This guidance was written prior to the February 27, 1997 implementation of FDA's 
Good Guidance Practices, GGP's. It does not create or confer rights for or on any person 
and does not operate to bind FDA or the public. An alternative approach may be used if 
such approach satisfies the requirements of the applicable statute, regulations, or both. 
This guidance will be updated h the next revision to include the standard elemnts of GGP's.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
POINTS TO CONSIDER FOR CERVICAL CYTOLOGY DEVICES 
Introduction 
This points-to-consider document supplements existing FDA guidance for premarket 
submission of in vitro diagnostic devices for approval or clearance.  The information 
requested is intended to be comprehensive but may not be all inclusive.  The emphasis is on 
FDA's particular concerns in the review  of cytology devices for gynecologic specimens. 
These products include: 
1.  Collection devices for the initial cervicovaginal specimen [spatulas, brushes, 
etc.J  (regulated under 21CFR 884.4530, class II) 
2.  Devices for making cell suspensions for thin layer or monolayer slides 
(unclassified)  - 
3.  Staining devices (regulated under 21CFR 864.3800, exempt) 
4.  Computer-assisted cell-locator devices (regulated under 21CPR 864.5260, class 
m 
5.  Semiautomated and automated computer-assisted image analyzers (unclassified) 
6.  Any other devices used in preparation, reading and interpretation of 
gynecologic cytology specimens. (These may be regulated or unclassified.) 
Designers of gynecologic cytology devices have study design and method validation 
challenges that are not found in other in vitro diagnostic devices.  Some examples are: 
* 
Over SO million Pap tests are performed each year and about 2 million are diagnosed 
as abnormal.  Small differences in performance of a &vice for Pap tests may result in 
major consequences in the detection rate of the tests. 
* 
The loss of even a few cells prior to making a final slide may be critical. 
Y  There are no animal models or sources of cellular materials to serve as positive or 
negative internal controls for each patient sample.  Points to Consider: Cervical Cytology Devices. Version 7/25/94 
* 
Repeat cervical cytology samples may be unreliable until the cervical. epithelium has a 
sufficient time interval to regenerate, usually at least 4 to 6 weeks. 
* 
Cytologic diagnoses are dependent on multiple pre-analytic factors including sample 
collection and preparation even before the demanding microscopic examination. 
* 
Cytologic diagnoses are based on qualitative criteria for image interpretation that may 
be interpreted differently among individual observers and among laboratories.  Some 
degree of subjectivity is unavoidable. 
FDA encourages sponsors to consult with the Division of Clinical Laboratory Devices 
(DUD) for guidance and review of protocols prior to submission of a fonnal application, 
preferably prior to commencement of clinicd studies.  If the studies in the submission 
document the safety and effectiveness of the device, the FDA clcarance/approval process can 
proceed in the most timely manncr within the limits of the queue of submissions. 
Minimal data required: 
I.  Device Description 
Provide the following infomation: 
Intended use 
A description of the clinical intended use including the clinical disorders for 
which the device is used, the scientific basis for the disorder(s), tbe clinical 
significance of the procedure or test results, the risk-benefit issues for use of 
the device, and the clinical utility. 
Principles of the procedure 
A description of the principles of the procedure or test methodology including 
what the device docs. how it is to be used, and who will use the device.  Is the 
device a component of a system or used as a stand-alone device? Is the device 
for initial diagnosis of slides, coafirmation of the diagnosis. screening, or 
monitoring?  Define who will use this device; cytotcchnologists, pathologists, 
clinicians, gynecologists, laypersons, or a combination of users. 
Devicc components 
A description of the components that are provided with the device.  Supply 
instructions for acquiring any components not included with the device.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
1  D.  Manufacturing process. 
2 
3  Documentation that the device is manufactured following FDA Good 
4  Manufacturing Practices including product design, quality control, consistency 
5  of manufactured product with the original submission product, stability of end 
6  product, and any other applicable feature of  the device. 
