SUMMARY MINUTES

MEETING OF THE CLINICAL CHEMISTRY AND

CLINICAL TOXICOLOGY DEVICES PANEL

OPEN SESSION

OCTOBER 29, 2001

**Meeting of the Clinical Chemistry and Clinical Toxicology Devices
Panel**

**Attendees**

October 29, 2001

*Chairperson*

Martin H. Kroll, M.D.

*Executive Secretary*

Veronica J. Calvin, M.A.

*Members*

Stephen Clement, M.D.

Cassandra E. Henderson, M.D.

Barbara R. Manno, Ph.D.

Arlan L. Rosenbloom, M.D.

*Consultants*

Andrew J. Ahmann, M.D.

Jose F. Cara, M.D.

*Consumer Representative*

Davida F. Kruger, R.N.

*Industry Representative*

Fred D. Lasky, Ph.D.

# Patient Representative

Diane Lellock

*FDA Representative*

Steven I. Gutman, M.D., M.B.A.

*Guest*

Bernard E. Statland, M.D., Ph.D.

Director, Office of Device Evaluation

CALL TO ORDER

Chairperson Martin Kroll called the meeting to order at 8:05 a.m. and
introduced Bernard E. Statland, M.D., Ph.D., director, Office of Device
Evaluation, FDA. Dr. Statland thanked the people responsible for pulling
the meeting together and noted that although alternative site testing
(AST) of blood glucose has produced some excellent benefits for
patients, it may not be as accurate as it needs to be.

Executive Secretary Veronica Calvin read the conflict-of-interest
statement. Panel member Davida Kruger had financial interests in firms
at issue that were related to the day's agenda but had received a
conflict-of-interest waiver and could participate fully in the meeting.
Panel members Martin Kroll and Arlan Rosenbloom had past or current
interests in firms at issue for matters that were not related to the
day's agenda and therefore could participate fully in the meeting. The
agency had also determined that Jose Cara had past interests in firms at
issue for matters that were related to the day's agenda, but because the
meeting's agenda involved general matters, he could participate fully in
the meeting. Diane Lellock, patient representative, had acknowledged
personal financial interests in a firm at issue. Ms. Calvin then
reviewed the outcome of the panel's November 13-14, 2000, meeting.

**FDA PRESENTATION**

Patricia Bernhardt, B.S., MT(ASCP), scientific reviewer, Division of
Clinical Laboratory Devices, Office of Device Evaluation, described the
FDA's concerns with AST glucose measurements. She explained that the
research on the devices that use blood samples drawn from sites other
than the fingertip (i.e., the forearm, upper arm, thigh, calf, or base
of the thumb) demonstrates discordance (i.e., lack of agreement) with
fingertip measurements. In some cases, the differences are so marked
that fingertip samples may produce readings in the hypo- or
hyperglycemic range while the AST sample results are in the normal
range.

Ms. Bernhardt said that the FDA wants to be sure that patients with
diabetes will be able to use the devices in an appropriate manner and
that the devices provide users with the information they need to manage
their diabetes. The FDA's current review process evaluates testing under
conditions of hypo- and hyperglycemia, but it does not evaluate testing
during rapid glucose changes. Also, the FDA does not know whether harm
has occurred as a result of AST because Medical Device Reporting (MDR)
data do not differentiate between sampling sites. The FDA became aware
of the problem of discordance when manufacturers who market or plan to
market the devices submitted information on the issue and possible
solutions to address it.

Ms. Bernhardt then presented information on several different data
presentation formats: Clarke Error Grid Analysis (EGA), time-elapsed
plots, Bland-Altman plots, and linear regression graphs.

Ms. Bernhardt explained that FDA reviewers had identified several points
that they thought should be addressed when developing guidance to
standardize the review of 510(k) applications involving AST devices:

-   Blood glucose testing before meals, regardless of the device used,
    demonstrates comparable results for fingertip samples and AST.

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-   When discordance occurs, it is observed after meals. Some patients,
    regardless of the device used, demonstrate comparable blood glucose
    levels between sampling sites some of the time, even when blood
    glucose is not in a steady state.

-   Testing has not been performed at night, and the effects of exercise
    and concurrent illness have been tested only in a limited way.

The FDA needs the panel's input in determining whether an appropriate
study design should address those issues. Bernhardt then presented the
questions before the panel.

FDA PRESENTATION

Marina Kondratovich, Ph.D., mathematical statistician, Division of
Biostatistics, Office of Surveillance and Biometrics, presented a
statistical overview of the various types of data presentations FDA has
seen in the 510(k) submissions for AST devices. She described the
different study designs in the applications and discussed the various
statistical analysis techniques. She said that the panel should consider
four aspects of study design in its deliberations: type of measurement
(i.e., single-point measurements vs. time series), state of glucose
level (i.e., steady, stabilizing, or dynamic), rate of glucose change,
and patient characteristics.

