Pan American Society for
Clinical Virology

Volume 26No. 2
November 1999

Contents:

FDA Regulation Issues Discussed
New 510(k) Paradigmby Robyn McGuire, PhD
Questions by Angela Caliendo, MD, PhD
Websites of Interestby Kathy Wright
Announcements

FDA Regulation Issues Discussed

There was considerable conversation at the recent Clinical Virology Symposium
regarding issues of FDA regulation and reimbursement for molecular testing. In
order to focus more attention on these matters, three contributions from members of
the PASCV are presented below. In the first article, Robyn McGuire discusses
aspects of FDA regulations as they may be perceived by a clinical laboratory. In
the next article, Angie Caliendo asks some of the questions commonly discussed
among clinical virologists with laboratory responsibilities. Lastly, Kathy Wright has
provided an extensive list of Web sites that are helpful in addressing the concerns
expressed in the two articles.

New 510(k) Paradigm

by Robyn McGuire, Ph.D.
Chemicon International, Inc.

Devices are classified as Class I (low risk to patient population) to Class III (high
risk). Immunofluorescence reagents fit in all three categories; Class I -respiratory
viruses, Class II - HSV,VZV, PCP, CMV, and Class III - HSV. As part of FDAMA, low
risk Class I and some II devices whose technology and associated risks are well
characterized and understood,have been exempted from premarket approval
(510(k) submissions).
This will enable examiners to spend more time on submissions based on new
technologies. For example, although immunofluorescence reagents for RSV are
now exempt from 510(k) submission, a membrane-based assay for direct detection of
RSV from patient specimens will require a submission. However, exemption from
510(k) submissions does not mean exemption from FDA review; exempt devices are
still subject to current good manufacturing practices (CGMP) and Design Controls.
Prior to the FDA Modernization Act (FDAMA), 510(k) submissions for FA reagents
could take from 6 months to more than a year. FDAMA now enables manufacturers
submit fast-track submissions. These may be ‘abbreviated’ - product development
followed ing Design Controls, or ‘special’ - meaning that consensus standards were
used to establish performance characteristics. The FDA has committed to clearing
a ‘special’ or ‘abbreviated’ 510(k)within 30 days if all the appropriate information is
included in the submission.

Design Controls

The establishment of Design Controls by the FDA has had a major impact on
manufacturers. For the first time, the FDA requires a documented history (Design
History File) of the design, development and launch of a new product. Design
History Files for Class II and III devices are subject to review by the FDA.
One of the objectives for the institution of Design Controls is to ensure that all
groups or individuals responsible for new product development (R&D, Marketing,
Production, etc) are included and consulted during each stage of product

development. This ensures thatthe customer needs as determined by Marketing, is
developed by R&D, is manufactured to the established specifications, andperforms
as expected in the customer’s hands. While requiring more documentation by
R&D, Design Controls ensure a consistent, logical progression of the development of
a new product, or change to an existing product.

Consensus Standards

Several national and international groups have established standards or
guidelines which labs and manufacturers used to calibrate assays, or to ensure
proper testing of assays. The NCCLS is one such organization. The FDA has used
these guidelines and standards in the past as a basis for the review of submissions.
As mentioned earlier,manufacturers can now satisfy part of the 510(k)submission
requirements by a declaration of conformity with an accepted consensus standard.
The One consensus standard that is usefulin the clinical virology lab is the
NCCLS Guidelines ILA18-A entitled:“Specifications for Immunological Testing for
Infectious Diseases:Approved Guideline”.
This document was initially developed for microbiology laboratories to validate
their home-brew assays. Itcovers such aspects of assay development as specificity,
cross-reactivity, reagent verification and performance characteristics.
Other excellent documents are NCCLS Guideline MM3-A entitled “Molecular
Diagnostic Methods for Infectious Diseases; Approved Guideline, and GP10-A,
“Assessment of the Clinical Accuracy of Laboratory Tests Using Receiver Operating
Characteristic (ROC) Plot; Approved Guideline. These and other standards
guidelines should be used by laboratories to validate any home-brew assay.

Product Labeling

On November 23, 1998, products for the clinical lab could be labeledin vitro
diagnostic use, Research Use Only (RUO), Investigational Use Only (IUO) or Analyte
Specific Reagent (ASR). As part of these label changes, the definitions of RUO
and IUO changed slightly and the term ASR was introduced.
The definition for in vitrodiagnostic use has not changed. The ASR regulation
went into effect on Nov. 23, 1998 while the RUO and IUO changes are still proposed
and have not been finalized.