7 
8  II.  Protocols 
9 
10  A.  General considerations for protocols 
11 
12  Submit the entire protocol and study plan to FDA for comment. 
13 
14  Provide a written protocol complete for all phases of the study that is 
15  applicable to all study sites before specimen coUection/selection begins.  It is 
16  the responsibility of the sponsor to ensure adherence to the protocol at all study 
17  sites.  - 
18 
19  Consult with a biostatistician during the initial planning stages of the protocol 
20  and during data analysis.  The most common reason for premarket submissions 
21  to fail is poor planning of the protocol.  Once a study is completed, it is almost 
22  impossible to make a poorly planned study acceptable. 
21 
24  Ensure that the study has a defined hypothesis and that the study design has the 
25  power to test this hypothesis. 
26 
27  Once the study begins, justify and document any and all changes to the 
28  protocol.  AIl changes  be written into the protocol.  Inform FDA of 
29  proposed protocol changes and what effects these changes will have on data 
30  interpretation.  Discuss these points with the biostatistician prior to 
3 1  implementation. 
32 
33  Collect data for each intended specimen type or target population. 
34 
35  Collect performance data using a final production model device and not a 
36  prototype. 
37 
all 
38  Appoint a study coordinator to oversee  aspects of the protocol study.  This 
39  person must have knowledge of all &tails of the study and serves to protect 
40  the integrity of the data. 
41 
42  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
Most study designs will compare a new cytology device to the conventional 
manually prepared and manual microscopy-read method.  In some cases, the 
new cytology devices may yield test results that were not detected by the 
conventional PAP test.  All abnormal diagnoses on slides that were previously 
diagnosed as negative must be reported to the laboratory.  This includes 
ASCUS and above, AGCUS and above, etc.  The sponsor has the responsibility 
of monitoring and assuring appropriate patient follow-up. A confirmatory test 
must be performed according to the Bethesda System ('Tl3S) guidelines. 
. 
B  Pre-Clinical Studies 
Define and test for the following performance characteristics: 
Accuracy (lack of bias) 
Comparison to a gold standard 
- 
Precision (lack of random error) 
Reproducibiiity (inter-observer, -laboratory, -instrument, intra-observer,- 
instrument) 
Percent agreement, adjusted 
Provide data to demonstrate the ability of the device to preserve 
morphological structure of the cells in comparison to the conventional 
smear; to capture adequate representation of endocervical components; 
and to indicate the presence of inflammation and infectious agents. 
FDA recommends adherence to usage of The Bethesda System (TBS) 
criteria. 
Stability 
Provide red-time studies from three different manufacturing lots which 
include data to demonstrate the stabiiity of any reagents and\or buffers 
under expected shipping, handling, and storage conditions including 
various extremes of temperature, humidity, and light.  This includes pre- 
collection buffer solutions and post-collection preservation of cellular 
morphology.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
C.  Clinical Studies 
1.  Study Design 
Provide the following study design information: 
a.  Patient inclusion and exclusion criteria. 
Account for all patients and provide explanation for all patients 
who are excluded from study. 
b.  Specific patient selection sampling plan. 
For methods not limited to the conventional Pap smear: 
* 
Prospective patient sampling is preferred so that within a 
defined time frame all patients are consecutively entered 
into the study.  If not, provide the detailed stitistical 
sampling plan used.  Frequently sponsors fail to use & 
consecutive patients during the prespecified study time 
period, therefore a clear description of the sampling 
method must be provided.  The method of sampling 
should be aelecteci to snsure tine rspmemitivenzss, 
completeness, and generalizability of the sample's data to 
the target population. 
For methods limited to the conventional Pap smear: 
* 
Retrospective studies may be permitted for methods that 
are solely based on the conventional Pap smear, e.g., 
computer-assisted Pap test reading versus manual Pap test 
reading.  However, these will be considered a feasibility 
study only. 