SPONSORS PRESENTATIONS

Nina Peled, Ph.D., M.B.A., vice president, scientific affairs, Amira
Medical, described research on the performance and comfort of the AtLast
blood glucose testing system in testing blood samples taken from the
palm of the hand. Compared with fingertip testing, the palm provided
both lag-free glucose readings and pain-free testing. Amira's series of
studies involved participants in a steady glycemic state, participants
in random glycemic states, participants going through rapid changes in
glucose levels, and participants going into hypoglycemic states. In all
four studies, palm samples provided results that compared favorably with
fingertip samples. Dr. Peled presented data as linear regression
analyses and time course data, all of which demonstrated a close fit of
the palm data to fingertip testing data. In addition, EGA indicated that
testing with blood samples from the palm could provide timely detection
of hypoglycemia. An additional study asked patients to rate the comfort
of the AtLast device; 76% of the participants preferred the palm over
the forearm as a test site, and 67% reported no pain with the device.
Dr. Peled concluded by asking that the FDA immediately clear the AtLast
device without labeling restrictions.

Ron Ng, Ph.D., DABCC, FACB, director, medical and clinical affairs,
Abbot Laboratories, MediSense Products, presented data on the accuracy
of the Sof-Tact system for testing blood glucose in samples taken from
the forearm. The Sof-Tact device increases perfusion by creating a
vacuum over the sampling site. EGA of a clinical study of lay users
demonstrated that the accuracy of the Sof-Tact system was clinically
acceptable. Dr. Ng also described results of a meal tolerance test, an
oral glucose tolerance test, and a hypoglycemia study designed to
evaluate the accuracy of the device; in all three studies, EGA indicated
that between 99.5% and 100% of the Sof-Tact results were clinically
acceptable. Dr. Ng concluded by saying that the data support use of the
device in both static and dynamic glucose conditions. Each manufacturer
should characterize its device in both static and dynamic conditions
with labeling appropriate to performance.

David L. Horwitz, M.D., Ph.D., vice president, medical and regulatory
affairs, LifeScan, Inc., described studies on the One Touch Ultra
System. He presented time series data comparing blood glucose levels
obtained from fingertip samples (analyzed according to the Yellow
Springs Instrument \[YSI\] method) with results from samples obtained
from the fingertip, forearm, and thigh analyzed using the One Touch
Ultra system. The study found that AST before meals gave accurate
results in nearly all patients; postprandial testing, however, did not
always give concordant results. A second study of a group of patients
who had participated in the first study produced results that were
consistent with the first study but which confirmed day-to-day
intrasubject variability in discordance. Dr. Horwitz noted that the
study results indicated that the greater the rate of change in glucose
levels, regardless of direction, the greater the difference between AST
and fingertip sample readings. As with other studies, most of the
participants tested in the LifeScan studies (79%) expressed a preference
for AST. Dr. Horwitz also described a LifeScan study conducted in Europe
that involved patient at-home comparison of finger and arm testing; most
patients (80%) had less pain or no pain with arm testing compared with
fingertip testing. EGA of the data from the European study showed that
96% of all data points were in the A or B zone, regardless of when the
samples were drawn, and that 99% of the points were in the A or B zone
when fasting samples were analyzed. Finally, Dr. Horwitz presented
LifeScan's recommendations: (1) Data in any studies recommended by the
panel should address normal perturbations in glucose and specific
anatomic sites; and (2) labeling should include information on expected
variations, appropriate timing of AST, and cautions about hypoglycemia.
Dr. Horwitz presented two labeling options for the panel's consideration
along with data indicating that patients understand the proposed
labeling.

Sara Weaver, R.D., marketing manager, LifeScan, Inc., described the
company's patient and physician education programs. The company educates
consumers and physicians through conference presentations, brochures,
and direct mail, among other techniques.

Dr. Kroll asked the panel members whether they had any questions for the
presenters. Dr. Cara asked Dr. Peled whether any children under age 14
or 18 had participated in the Amira studies. Dr. Peled responded that
arm sampling had been used in very young children with acceptable
accuracy 2 hours postprandial. Dr. Horowitz said that the LifeScan
device had been tested on children as young as 8 years old and that
equivalent results had been obtained for arm and finger testing.

