RE: [Histonet] ASR disclaimer question

From:"Morken, Tim - Labvision"

Disclaimer: I am part of a company that is FDA registerd to sell ASR and IVD
antibodies, and RUO antibodies and IVD detection systems. 

The part of the CAP checklist you mention (reproduced below) is not new as
far as ASR's are concerned, but is new for RUO's. 

ASR's were introduced to allow vendors to sell, and labs to use, antibodies
that did not meet the "exempt" criteria of the Class I IVD IHC reagents.
Exempt antibodies are those that are used in conjuction with other tests -
antibody or otherwise - to reach a conclusion. Most of the antibodies being
sold as ASR's today are those that are meant to be stand-alone predictive or
prognostic tests (ER, PR, etc)  and so require either FDA premarket approval
- requiring validation testing by the manufacturer, or are Class III
infectious agent antibodies that require extensive proof they detect what
they are supposed to detect. 

ASR's must be sold to only CLIA certified clinical diagnostic labs and the
vendor cannot include any information about how to use the antibody - the
lab is supposed to validate the antibody in-house. However, ASR's are sold
only by FDA-registered vendors, so are under GMP guidelines (good
manufacturing practices) and are inspected by the FDA, so you do have some
assurance that the antibodies are at least working right (the vendor must
show the antibody labels the target molecule by some kind of test - western
blost, elisa, IHC).

If all your antibodies come with use instructions, then you are getting
either IVD or RUO antibodies. If you use RUO antibodies, then,according to
this new checklist, you must  make a reasonable effort to find a supplier
that is FDA registered (most RUO-only suppliers are not FDA registered and
are not supposed to sell to clinical labs for clinical use applications).
Apparently the CAP has recognized that some antibodies are not available
through FDA registered vendors, so have allowed labs this as a way out of
that problem. That is going to open a whole new can of worms because now
labs are going to use antibodies that have been manufactured under no
requirements at all - FDA registerd labs must follow GMP (good manufacturing
practices) and under go FDA inspections. RUO-only vendors have none of these
requirements. I would say that getting ASR's is a better bet than getting
RUO's in this case. An RUO vendor does not have to test the antibody at all.
What is really interesting is that CAP apparently makes no requirement to
put in any disclaimer about the use of RUO antibodies. I can't find anything
about that in the general lab checklist either. It seems, then, that a lab
can use RUO's like IVD's now. 

So, maybe you are in the situation that you don't use any ASR's but do use
IVD and RUO antibodies. From how I read the current CAP comments, you are
right that you don't need any disclaimer. It's now become a really strange
situation! If someone sees it differently I'd like to hear any comments.

As far as "home brew" terminology is concerned, the FDA has  defined "home
brew" as any test that is not a complete, self-contained, FDA-approved kit.
The primary reason they developed this whole IVD/ASR/RUO system is so that
labs CAN make home brew tests. With this system a lab can mix and match
antibodies and detection systems to their hearts content. The only part the
FDA is concerned about is the analytic part of the test - the specific probe
that detects the specific target. All the detection systems are termed
"general laboratory reagents" and are not considered under this system
(though detection kits can be termed IVD if they are produced by a FDA
registered vendor). In fact, it is only if you BUY the reagent that FDA
applies these rules: FDA has said that if you make the antibody in house, it
is not considered an ASR, IVD or RUO - and you don't need any disclaimers
(assuming you a CLIA certified lab an the lab still needs to document the
validation procedure).

Tim Morken
Lab Vision - Neomarkers

ASR/IVD/RUO commentary

**REVISED**	12/01/2003

ANP.12425             Phase II	N/A   YES   NO

If patient testing is performed using Class I analyte-specific reagents
(ASR's) obtained or purchased from an outside vendor, does the patient
report include the disclaimer required by federal regulations?

NOTE:  ASR's are antibodies, both polyclonal and monoclonal, specific
receptor proteins, ligands, nucleic acid sequences, and similar reagents
which, through specific binding or chemical reaction with substances in a
specimen, are intended for use in a diagnostic application for
identification and quantification of an individual chemical substance or
ligand in biological specimens.
By definition, an ASR is the active ingredient of an in-house-developed
("home brew") test system.  ASR's may be obtained from outside vendors or
synthesized in-house.  ASR's from outside vendors are supplied individually.
They are not bundled with other materials in kit form, and the accompanying
product literature does not include any claims with respect to use or
performance of the reagent.

Class I ASR's in use in the anatomic pathology laboratory include some
antibodies for immunohistochemistry and nucleic acid probes for FISH and

Class I ASR's are not subject to preclearance by the U.S. Food and Drug
Administration or to special controls by FDA.  Thus, if the laboratory
performs patient testing using Class I ASR's obtained or purchased from an
outside vendor, federal regulations require that the following disclaimer
accompany the test result on the patient report:  

"This test was developed and its performance characteristics determined by
(laboratory name).  It has not been cleared or approved by the U.S. Food and
Drug Administration."