If negative archival slides are used, there must be an 
IRB-approved written protocol detailing what will be 
done with the study information from the new device.  If 
the new method yields abnormal diagnoses (including 
ASCUS and above, AGCUS and above, etc.) on slides 
that were pteviously diagnosed as negative, the laboratory 
that diagnosed the conventional PAP slide must be 
notified. The sponsor has the responsibility of  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
monitoring and assuring appropriate patient foIlow-up.  A 
confirmatory test must be performed according to TBS 
guidelines. 
For all devices: 
* 
Select the endpoint of the clinical studies that will 
support the clinical intended use. 
Novel and unproven devices may require the most 
stringent data with endpoints that may include clinical 
outcomes, i.e., effect of the device on morbidity and/or 
mortality, colposcopy results, and directed biopsy results 
as clinically indicated.  Surrogate endpoints include 
colposcopy with directed biopsy, conventional Pap test 
versus thin-layer or monolayer Pap test, manually read 
and interpreted Pap test vs. computer-assiste&or 
automated Pap test. 
* 
Define study period from which the patients will be 
selected. 
* 
Provide the type and num'oer of study centers. 
Carefully select clinical study sites to represent the 
spectrum of demographic features appropriate for the 
study of cervical pathology and include low prevalence 
and high prevalence populations for the diseases for 
which the device is to be used. 
* 
Provide the number of patients per center. 
Study adequate numbers of patients with confirmed 
positive and confinned negative results from each site to 
allow for site stand-alone analysis and to support the 
difference detected in clinical sensitivity and clinical 
specificity at the pre-specified statistical significance level 
and power. 
* 
Justify statistically all pooling of data from multi-center 
studies.  Collect sufficiently large numbers of specimens  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
from each study site to allow for stand-alone analysis at 
each site. 
c.  Hypothesis testing 
Null and alternative hypotheses for 3 by 3 categorical 
classification of ordinal data. 
The Bethesda System (TBS) cervical cytology diagnoses 
represent qualitative or categorical data, e.g., negative, atypical 
squamous cells of undetermined si@icance  (ASCUS), low 
grade squamous intraepithelial lesion (LGSIL), high grade 
squamous intraepithelial lesion (HGSIL),e tc.  TBS diagnoses 
can be grouped into three treatment categories: negative,  - 
ASCUS, and LGSIL and above.  These data are ordinally scaled 
and may be formed into two (new device and reference) 
- 
stochastically ordered distributions. 
Clearly define the null and alternative hy-pcdheses to be tested for 
the 3 by 3 ordmal classification tables as shown above.  The null 
hypothesis should be reasonably and consistently constructed 
from the data analyses of the pilot studies for the reference and 
the new device.  ?he alternative hypothesis is the hypothesis 
designed to include all possibilities not included in the null 
hypothesis. 
For example: 
Null hypothesis = The two marginal distributions of clinical 
outcomes (negative, ASCUS, LGSIL and higher) are eaual 
between the new and reference devices. 
Alternative hypothesis = The two marginal distributions of 
clinical outcomes are not equal between the new and the 
reference devices (two-sided).  This hypothesis considers the 
possibility that the device can be either better or worse than 
the reference device. 
Perform appropriate statistical significance testing for the 3 by 3 
ordinal classification data.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
If the null hypothesis is rejected in the above test for the 3 by 3 
classification data, perform statistical significance tests for two 2 
by 2 classification tables by combining ASCUS into the negative 
or positive (LGSL and above) groups. 
For each of the 2 by 2 tables, if the patient true disease status is 
known, calculate the clinical sensitivity values for the disease 
positive group and the clinical specificity values for the disease 
negative group for both the reference and new device.  If the 
patient true disease status is not known, calculate the proportions 
of disease (LGSIL and higher) for the reference and new device 
respectively. 
