authenticated by the Philippine Consulate from the country of origin;
(5) Clinical Trial data (Multi–centre) studies;
international publications;
(6) Descriptions of antigen and/or antibody component;
(7) Product specifications and physical description of the
kit for evaluation
b. Performance
Evaluation Requirements:
(1)
Submission of
test systems intended for evaluation;
(a) A minimum of 1000
tests equally divided into two production lots;
(b) Submission of seroconversion or performance panel,
details of these panels can be obtained at NRL–SLH/SACCL.
(c) Kits submitted for evaluation should have an
expiration date of at least 6 months from the date of submission.
(d) Must be transported according to the manufacturer’s
recommendation.
(2)
Payment of
performance evaluation fee to defray cost of supplies and reagents used for the
preparation of serum panels and actual conduct of evaluation subject to change
as maybe deemed necessary.
A
Notice for Submission of Samples will be provided by NRL–SLH/SACCL to the
applicant company upon completion of above requirements. Result of evaluation and
recommendation of NRL–SLH/SACCL will be forwarded to FDA within two (2) months
after submission of all requirements.
2. Renewal /
Re–evaluation for Screening Test System
a. Preliminary
Evaluation Requirements:
The
applicant company shall submit the following requirements:
(1) Latest Certificate of Product Registration
(2) Assay Package Inserts
(3) List of raw materials used as components of the kit;
(4) Product specifications and physical description of the
kit for evaluation.
b. Performance
Evaluation Requirements:
(1)
Submission of
test systems intended for evaluation
(a) A minimum of 1000 tests;
(b) Kits submitted for evaluation should have an
expiration date at least 6 months from the date of submission;
(c) Must be transported according to the manufacturer’s
recommendation;
(2)
Payment of
performance evaluation fee to defray cost of supplies and reagents used for the
preparation of serum panels and actual conduct of evaluation.
A
Notice for Submission of Samples will be provided by NRL–SLH/SACCL to the
applicant company upon completion of above requirements. Result of evaluation
and recommendation of NRL–SLH/SACCL will be forwarded to FDA within two (2)
months after submission of all requirements.
3. Initial/Renewal/Re–evaluation
for other test systems
The
applicant company shall submit the following requirements:
a. Preliminary
Evaluation Requirements
(1) All or any of the following (certified true copy):
· US FDA Approval
· Europe EC Design
Examination Certificate
· Australian
Register of Therapeutic Goods recommendation
· Canada HPFB
recommendation
· Japan NIID
evaluation
· WHO
Prequalification evaluation
· Certificate of
Registration issued by the Health authority of the country where the product is
being sold
(2) Assay Package Inserts
(3) Good Manufacturer Practice Certificate, certified true
copy
(4) Certificate of distributorship from manufacturer
source authenticated by the Philippine Consulate from the country of origin;
(5) Clinical Trial data (Multi–centre) studies;
international publications;
(6) Descriptions of antigen and/or antibody component;
(7) Product specifications and physical description of the
kit for evaluation
c. Performance
Evaluation Requirements:
(1)
Submission of
test systems intended for evaluation;
(a) A minimum of I kit or as needed;
(b) Kits submitted for evaluation should have an
expiration date at least 6 months from the date of submission;
(c) Must be transported according to the manufacturer’s
recommendation;
(d) Submission of seroconversion or performance panel,
details of these panels can be obtained at NRL–SLH/SACCL.
(3)
Payment of
performance evaluation fee to San Lazaro Hospital to defray cost of supplies
and reagents used for the preparation of serum panels and actual conduct of
evaluation.
A
Notice for Submission of Samples will be provided by NRL–SLH/SACCL to the
applicant company upon completion of above requirements. Result of evaluation
and recommendation of NRL–SLH/SACCL will be forwarded to FDA within two (2)
months after submission of all requirements.
B. Procedural
Guidelines
Technical
Procedures and Implementing Guidelines in Performing the Assay Evaluation for
Hepatitis B (HBsAg), Hepatitis C (anti–HCV) HIV (anti–HIV), syphilis and other Test
Systems
1. Review of
preliminary evaluation requirements
The
applicant company is required to submit all requirements as stated in the
Policies and Procedures and allow the NRL–SLH/SACCL to review the documents and
other pertinent data related to the test systems to be evaluated.