Dr. Manno asked whether any of the Amira studies had noted differences
between patients who had highly calloused palms and those who did not.
Dr. Peled responded that the Amira research took place in a farm
community and that many of the participants had calloused palms;
however, no differences were found related to calloused palms. Dr. Manno
also asked how old the oldest patients were in the studies. Dr. Peled
responded that the patients in the Amira studies were up to 64 years
old, and Dr. Ng indicated that some of the patients in the MediSense
studies were age 70 and older.

Dr. Henderson asked whether any issues related to capillary fragility
had arisen in the MediSense study, and Dr. Ng said no. He noted that of
the two MDR reports received on the device, one involved bruising; in
the study, however, no problems were seen. Dr. Henderson asked how many
Sof-Tact devices were in use, and Dr. Ng responded that thousands had
been distributed in the United States and abroad. Finally, she asked
whether any studies had been conducted on pregnant patients, and Dr. Ng
said that although that group was not studied specifically, it was
conceivable that some of the participants were pregnant during the
research.

Dr. Rosenbloom asked whether the duration of diabetes was a factor in
the studies, given that thickening of the skin can occur with long-term
diabetes. (He also noted that technically, the correct term is
*alternative* site testing, not alternate site testing, as many people
use.) Dr. Horowitz said that the LifeScan found no connection between
the accuracy of the One Touch Ultra system and duration of diabetes. Dr.
Rosenbloom then asked whether the Sof-Tact device might have different
functional characteristics for people with stiff forearm skin, but Dr.
Ng responded that so far, no difference in functionality had been seen.

Dr. Ahmann asked whether the relative means were available for the pain
comparisons of palm testing and arm testing, but Dr. Peled indicated
that she did not have those data. Dr. Ahmann also asked whether Amira's
research had addressed the concomitant use of medications such as
aspirin and beta blockers, and Dr. Peled responded that it had not.

Ms. Lellock asked for clarification of the meaning of "vigorous
rubbing," which Eve Conner, Ph.D. (a speaker scheduled for after the
morning break) provided. Dr. Ng pointed out that the Sof-Tact device had
been designed so as not to require rubbing.

Dr. Cara wanted to know whether LifeScan had attempted to evaluate what
percentage of patients actually read the labeling, and Dr. Horwitz
replied that it had not. Dr. Clement noted that LifeScan had given
considerable thought to labeling and asked whether Dr. Horwitz would
recommend using fingertip testing instead of AST if hypoglycemia was
suspected, before meals, and after exercise. Dr. Horwitz replied that
most patients can tell if their glucose level is changing rapidly and
that issues related to hypoglycemia are addressed in LifeScan's labeling
recommendations. Dr. Rosenbloom, however, noted that labeling is
confounded by intrapatient variability: Even experienced patients cannot
always tell when they are undergoing rapid blood glucose changes.

Eve Conner, Ph.D., vice president, quality assurance/regulatory affairs,
TheraSense, Inc., presented data on her company's FreeStyle system. The
data demonstrate the safety and effectiveness of AST; AST meets
important patient needs; an adverse event rate of only one per 3 million
tests has been reported; and the product is properly labeled. The
benefits of AST outweigh the risks.

Geoff McGarraugh, director of chemistry, TheraSense, Inc., presented
data on clinical studies of the FreeStyle system as used with blood
samples from the forearm. Time course studies indicated that the glucose
levels for the arm samples lagged those of the fingertip samples by
approximately 20 minutes, but the lag was made clinically insignificant
by rubbing. Because the lag is not always eliminated by rubbing,
however, the "simple, conservative" instructions are to use fingertip
samples if hypoglycemia is suspected. Six-month outcome studies
demonstrated that glucose control was maintained with the FreeStyle
system. Moreover, three-fourths of the participants preferred arm
testing. Mr. McGarraugh disputed the findings of two studies not
sponsored by TheraSense that contradicted his company's findings; he
said that the design of both studies was flawed, and he presented data
to support his assertions.

Dr. Conner described TheraSense's approach to labeling and presented a
slide of an attention-getting label included in the FreeStyle packaging
intended to motivate the user to read the labeling. She noted that the
current labeling informs the user about the potential physiologic lag,
explains when lag might be expected, provides the user with simple
instructions for minimizing the lag, and recommends fingertip testing
when testing for hypoglycemia or if the user has hypoglycemic
unawareness. Labeling comprehension studies, outcome studies, and user
experience all indicate that patients understand the labeling well. The
rate of serious adverse events is very low, and no adverse event
sequelae or deaths have been reported.

Martin Abrahamson, M.D., chief, Adult Diabetes, Joslin Diabetes Center,
discussed his clinical experience with the FreeStyle device. AST is
considerably less painful than and has comparable accuracy to fingertip
testing, provides alternatives for people unwilling to test on fingers,
and assists parents when testing children. AST increases compliance and
thus helps patients manage their diabetes, and it has a clinically
acceptable error rate.