When the patient's true disease status is known, perform 
statistical significance testing for comparing two true clinical 
sensitivities and two true clinical specificities (or for two true 
proportions of disease if patient disease is not known) between 
the reference and new device.  The appropriate procedure for the 
multiple comparison problem needs to be considered since each 
of the above 2 by 2 tables were reconstructed from the SAME 3 
by 3 table when the 3 by 3 ordinal data leads to the rejection of 
the null hypothesis. 
d.  Confidence Intervals 
For the above 2 x 2 tables provide the 95 percent confidence 
intervals for true clinical sensitivity based on the disease- 
positive confirmed group and clinical specificity based on the 
disease-free conf?irmed group for the new device if the patient 
disease status is known. 
Also, provide the 95 percent confidence intervals for the 
differences of the two true clinical sensitivities and two true 
clinical specificities between the new and reference devices. 
This calculation can be useful in making clinical decisions. 
When the patient's true disease state is not known, provide the 
true proportions of disease states, LGSIL or higher, along with 
the 95 percent confidence intervals for the difference between 
the two true proportions.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
e.  Justification of Sample Size 
The foIlowing must be clinically and statistically pre-specified 
for estimating the required sample size: 
* 
Type I error (probability of rejecting a true null 
hypothesis) 
* 
Power (probability of rejecting a false null hypothesis) 
* 
Hypothetical clinical sensitivities and specificities (true 
disease status is known) 
* 
Hypothetical proportions of LGSIL, HGSIL, and 
carcinomas (true disease status is not known) 
*  Disease prevalence  - 
Collect a sufficient number of disease positive and negative 
samples to test the difference to be detected in clinical 
performance characteristics between the new device and the 
standard reference device at the prespecified statistical 
significmce IeveI and power. 
f.  Specify Statistical Analysis for ORDINAL Data for the 
following parameters: 
Clinical Sensitivity 
Clinical Specificity 
Positive and Negative Predictive Values 
Inter- and Intra-observer agreement (masked) 
g.  The study population must simulate the intended population for 
the device. 
* 
Sample and perform testing at 3-5 different geographical 
sites.  Selection of U.S. sites is strongly encouraged. 
Only one testing site may be the manufacturer's own test  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
site.  Simulate the testing and the use of the device for 
the site(s) for which the device is intended. 
* 
Collect specimens from populations with a range of low 
and high prevalences for the disease(s) to be detected by 
the device according to its intended use. 
* 
Sample examples of all the cervical diseases and 
conditions covered by the Bethesda System (TBS). 
Clearly list in the intended use statement any exclusions 
of diagnostic categories, e.g., "this device is not intended 
to process, detect, interpret inflammatory cells, etc." or 
"no examples of X condition were detected or analyzed 
by this device during the premarketing studies.  The 
performance of this device is not known for X condition." 
(X is a rare condition not readily detected in prospective 
clinical studies of a size with sufficient power for most 
- 
conditions.) 
Design preclinical tests to support, at least theoretically, 
that the device is safe and effective for all intended 
conditions claimed, even the most rare ones. 
Design post-market studies to validate the safety and 
effectiveness of the device for rare conditions using 
sufficient numbers of clinical samples. 
* 
Plan for any other sampling requirement for other 
conditions claimed in the intended use statement, e.g., 
processing of the samples for viral culture, nucleotide 
studies, etc. 
2.  End-point: Clinical accuracy. 
A validation of an in vitro diagnostic method requires an independent 
reference endpoint as a measure of accuracy (truth).  Also, once a 
reference method is chosen,  results must be compared with this 
method. 
Measure how well the device represents the true clinical condition of 
the patient from whom the sample was taken.  Collect and analyze all 
the results from the screening cytotechnologist for all specimens and  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
I 
separately analyze the results for all the specimens referred to the 
pathologist.  Ensure that the protocol's criteria for referral from the 
cytotechnologist to the pathologist are followed for all cases, both the 
new device and the reference method.  Mask all comparisons of the new 
device to the reference method. 
The following endpoints are listed in descending order of  their power 
as scientific evidence for validation of a new device, beginning with the 
gold standard method: 
a.  Clinical outcome 
This is the gold standard reference for accuracy and clinical 
utility but has the disadvantage that long term follow-up 
intervals are required to evaluate gynecology cytology. 