ASR

Analyte Specific Reagents consist of antibodies, antigens, oligonucleotides,
ligands or any critical components or ‘active ingredient’ used by the laboratory to
develop a ‘home brew’ assay. The majority of these reagents are considered by the
FDA to present a low risk to public health and are classified as Class I devices
(exceptions to this are ASRs for blood banking, and HIV testing and some tumor
markers).
ASRs, while are exempt from the 510(k) submissions, must be manufactured under
current good manufacturing practices (CGMP), and be registered with the FDA.
Prior to November, 1998, these reagents were labeled RUO.
As ASRs are the building blocks of a clinical test, the information that the
manufacturer can provide about the reagent is also regulated by the FDA. The
reagent must be labeled: “Analyte Specific Reagent; analytical and performance
characteristics of this ASR are not established". The data sheet can only include
the basic information regarding the purity of the critical component, and
physicochemical characteristics. No recommendations for use or titer can be
given, as the manufacturer has no knowledge of how the reagent will be used. In
addition, the FDA limits the sale of ASR's to device manufacturers, CLIA high-
complexity labs, VA facilities and public health laboratories, plus other non-clinical
facilities.
The main impact of this regulation on the clinical lab was has been the
requirement to add a disclaimer on the results reported to the ordering physician.
While there is some flexibility in the wording of this disclaimer,the intent is to
indicate that the results were “determined by a test whose performance
characteristics have not been cleared by the FDA”.

Research Use Only

Once the proposed guidelines for RUO and IUO labeling has been finalized, the
term “Research Use Only; Not for use in diagnostic procedures” will be limited to the
initial research phase of product development, or to laboratory research that is
entirely unrelated to product development. This is usually the verification stage
where assay protocols, kit components, and analytes are optimized. Collection of

clinical data to support a submission to the FDA cannot be made at this stage of
development, a separate clinical study must be established.
According to an FAQ from the FDA, some examples of RUO labels include:
reagents for amplified nucleic acids in an application defined by an end user;
assays used for epidemiology; assays for new viruses or analytes with unknown
disease association. Also included arein vitroassays for pharmaceutical trials to
support efficacy of a pharmaceutical (and there is no interest in commercializing
the assay itself).

Investigational Use Only

Investigational Use Only (IUO) labeling is will be limited to clinical investigation
to determine the safety and effectiveness of the device for its intended clinical use,
to develop performance characteristics for the product, and to establish the
expected values. During the clinical study and following 510(k)submission, the
product must still be labeled IUO until such time as it is cleared.
From the lab’s perspective, a test result obtained from an IUO assay may be
reported, as long as the result is confirmed with another FDA -cleared diagnostic
product or medically established procedure.
Conclusion

The impact of the Food and Drug Administration Modernization Act (FDAMA) is
still continuing to be felt by clinical laboratories and device manufacturers. There
are still more issues to be resolved, including reimbursement and CLIA waivers.
Manufacturers already have a voice in commenting on these issues through
various interest groups. Laboratories must also find an outlet for comment or these
decisions will not be made with their interests in mind.

Questions

by Angela M. Caliendo, M.D., Ph.D.
Microbiology Laboratory
Emery University Hospital

Here are some questions and comments that have come up regarding the FDA
and reimbursement for molecular microbiology/virology tests. The test approval is
an FDA issue, while the reimbursement is a HCFA issue. So, we probably need
some guidance from both organizations.
I’ll be honest, my concern is that if we ask these questions we are going to get
answers that we do not like. That is the non-approved commercial tests can not be
performed for clinical testing and/or that they can not be reimbursed. Once we
receive this information we will no longer ba able to plead ignorance!
There are many laboratories using non-FDA approved commercial assays,
probably the most common is the bDNA HIV viral load assay. So, this could be a
problem for many. Several colleagues I have spoken with really don’t want to ask
these questions because they don’t want to hear the answers. We may remove all
doubt and put ourselves in a very difficult situation. The reality seems to be that
both performing clinical trails and the approval process for molecular assays are
very slow.
So, laboratories are going to be facing issues regarding non-approved tests for
years to come, therefore some guidance is needed. With all of that said, here are
some of my thoughts.
Are clinical laboratories permitted to use non-FDA approved (or cleared)
molecular tests and are we able to bill Medicare/medicaid for these services? For
example, qualitative HCV PCR (Roche) is recommended as an option for
confirming a positive HCV EIA. However, no test is FDA approved. Does this mean
we can not use a non-approved commercial assay or that we can use it but can’t bill
Medicare/Medicaid?
The clinical necessity of HIV viral load has been well established and the tests are
widely used. However, only one of the three widely used commercial assays is FDA
approved (Roche is approved, bDNA and NASBA are not). Are laboratories
permitted to use and bill (Medicare/Medicaid) if they are using a non-FDA approved
test. The currently available molecular microbiology CPT codes do not make any
reference to testing method used. But, if a laboratory or hospital were to undergo a
Medicare audit, the test method could eaasily be identified. Is this a problem? Is
HIV an exception, would other pathogens (HCV, CMV) be treated differently?
I understand that individual states can deem a test medically necessary and
choose to reimburse for the test even if it is not FDA approved. How does this
process occur? Could the organization become more active in this process?