Finally, Dr. Conner presented TheraSense's recommendations to the panel.
The FDA should follow the current guidance document with regard to the
data and data analysis required for AST devices. Time series data could
help determine relevant physiological issues. Labeling, too, could
follow the general requirements in the current guidance document and
should advise patients that AST differs from fingertip testing.
Different devices should have different cautionary statements, depending
on the data. Finally, 510(k) applications should include performance
data to support claims; the devices should continue as over-the-counter
(OTC) devices; manufacturers should be responsible for education of end
users and health care professionals; and a public health notification is
not warranted.

Luann Ochs, M.S., director, regulatory submissions, near patient
testing, Roche Diagnostics Corp., described a series of Roche studies
that found that AST measurements are equivalent to fingertip results if
the patient's blood glucose is in a steady state. The studies also found
that the differences between forearm testing and fingertip testing
appear to be caused by physiological differences in the testing sites,
which vary among patients. Roche's position is that AST is generally
safe and effective for people with diabetes, but health care providers
and device users need to understand how to use AST properly. With
Roche's Accu-Chek system, 15% of hypoglycemic events were missed with
AST, meaning that 5 of every 1,000 AST tests could be an undetected
hypoglycemic event.

Ms. Ochs presented data from Roche's labeling comprehension studies for
labels describing how to use Accu-Chek for AST; the studies found that
patients had excellent understanding of the labeling materials. She
stated that manufacturers can ensure that consumers receive the
information on AST that consumers need. Finally, Ms. Ochs said that
Roche recommends two paths for future 510(k) review. First, if a
manufacturer agrees to precautionary statements, the review criteria
should be the same as for a fingertip test; if a manufacturer believes
the precautions are not necessary for its device, however, it should
provide evidence to that effect.

**OPEN PUBLIC HEARING**

Theodore Koschinsky, M.D., German Diabetes Research Institute,
Dusseldorf, Germany, presented data from his study of AST. He tested the
FreeStyle, Sof-Tact, and One Touch Ultra systems under conditions of
extremely rapid blood glucose change. He found significant lag with each
system, even when the site was rubbed. Results comparing base-of-thumb
samples with fingertip samples showed minimal lag, however. Dr.
Koschinsky stated that blood glucose kinetics in the thumb are identical
to those in the finger. The observed differences in the results are not
device specific and have to do with the testing site. Dr. Koschinsky
provided information on the anatomy and physiology of capillary blood
sampling to explain some of the differences in the results. Further AST
research should include studies of the effects of rapid blood glucose
changes in standardized experimental design for each device and for each
alternative site recommended; incidence of AST failure in observational
studies; characterization of patient-specific risk factors; and effects
of various types of exercise in both experimental studies and
observational studies. Dr. Koschinsky concluded by saying that any
glucose-monitoring technology that depends on blood or interstitial
fluid kinetics within the upper dermal compartment, such as optical and
transdermal approaches, must be examined for the effects of rapid blood
glucose changes.

Russell O. Potts, Ph.D., vice president of research and development,
Cygnus, Inc., described the GlucoWatch, a glucose-monitoring device for
adults with diabetes. He described the device's intended use, the
reverse iontophoresis process that operates the device, and reasons for
the differences between values ascertained by the GlucoWatch and other
testing systems. He concluded by saying that the GlucoWatch is a unique
device that provides better detection of hypo- and hyperglycemia than do
existing blood glucose meters.

Clare Rosenfeld, former national youth advocate for the American
Diabetes Association, spoke about her experience with the One Touch
Ultra system. She stated that it has helped her manage her diabetes and
has improved her quality of life. When she first started using AST, she
tested on both her finger and her arm. Because of her personal testing
results, she feels confident in using either fingertip or arm samples
when she feels that her levels are normal. When she is unsure, she uses
fingertip samples. Ms. Rosenfeld said that the current labeling of AST
systems offers the information consumers need to use the products
safely.

Craig C. Orlowski, M.D., Department of Pediatric Endocrinology,
University of Rochester, New York, stated that among his patients, he
has found no instances of severe hypo- or hyperglycemia as a result of
using AST. He believes that his patients are testing more often with AST
because they have less pain than with fingertip testing.

Laura Billetdeaux of Children With Diabetes (CWD) and her son, Sam, said
that AST has made a huge difference in how her son manages diabetes. She
described how AST makes life easier both for parents of diabetic
children and for their children. Ms. Billetdeaux summarized the results
of two online CWD surveys, in which most respondents replied that AST
was very or somewhat important in their diabetes management. Finally,
she read several excerpts from letters from parents in support of AST.