The CAP recommends additional language, such as "The FDA has determined that
such clearance or approval is not necessary.  This test is used for clinical
purposes.  It should not be regarded as investigational or for research.
This laboratory is certified under the Clinical Laboratory Improvement
Amendments of 1988 (CLIA-88) as qualified to perform high complexity
clinical laboratory testing."

The above disclaimer is not required when using reagents that are sold in
kit form with other materials and/or an instrument, and/or with instructions
for use, and/or when labeled by the manufacturer as Class I for in vitro
diagnostic use (IVD), Class II IVD, or Class III IVD.

Most antibodies used in immunohistochemistry are labeled "for in vitro
diagnostic use" and thus do NOT require the disclaimer.

Antibodies, nucleic acid sequences, etc., labeled "Research Use Only" (RUO)
purchased from commercial sources may be used in home brew tests only if the
laboratory has made a reasonable effort to search for IVD or ASR class
reagents.  The results of that failed search should be documented by the
laboratory director.

The laboratory must establish or verify the performance characteristics of
tests using Class I ASR's and RUO's in accordance with the Method
Performance Specifications section of the Laboratory General checklist.

The laboratory may put an ASR disclaimer on the pathology report for all
immunostains, FISH and ISH studies collectively used in a particular case.
Separately tracking each reagent used for a case and selectively applying
the disclaimer to only the class I ASR's is unnecessary. 



REFERENCES: 1) Department of Health and Human Services, Food and Drug
Administration. Medical devices; classification/reclassification; restricted
devices; analyte specific reagents. Final rule. Fed Register. 1997(Nov
21);62243-45 [21CFR809, 21CFR864];  2) Caldwell CW. Analyte-specific
reagents in the flow cytometry laboratory. Arch Pathol Lab Med.
1998;122:861-864;  3) Graziano. Disclaimer now needed for analyte-specific
reagents. Northfield, IL: College of American Pathologists CAP Today.
1998;12(11):5-11;  4) Analyte Specific Reagents; Small Entity Compliance
Guidance., February 26,
2003;  5) Shapiro JD and Prebula RJ. FDA's Regulation of Analyte-Specific
Reagents. Medical Devicelink, February 2003.;  6) U.S. Department
of Health and Human Services, Food and Drug Administration.;  7) U.S. Department of Health and Human
Services, Food and Drug Administration. 

-----Original Message-----
[] On Behalf Of Pat Zeitlow
Sent: Tuesday, March 15, 2005 7:30 AM
To: Histology SLU;
Subject: RE: [Histonet] ASR disclaimer question

Interestingly, I just got inspected yesterday and had a lengthy discussion
with the inspector on ASR disclaimers.  My strong opinion is that you do not
need to use the disclaimer unless you are using antibodies or reagents that
would be considered "home brew" (i.e. Detection systems not purchased ready
to use, antibodies with no
instructions for use, etc.).    All of the reagents and antibodies that
we use (regardless of manufacturer labeling) come with directions for use
and performance indications, therefore we do not use the disclaimer.
Naturally we validate every antibody and reagent before placing any protocol
in use. There is a lengthy commentary in the newest checklist that I think
clearly supports our decision not to use the disclaimer. The quote you
included says it all.  I produced a copy of the final rules with that
highlighted for the inspector.  I did not get sited nor was it recommended
that I add the disclaimer.  I look forward to the many opinions I will read
on the Histonet.


-----Original Message-----
From: Histology SLU [] 
Sent: Tuesday, March 15, 2005 9:14 AM
Subject: [Histonet] ASR disclaimer question

Hello All:
 I have information from the CAP website from 10/2003 that states: 'The FDA
very clearly distinguishes ASR's from immunohistochemistry (IHC) reagents
(final rule effective Aug. 17 1998).  The FDA defines IHC's as "in vitro
diagnostic devices....intended to identify, by immunological techniques,
antigens in tissue or cytologic specimens."  Unlike ASR's, IHC's are labeled
by manufacturers with directions for use and performance indications.'  I
have checked with all of my vendors and all actually label their antibodies
as IVD, research, or ASR.  Those companies that have ASR antibodies
available always use the letters ASR in the catalog number (at least all of
the ones I have contacted). Using all of this information, our lab does not
use ANY ASR's, so in you all's professional opinion, must we include the
For those of you that have been inspected lately, what specifically are the
inspector's comments about this topic?
As always, it will be great to hear all of your feedback.  Thanks, in

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