Longer clinical studies may be required for devices that 
are not based on conventional Pap smears because it may 
not be possible to use archival cases for longitudinal 
studies. 
b.  Cervical biopsy 
This method is less than a gold standard because of difficulty in 
biopsy sampling.  Biopsies may yield false negative results from 
sampling error.  Some of these patients may have a negative 
cytology but actually have a pre-neoplastic or neoplastic 
condition.  Also, there are additional problems in that it is not 
practical to biopsy a large number of patients with negative or 
ASCUS or AGCUS cytology. 
c.  Colposcopy examination and directed cytology andor biopsy 
sampling 
If  a colposcopy cervical cytology sample is to be used for 
confirnation, ensure that a sufficient time has elapsed from any 
previous cytology sampling to allow for cervical epithelium to 
regenerate (4 to 6 weeks). 
3.  Surrogate end-point: Specimen accuracy. 
A conventional Pap smear with refereed manual microscopic  Points to Consider: Cervical Cytology Devices, Version 7125194 
reading may be used as a data subset to resolve discrepancies 
and to assess specimen accuracy. 
Masked manual microscopy is an acceptable surrogate reference 
method (a less-than-gold standard) for devices using a 
conventional Pap smear and as a comparison method for thin- 
layer or monolayer slide preparations.  Record the masked 
refereed diagnoses before performing any unmasked comparison 
or "consensus" readings of slides or images. 
Mask each cytotechnologist and pathologist to the results of the 
comparison method and each other's results for the conventional 
Pap smear and for the new device, e.g., an automated or semi- 
automated image analysis or computer-assisted cell locator 
device. 
Document that the masking code will not be broken until all the 
data is gathered and recorded.  It is important to maintain the 
final 
masking code until the  data analysis. 
Sample collection 
4.  Cellection dzvice lor cervicd specimens. 
Limit cervical sampling collection devices to those that are FDA 
cleared.  The device must sample the endocervix and the 
exocervix.  Data should be collected to ensure TBS criteria for 
adequate cellularity, endocervical component, etc.  The Ayres 
spatula used alone is not sufficient for endocervical sampling. 
The Brush used alone is not sufficient for exocervical sampling. 
A combination of collection devices or a combination device, 
e.g., cervical broom provide sufficient sampling of the 
, 
endocervix and exocervix. 
One disadvantage is that some brushes may cause 
excessive bleeding and may not be used during 
pregnancy. 
b.  Devices that are not based on collection, preparation, and 
observation of conventional Pap smear slides, e.g., thin or 
monolayer slides.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
An Institutional Review Board (IRB) approval and informed 
consent is required if a patient is to be screened by a method 
that does not allow for a conventional Pap test (conventional Pap 
smear read manually by a cytotechnologist with potential for 
referral  to a pathologist). 
Specimen collection may be handled in one of the following two 
ways: 
If a Pap smear is to be made, collect the cervical sample and 
prepare a conventional Pap smear in the usual fashion before 
performing any of the steps for the non-Pap smear slide.  The 
sample for the new methodology, e.g., thin layer or monolayer 
suspension may be made from the residual material on the 
collection spatda, brush or broom. 
If no conventional Pap smear is made before sampling for the 
thin layer or monolayer preparation, randomize the study 
subjects into two g~oups: One group will have a conventional 
Pap smear and the other group will be sampled for the non- 
conventional method, e.g., thin layer or monolayer slides. 
Appropriate statistical design is needed to ensure equal or nearly 
equd mm-krs ~f saiiples in ekch of the two groups.  This 
method may require an Investigational Device Exemption (DE) 
and signed patient consent forms as well as an IRB approval if 
the study is a PMA. 
The end-point for these studies is a comparison of the proportion 
of TBS diagnoses found in each of the two study groups. 
See attached addendum for additional sampling considerations. 