Paul Madden, M.Ed., special assistant to the president, Joslin Diabetes
Center, said that AST helps people manage their diabetes in part because
it allows people to vary parts of their diabetes management program,
thereby removing some of the boredom and giving them a feeling of
greater control. AST also reduces pain, thus encouraging more frequent
testing. Any therapy that allows patients to check blood glucose more
often will help them stay in the normal range, enhancing quality of life
and improving health.

Dr. Kroll noted that the panel had received more than 30 e-mails from
parents in support of AST.

OPEN COMMITTEE DISCUSSION

Dr. Kroll asked whether any of the panel members had questions for the
TheraSense or Roche representatives. Dr. Henderson asked whether any
studies had looked at patients with peripheral vascular disease or at
pregnant women. Dr. Conner said that the TheraSense studies had a broad
range of participants, from 5-year-olds to people in their 80s, and that
the results for those participants were good. Two TheraSense studies are
currently examining time series data in pregnant women with diabetes.

Ms. Kruger noted that if circulatory problems were an issue, one would
see that in fingertip testing as well as arm testing. Dr. Rosenbloom
asked whether skin bruising or skin fragility issues occurred with the
Sof-Tact device. Paul Locke from the University of Massachusetts Medical
School, one of the clinical researchers for several of the studies on
the Sof-Tact device, said that more than one-third of the patients in
his study were older than age 50. He did not see any problems with
ecchymosis or bruising in elderly populations.

Dr. Cara said that he was pleased with the results of TheraSense's
outcome study but was surprised to find that the willingness to test was
no different for people using AST and people using fingertip testing.
Dr. Conner replied that the participants were already in fairly good
control of their diabetes, so it is not surprising that compliance did
not increase significantly. Many of the participants preferred the
FreeStyle device. Dr. Cara asked whether TheraSense had looked at the
correlation between symptomatic hypoglycemia and hyperglycemia as
established by fingertip testing and AST; Dr. Conner said that
TheraSense had not looked at that correlation.

Dr. Ahmann asked whether TheraSense had compared preferences of meters,
and Dr. Conner said the company had not.

Dr. Clement noted that the therapeutic paradox of diabetes is that
intensive insulin therapy saves lives but the risk of hypoglycemia
increases as one gets closer to the target range. Self-monitored blood
glucose data are critical for intensive diabetes treatment, and patients
must be taught to use their own data. AST can provide useful information
about glycemic control and can be a guide for titrating nighttime
diabetes medication. Accuracy is important, and the burden of proof is
on the companies. The technology has wonderful potential, and dynamic
testing can help ferret out the differences.

Dr. Kroll reread the questions before the panel. The panel addressed
each question in turn in a round-robin process.

1.  **Should FDA's review of these devices include dynamic as well as
    steady-state data or are there more appropriate and less burdensome
    ways to address this public health issue? If additional data are
    necessary to characterize device performance:**

-   **What are appropriate study designs that will capture potential
    discordance during episodes of rapidly rising and falling glucose
    levels?**

-   **What is the minimum data set to be studied?**

-   **What are appropriate analytical or statistical tools to be applied
    to the data (i.e., standard regression analysis, Clarke Error Grid
    analysis, time elapsed plots)?**

Panel members concurred that dynamic studies are needed and that it is
appropriate for FDA to review dynamic data before clearing the device
for market. Many expressed the need for studies involving children,
people with co-occurring health conditions or concomitant mediation use,
the role of exercise. In addition, studies are needed to ascertain
individual characteristics that could lead to discordance. Panel members
suggested the need for additional time series data and studies using
insulin challenges. Several members found it reassuring that no
incidents of missed hypoglycemia have been reported.

Dr. Henderson stated that the devices are excellent clinical tools, but
they need improvement. Ms. Kruger noted that the data indicate that
companies are responsive to concerns and that it is important to
remember that the devices represent an advance in diabetes care.

Dr. Clement noted that the discordance can be troublingly high. The
methodology of glucose challenge followed by insulin is useful. It would
be good to separate the data into upflow and downflow phases and to
analyze the phases separately using Bland-Altman plots. If a company
developed a method to minimize lag, it could say that the devices are
substantially equivalent to fingertip testing. The devices have to be
challenged in a rigorous way; random testing is not quite rigorous
enough.

Dr. Kroll noted that diabetes is a dynamic disease---it cannot be
evaluated in a steady state. It is important for studies to look at time
course data as well as hypo- and hyperglycemia and insulin challenges
and to get away from stationary statistics. In addition, not all people
experience time lags; it is important to identify how significant the
time lags are and how often they occur and to analyze them by group.
People who do not experience lags do not need additional blood glucose
testing.