2. Performance
procedures and conditions
a. Test kits will be
accepted only after requirements were completed and the following must be
strictly adhered to:
(1)
A total of 1000
test for each test systems are to be submitted to be used for the entire
evaluation procedure including repeat tests whenever necessary. Unused test
kits will be returned to the applicant company after the evaluation has been
completed;
Table
1: Performance Panel Component
|
Component
|
Number
|
|
1.
Known negative
samples
2.
Known positive
samples
(high
and low titer)
3.
Seroconversion
Panel
4.
Samples
positive for other diseases (cross reactivity)
|
≥ 500
≥ 300
≥ 15
≥ 20
|
(2)
Expiration of
test kits should be at least 6 months onwards from the date of submission;
(3)
Two different
production lot numbers should be submitted for every test system to determine
lot variability of the kit;
(4)
Proper transport
of test kits according to the manufacturer’s recommendation must be strictly
observed so as not to compromise the result of the evaluation.
(5)
Submission of
seroconversion or performance panels based on NRL– SLH/SACCL specifications.
Details of acquiring such panels shall be coordinated to NRL–SLH/SACCL.
(6)
Payment for the
performance evaluation of the test system shall be required to defray cost of
supplies and reagents used in the preparation of panel sera and actual conduct
of evaluation subject to change upon notice.
b. Test results will
be analyzed by NRL–SLH/SACCL and released to FDA– CDRRHR 1 – 2 months after
submission of all requirements.
For
a screening test system to be considered acceptable for registration, it must
meet the following recommended requirements set by NRL–SLH/SACCL;
(1)
Sensitivity (in
performance assay)
· The ability of a
test system to give a positive result in the presence of the target marker;
· The ability of a
test system to detect the smallest amount of the target marker that can be
precisely detected
(2)
Specificity (in
performance assay)
· The ability of a
test system to give a negative result in the absence of the target marker
· The ability of
the method to determine solely the target marker
Table
2: Criteria for passing of screening test systems
|
|
DIAGNOSTIC
|
|
|
|
SENSITIVITY (%)
|
SPECIFICITY (%)
|
|
HIV
|
≥ 99
|
≥ 99
|
|
HBV
|
≥ 99
|
≥ 99
|
|
HCV
|
≥ 99
|
≥ 99
|
|
SY
|
≥ 99
|
≥ 99
|
(3)
Time interval
obtained with seroconversion panel (Sensitivity) – results should be comparable
or more sensitive than the benchmark assay used.
(4)
Delta value – a
means of comparing the efficacy of immunoassay in separating the negative and
positive serum populations.
(5)
Reproducibility –
the percentage of concordance on any sample tested on duplicated runs.
Reproducibility should not be <90%.
For
other test formats to be considered acceptable for registration, it must meet
the performance as claimed by the manufacturer and/or comparable with other
test systems already available in the market.
c. Result of test
systems that did not meet the NRL–SACCL criteria will be forwarded directly to
FDA–CDRRHR. Follow–ups won’t be entertained during the course of evaluation
process. Any queries regarding the results of the evaluation should be directed
to FDA–CDRRHR otherwise a formal discussion can be made officially through the NRL–SLH/SACCL.
VI. SEPARABILITY
CLAUSE
If
any part, term or provision of this Order shall be declared invalid or
unenforceable, the validity or enforceability of the remaining portions or
provisions hereof shall not be affected and this Order shall be construed as if
it did not contain the particular invalid or unenforceable part, term or
portion.
VII. REPEALING
CLAUSE
All
administrative orders, administrative issuances, rules and regulations, bureau
circulars and memoranda or any parts thereof inconsistent with the provisions
of this Order are hereby modified, repealed and/or revoked accordingly.
VIII. EFFECTIVITY
This
Administrative Order shall take effect fifteen (15) days after publication to
an Official Gazette or a newspaper of general circulation.
JANETTE LORETO – GARIN,
MBA–H
Acting Secretary of
Health
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