4.  Sample processing 
Consideration must be given to the method for processing the cervical 
sample.  The information and data submitted for a smear would vary 
from that of a suspension or a differential separation of the cervical 
sample.  The differential separation of cervical cells from mucus, red 
blood cells, leukocytes, and acellular material would require proof that 
diagnostic and contextual cells were not lost in the processing of the 
sample.  The method of separation, filtration or centrifugation, must be 
addressed as well as the type of fixation.  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
5.  Slide preparation 
Issues involving the transfer of the cervical specimen to the slide will 
vary according to the method used.  The transfer of cells from a 
suspension by filtration, centrifugation, or sedimentation is vastly 
different from a direct smear. 
6.  Cell finding-locating device 
Issues to be addressed for this type of device include the theory of 
operation, the sensitivity and specificity of the image processing for the 
selection of cells.  Does the device provide for marking of suspicious 
cells?  What is the operatorlinstrument interaction? What type of long- 
term record is provided?  Documentation for software that was designed 
as part of the cell-locating device should be provided. 
7.  Image interpretation  - 
For devices that provide an image interpretation, issues to be addressed 
include the theory of operation, the comparison with conventional 
microscopy, operatorZinstrument interaction, long-term record keeping, 
and a hazard analysis and software documentation conforming to the 
criteria cntlked Ir, Rzviewer Geirkzrka .iim- Computer c2.xtrolle8 
Medical Devices Undergoing 51 O(k) Review. 
III.  Data 
A.  Record keeping 
Stratify data and results by TBS diagnoses for claimed intended use by 
screening cytotechnologist and pathologist.  The following terminology should 
be used:  high grade squamous intraepithelial lesion (HGSIL), low grade 
squamous intraepithelial lesion (LGSIL), atypical squamous cells of 
' 
undetermined significance (ASCUS), atypical glandular cellular of 
undetermined significance (AGCUS), etc.  The definition of ASCUS should be 
confined to the TBS category.  The descriptive diagnoses pertaining to presence 
of inflammation and infection as well as reactive changes and specimen 
adequacy should also be noted. 
B.  Data integrity 
1.  Retain all original work sheets and make them availabIe for planned or  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
unannounced FDA inspections.  In cases where the original form does 
not remain with the study, all transcribed data should show the initials 
of the recorder and the date of transcription.  If original work sheets 
may not be available at a later date, it is important to provide a 
verification for the transcribed data which should include the initials of 
the individual verifying the transcription and the date of verification. 
Document in writing any correction or modification of originaI work 
sheets.  Corrections or modifications should follow standard good 
laboratory practices in that a single line is drawn through the notation 
that is changed.  The correction is written above the line.  Record the 
date and the initials of individual making any changes. 
Ensure the integrity of data on computerized work sheets (databases) so 
that there is permanent recording of date of input of all data and all 
revisions. 
- 
Mask reading, interpretation, and recording of data.  Mask all data 
analysis and interpretation. 
At the intended site of use, conventional manually prepared Pap slides 
and s!ides  prepared with a new dwice or read by B ficw device, e.g.. 
computer-assisted reader or cell locator, may result in  screening 
diagnoses that fall between TBS categories.  It is most likely that these 
slides will be treated like the diagnosis of the higher rather than the 
lower TBS diagnosis bracketing the provisional diagnosis.  The slide 
would be referred by the cytotechnologist to the next higher trained 
observer. 
If the pathologist's diagnosis falls equivocally between two TBS 
diagnostic categories, it would be expected that the pathologist would 
refer the slide to another pathologist or would note the equivocal 
diagnosis in the report to the clinician for appropriate follow-up. 
Record all diagnoses on the work sheet that are not definite TBS 
diagnoses, e.g., hedging diagnoses such as tentative, provisional, 
presumptive, rule out, WO, or question mark ?,  as the next higher 
grade.  Establish a written algorithm in the protocol for all possible 
diagnostic variations befo~th e study begins. 