There seems to be a disconnect between in-house developed assays and non-FDA
approved commercial assays. If we do a validation of an in-house assay we can
perform and bill for the test. Can we use and bill a non-approved commercial assay
if we do a validation consistent with the CLIA 88 guidelines? If not, why not? Many
of these commercial tests are better standardized and validated than in-house
assays, yet they are not available to the laboratories.
Can commercial non-approved tests be modified so that they are considered in-
house assays rather than commercial assays. The laboratory could modify some
aspect of the test ot better suit the test for their laboratory and then validate the
assay. Is this an acceptable option?
Must a laboratory include the ASR disclaimer on the report of all in-house
developed assays?
How does the use of a non-approved molecular test (qualitative HCV PCR) differ
from the use of a non-approved fluorescent antibody in the virology laboratory?
Laboratories have been using non-approved commercial reagents for years.

Websites of interest

by Kathy Wright, Scientific Reviewer
Microbiology Branch, DCLD, ODE, CDRH, FDA

1..Websites for our Center in which in vitrodiagnostic (IVD) devices fall:
http://www.fda.gov/cdrh
Center for Disease and Radiological Health Home page:
http://www.fda.gov/cdrh/topindx.html
Topic index (alphabetical index):
http://www.fda.gov/cdrh/indexps.html
Premarket Notification [510(k)] :
http://www.fda.gov/cdrh/reengine.html
FDA reengineering update:
http://www.fda.gov/cdrh/modact/modern.html
Modernization Act Info:
http://www.fda.gov/cdrh/modact/k981.html
Intended Use (latest FDA thoughts of how devices are looked at, e.g.,
whether there is a reasonable likelihood that the device will be used for an
intended use not identified in the proposed labeling for the device):
http://www.fda.gov/cdrh/comp/fr01598b.html
or the more recent FR notice:
http://www.fda.gov/cdrh/comp/ivddrfg.html
Commercialization of In Vitro Diagnostic Devices (IVD's) Labeled for
Research Use Only or Investigational Use Only; Draft Compliance Policy
Guide. Note:
[This is in draft form but it will be available in its final form on the
internet soon.)
Access to recent info on CLIA 88 and CDC through our website.
http://www.fda.gov/cdrh/clia/index.html.

2. More sites:
Div. of Small Manufacturers Assistance (DSMA)
http://www.fda.gov/cdrh/dsma/dsmamain.html#contents
Device Advice (good basic info including definitions):
http://www.fda.gov/cdrh/devadvice/11.html#start
Good Manufacturing Practice (GMP) Requirements and Quality System
(QS) Regulation Information:
http://www.fda.gov/cdrh/dsma/cgmphome.html
CDC Division of Laboratory Systems
http://www.phppo.cdc.gov/DLS
Clinical Laboratory Improvement Act (CLIA 88) info :
http://www.phppo.cdc.gov/dls/clia/default.asp
CDC Waived Tests (different from FDA exempt tests):
http://www.phppo.cdc.gov/dls/clia/waived.asp
FDA Consumer information:
http://www.fda.gov/cdrh/consumer/index.html
MedWatch (reporting adverse events using a device):
http://www.fda.gov/medwatch/revise.htm

Disclaimer:The preceding/proceeding comments are personal opinion and are not
meant to express the policies of the FDA.

Announcements

1. Smith Kline Beecham Pharmaceuticals
will provide 3 additional travel awards valued
at $600 each to the PASCV for travel to the Virology Symposium.

2. Diagnostic Hybrids will sponsor 2 travel awards for undergraduates.
The PASCV and the Clinical Virology Symposium express their gratitude for these
awards and the commitment shown by the sponsors to foster clinical virology among
young investigators and now, undergraduates. With these awards, and including the
Mario Escobar award,a total of 10 awards will be available for travel to the
Symposium in 2000.

3. Ken McIntosh attended the first meeting of the Portuguese Society for Virology
on March 5, 1999 in Lisbon. The new society was formed by a group of clinical,
diagnostic, and basic virologists from all of the medical and academic centers of
Portugal. The society has established close ties with the European Society for
Clinical Virology and would like very much to do the same with its Pan-American
counterpart. Those who would like more information can get in touch with Victor
Manuel Jorge Duque, M.D., Departamento de Doencas Infecciosas, Hospitais da
Universidade de Coimbra, Avenida Bissaya Barreto, 3049 Coimbra Codex, Portugal;
tel: 351-39-402-901; email: viroinf@mail.telepac.pt