Dr. Cara noted that people with diabetes hate few things more than blood
glucose monitoring; AST is an important technology that needs to be
explored. He cautioned the FDA against moving backward. Manufacturers
could also look at other processes to increase perfusion besides
rubbing, such as warming.

Dr. Lasky thanked the manufacturers for the comprehensive data they
provided and said that it is important to analyze the data carefully;
although it is helpful to look at average data, averages often mask data
of concern. Agreement tables are helpful, but they are more static than
dynamic. In addition, not every alternative site provides the same kind
of information.

Dr. Cara said that manufacturers should address the dynamic nature of
blood glucose monitoring. The outcome of monitoring is not an isolated
number---it occurs in context. A better understanding is needed of some
of the other factors involved in using blood glucose numbers for the
most effective monitoring. EGA does not address those factors.

Ms. Kruger noted that one can ask only so much of manufacturers. It is
the clinician's responsibility to know the different characteristics of
his or her patients. In practice, diabetes is not what the book says.

Dr. Ahmann said that although much of the variation in the data comes
down to interindividual variation, intradindividual variation is also an
issue. Dr. Cara added that whatever device is being evaluated needs to
be evaluated in a real-life situation.

Dr. Gutman asked the panel to identify the minimum parameters of a
dynamic study. Dr. Clement described a protocol for an outpatient
setting that involved giving the patient a glucose challenge and
measuring the up slope; then administering insulin and measuring the
down slope; and, finally, measuring the resulting error. In
base-of-thumb samples, for example, the acceptable error rate could be ±
20%, 95% of the time. Dr. Clement remarked that fingertip testing
remains the gold standard.

Dr. Kroll said that an additional type of study would be one in which
manufacturers characterized individual lag. He suggested that stable lag
in a person could enable the use of a higher value for AST to indicate
hypoglycemia.

Dr. Rosenbloom said that it would be interesting to see a criterion
based on discrepancies---the number of episodes hypoglycemia is
identified (or missed) with fingertip testing versus AST; ideally, there
should be no difference. More frequent testing should catch a greater
number of hypoglycemic episodes.

Ms. Lellock said that if a person feels hypoglycemic, he or she should
treat the hypoglycemia even if the results of a blood glucose test
indicate otherwise---no test is perfect.

Dr. Cara added that having 3- to 6-month real-life experience with a
meter is important; he would be pleased to see TheraSense's outcome
data.

Dr. Lasky added that manufacturers have expressed universal agreement to
work with the FDA to use each manufacturer's information. They see a
real benefit to developing general guidelines and determining what
clinical data would be needed to obtain FDA clearance of AST and related
technology.

2.  **Should FDA require manufacturers to include strong cautionary
    labeling about this problem unless they provide data demonstrating
    that the discordance is unlikely to occur with their particular
    device?**

Panel members agreed that the FDA should require manufacturers to
include strong cautionary labeling.

Ms. Lellock liked TheraSense's red warning label. If manufacturers know
that their devices lag behind fingertip testing, they should warn the
consumer. If there is no lag, however, there is no need for a warning
label.

Dr. Lasky agreed that manufacturers should provide cautions in labels,
particularly for forearm samples, and added that he would like to see a
better definition of "unlikely" because it has important implications
for labeling. He noted that standard definitions for terms such as
"possibility of occurrence" are used in the field of risk management and
that many manufacturers rely on such definitions in their product
development.

Dr. Cara noted that the meters have not been thoroughly evaluated for
AST in women and children. He said that labeling needs to include
information on fingertip testing, on hypoglycemia, and on what is still
not known about using AST. Dr. Ahmann noted that the information on
thumb testing indicates that differences are a function of the
collection site, not the meter itself.

Dr. Kroll agreed that a better definition of "unlikely" was needed. If
it could be shown that AST was identical to fingertip testing,
cautionary labeling would not be required. Labeling should emphasize
that patients need to work with their physicians to establish whether
they experience a lag. Unlike other tests, the results are specific to
each user and could change over time with changes in microcirculation
and so forth.

Dr. Clement liked LifeScan's proposed labeling---he remarked that
"black-box" warnings just scare people. He added that the issue of
whether patients' glucose is stable or unstable is an illusion. At
certain times, fingertip testing is simply appropriate.

Ms. Kruger said that the companies had done a remarkable job of
gathering data without the FDA saying that they had to. She suggested
using the term "health care team" rather than "physician" in labeling.

Dr. Henderson said that labeling should mention the issue of lag; she
believes that people either don't read black boxes or don't use the
product. She would add a blurb titled "fingertip testing opportunities,"
which would list the times when such testing is indicated. Labeling
should be a jumping-off point for the patient education process.