Ensure that data entry personnel are aware of TBS diagnostic criteria. 
Any equivocal or hedging diagnoses should be referred to the next level  Points to Consider: Cervical Cytology Devices, Version 7/25/94 
reviewer in the cytology protocol, i.e., all slides that are not 
unequivocalIy negative. 
If  the device is computer-assisted, venfy abnormal cells by manual 
microscopy to check and recheck cells identified as abnormal. 
If it is not possible to check abnormal cells by manual microscopy, 
justify the safety and effectiveness of the new methodology. 
If the device displays abnormal cells on a computer monitor, document 
how these images are stored for additional observers to re-analyze. 
Provide instructions in the study protocol to ensure adherence to the 
manufacturer's protocol by the cytotechnologists and pathologists. 
Devices that allow for little or no opportunity for human intervention, in 
particular a software-controlled "black box-type" devices, may require 
software validation studies to document that the device can 6e expected 
to maintain reasonable performance for its intended purpose with the 
full range of expected specimens. 
1.  Training Requirements 
St~tteh e kind and amount of training requirements for any step and interpretation that 
differs from the conventional Pap test (manually prepared smear, manually processed, 
and read and interpreted without computer assistance). 
Recommend the appropriate procedures for the laboratorian and laboratory to convert 
from conventional Pap test methodology to that of the new device. 
Some training issues to consider are: 
Will the new device affect the appearance of the finished slide? 
Will the sIide be a conventional Pap smear or a thin layer or monolayer slide? 
Will the new slide methodology contain all of the components of the 
conventional slide? 
If not, what is the possibility of misdiagnoses from loss of that (those) 
components?  Points to Consider: CervicaI Cytology Devices, Version 7125194 
1  How will these issues concern the clinician during sample collection, sample 
2  preparation, slide preparation, and final interpretation of result? 
3 
4  How will these issues affect the cytotechnologist during sample processing. 
5  slide preparation, identification of  abnormal cells, and interpretation of celIs 
6  from the preparation? 
7 
8  Consider how these issues affect the pathologist in identification of abnormal 
9  cells and interpretation of abnormal cells? 
10 
v. 
11  Workload Limit 
12 
13  All gynecologic cytology devices submitted for FDA approval or clearance must have 
14  an evaluation of their workIoad limit.  This applies to devices for making cell 
15  suspensions for thin layer slides, computer-assisted cell locator devices, serni- 
16  automated and automated computer-assisted image analyzers, and any other device 
17  used in the preparation, reading, and interpretation of gynecologic cytology- specimens. 
18  Data must be provided to assess and evaluate the fatigue factor in order to establish 
19  appropriate workload limits. 
20 
21  VI.  References 
22 
23  National Cmcar Institute VJoiksh~pT. he i98E Eethesda System for rzporthg 
24  cervicaVvagina1 cytological diagnosis. JAM. 1989;262:931 -934. 
25 
26  Broder S. Rapid communication--the Bethesda system for reporting cervicdvagind 
27  cytologic diagnosis--report of the 199 1 Bethesda Workshop. JAA4A. 1992;267:1 892. 
28 
29  Kumm RJ, Henson DE, Herbst AL, et a]. Interim guidelines for Management of 
30  Abnonnal Cervical Cytology. JAMA. l994;27 1 :1 866- 1869. 
3 1 
32  Kurman RJ, Solomon D. The Bethesh System for Reporting CervicaUVaginal 
33  Cytologic Diagnoses: De$nitions,  Criteria, and Explanatory Notes for Terminology 
34  and Specimen Adequacy. New York, NY:Springer-Verlag NY Inc;1994. 
35 
36  Center For Devices and Radiological Health, Food and Drug Administration. Reviewer 
37  Guidance For Computer Controlled Medical Devices Undergoing SlO(k) Review. 
38  August 29, 1991. This document is available from the Division of SmalI 
39  Manufacturers Association @SMA),  1-800-638-204 1.