Dr. Rosenbloom noted that lag was unlikely to occur with testing at the
base of the thumb. Labeling should state that patients should use
fingertip testing instead of AST for sick-day management.

3.  **Should FDA:**

-   **rescind the clearance for labeling for alternative site testing if
    the 510(k)s do not address this new scientific issue?**

-   **make these products prescription home-use?**

-   **require additional data and labeling changes?**

Some panel members felt that rescinding clearance should be an option if
manufacturers do not address the issue of discordance. Dr. Lasky said
that rescinding clearance is a difficult issue because the companies
appear to have been forthcoming with the data. He noted that no adverse
events have been reported and that manufacturers have been responding
effectively and responsibly. Ms. Kruger said that the FDA should not
rescind existing clearances because the FDA has to move forward. Dr.
Henderson said that the data requirements should be in place for new
applications; she was not sure that the FDA should rescind existing
clearances. With regard to risk management, she noted that "unlikely" is
not a difficult concept.

Members generally agreed that the devices should not require a
prescription because doing so would create a burden for consumers and
would not guarantee better patient education. Ms. Lellock, however, said
that the meters should be prescription home-use devices because doing so
could help ensure that everyone who purchases a meter receives proper
training in how to use it. Dr. Rosenbloom asked whether one reason for
requiring a prescription for AST devices would be to ensure third-party
payment. Dr. Clement noted that the issue is moot because all insurers
require prescriptions for reimbursement anyway, even for OTC
medications.

Panel members agreed that they had adequately addressed the labeling
issue in the second question. Dr. Rosenbloom asked Dr. Gutman whether
meters that have not been tested for particular sites will need further
testing. Dr. Gutman answered that FDA would explore that issue; FDA does
not look at off-label use, only at uses for which manufacturers make a
claim. Rosenbloom noted that AST is becoming a popular
alternative---people will assume that whatever meter they have is good
for their purpose, so the labeling should note that it is only
appropriate for certain use. Ms. Kruger said that cautionary labels are
not needed for meters not approved for AST. Dr. Clement suggested giving
the sponsor two options: (1) accepting labeling as discussed or (2)
providing data from dynamic testing that indicate no systematic bias in
the upslope and downslope or differences between YSI results and the AST
device. Dr. Kroll emphasized that labeling needs to be prominent and
that even with good labeling, some patients need considerable help with
learning to use glucose-monitoring devices---the concepts are difficult
for some people.

4.  **Are there other activities or issues that FDA should consider with
    regard to this important public health issue, such as:**

    -   **a public health alert**

    -   **targeted postmarket surveillance**

    -   **educational outreach activities to stakeholders and other
        government and nongovernment entities to promote additional
        research in this area?**

The panel generally concurred that the FDA should consider the
activities listed in the question, although the members had mixed views
on the need for a public health alert.

Ms. Lellock thought that a public health alert would be useful because
not everyone is aware of the lag issues, but Dr. Lasky said that an
alert was not warranted because it could create a panic situation; it
would not be good for patients to stop monitoring themselves. Dr. Ahmann
said that any public health alert would have to be done
cautiously---media coverage of the alert would magnify its impact. Dr.
Manno and Dr. Cara agreed that a public health alert was not warranted.

Dr. Henderson thought targeted postmarket surveillance was important,
particularly with regard to pregnant women and concurrent illnesses. Dr.
Rosenbloom added that such surveillance is important for children, too.
Dr. Ahmann indicated that targeted postmarket surveillance might be a
good option; he is skeptical of the effectiveness of MDRs and said that
they are not that helpful except to spot trends. In addition, it is not
likely that people will blame errors on the meter. More companies should
look at the base of the thumb as a test site. Dr. Lasky suggested
separating postmarket surveillance from postmarket clinical studies and
agreed that studies on specific populations are warranted. Lasky noted
that from an industry perspective, surveillance connotes regulatory
consequences and that surveillance requirements are already in place in
the form of MDRs.

Dr. Kroll noted that glucose measurement is a dynamic, time-dependent
process and that old statistical techniques fail in this area;
additional outreach is needed to promote research. Dr. Cara encouraged
FDA to work with other agencies and organizations to get the information
out to a broad audience. Dr. Lasky said that education and outreach
efforts were warranted and noted that manufacturers were expected to
work with the diabetes associations to carry out such efforts.

OPEN PUBLIC HEARING

Dr. Kroll read into the record a letter from Sonia Cooper, president of
the Children With Diabetes Foundation. Her letter noted the advantages
of AST for diabetic children and their parents in terms of reduced pain
and better monitoring. In addition, children often do not wash their
fingers before testing, leading to distorted readings; AST can address
that problem.

C. Kurt Alexander, M.D., CDE, FACP, FACE, a physician in Indiana who was
an investigator in the Roche study (but was not representing Roche at
the meeting), said that the study was designed to determine whether
fingertip readings and AST readings differed and whether it could be
predicted who might demonstrate discordance. The study found that
discordance could not be predicted. Alexander described different
patient education inserts and noted that even physicians may not be
aware of the differences between AST and fingertip testing. He asked the
FDA to not restrict patient access to the new technology because it
enhances adherence and because patients seek new opportunities in
testing. He said that patients, diabetes educators, physicians, and
caregivers need to be informed of the differences among testing sites
and that some patient occupations may be inappropriate for AST (e.g.,
pilots, heavy machinery operators, high-rise construction workers).
Alexander said that the trend is toward increased postprandial glucose
testing, which makes education regarding differences even more
important. When new information becomes available, companies should be
allowed to distribute it immediately. In addition, before recommending
AST for specific populations, it should be tested in those populations.

Maria C. Matas-Chamberlain, R.N., a nurse and certified diabetes
educator (CDE) who has had diabetes for 20 years, spoke in favor of AST,
saying that it has been very helpful to her and that because AST is pain
free, she has seen it motivate people to test their glucose. She
emphasized that CDEs must be kept informed about the technology.

Natalie Bellini, R.N., CDE, said that she has had diabetes for 32 years.
She spoke in favor of AST and said that it makes a huge psychological
difference for diabetics.

Carolyn D. Jones, J.D., M.P.H., Advanced Medical Technology Association
(AdvaMed), said that the AdvaMed Blood Glucose Monitoring Working Group
strongly supports the development and use of AST technology. Clinical
research has demonstrated the accuracy of AST; evaluations should
simulate real-life conditions rather than extreme conditions. Jones
presented AdvaMed's "points-to-consider" for FDA's use in evaluating AST
systems:

1.  Manufacturers should use the same accuracy criteria they use to
    assess differences between glucose meter and laboratory results from
    fingertip blood samples; the reference sample should be obtained at
    the fingertip regardless of the AST site.

2.  Studies to confirm the acceptability of an AST site should be done
    under the proposed conditions of use. Postprandial blood samples
    provide an adequate range of glucose change to evaluate
    non-steady-state system performance. Performance claims should be
    supported by a statistically sound study.

3.  Data specific to each proposed alternative site should be obtained,
    and labeling claims should be limited to the specific sites that
    have been evaluated. AdvaMed believes it is appropriate to establish
    a set of precautionary statements to include in labeling.

4.  AdvaMed supports the continued use of current systems on the market
    and FDA clearance of new systems as long as manufacturers inform
    users of the limits of AST.

5.  Manufacturers are in the best position to give the proper education
    and training to consumers.

6.  Prescription use is not warranted for AST products.

Finally, Jones presented suggested language for labeling.

**OPEN COMMITTEE DISCUSSION**

Dr. Henderson remarked that she saw no controversy with AST; it seems to
be a good tool, albeit an imperfect one. Dr. Gutman remarked that one of
the uses of a panel was to provide that kind of feedback to FDA; he
noted that what may have seemed alarming 6 to 8 months ago may no longer
be so in light of newer information. However, challenges still lie
ahead.

Dr. Clement observed that the term "hypoglycemic unawareness" is not a
common term and that perhaps other language should be used to describe
the condition.

Dr. Lasky noted the increased effort toward standardization of in vitro
diagnostic products, particularly internationally. FDA has been active
in the standardization process; any criteria that are relevant to AST
use should draw on the document outlining criteria for whole-blood
glucose monitoring that was developed as part of a working group on
standardization and which FDA has been critiquing.

Dr. Kondratovich asked the panel members what they thought an
appropriate study design might be. Dr. Clement responded that serially
measuring the blood glucose of individual patients while provoking
hyper- and hypoglycemia would provide good information. Dr. Kroll
concurred with Dr. Clement that time series data are necessary and that
single data points are inadequate. Dr. Rosenbloom suggested that
single-point measurements could be useful for accuracy studies, but Dr.
Kroll noted that paired single-point values are valid only if they come
from the same sample; a problem with other studies is that they do not
always use the same sample.

**ADJOURNMENT**

Dr. Kroll thanked the participants and adjourned the meeting at 3:56
p.m.

I certify that I attended this meeting of the Clinical Chemistry and
Clinical Toxicology Devices Panel on October 29, 2001, and that these
minutes accurately reflect what transpired.

> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Veronica J. Calvin, M.A.
>
> Executive Secretary

I approve the minutes of the October 29, 2001, meeting

as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Martin H. Kroll, M.D.

Chairperson