[Federal Register: October 15, 2001 (Volume 66, Number 199)]
[Notices]
[Page 52418-52420]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15oc01-52]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 80N-0042]
RIN 0910-AA01
Anticaries Drug Products for Over-the-Counter Human Use; Use of
Intraoral Appliance Models for Compliance With Biological Testing
Requirements; Request for Information and Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is requesting
information and comments on the use of intraoral appliance (IOA) models
as a substitute for the animal caries reduction (``rat caries models'')
biological test required by the monograph for over-the-counter (OTC)
anticaries drug products to demonstrate the availability of fluoride in
OTC dentifrice formulations. This notice is part of the ongoing review
of OTC drug products conducted by FDA.
DATES: Submit written or electronic comments by January 14, 2002.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/
dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Robert L. Sherman, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
The testing procedures for fluoride dentifrice drug products in 21
CFR 355.70 of the final monograph for OTC anticaries drug products (60
FR 52474, October 6, 1995), include both in vitro and biological
testing to demonstrate the effectiveness of OTC anticaries dentifrices.
The two in vitro tests (fluoride enamel uptake and enamel solubility
reduction) demonstrate that fluoride is chemically available. The
biological testing (animal caries reduction) assures that the fluoride
is also bioavailable to alter tooth structure and make the tooth
resistant to caries.
In the preamble to the final monograph for OTC anticaries drug
products, FDA encouraged the development of additional testing
procedures, such as remineralization tests. The agency noted that
sufficient data were not available to correlate these tests
specifically with clinical studies that demonstrate the effectiveness
of fluoride dentifrices (60 FR 52474 at 52499). The agency stated that
it would consider such tests as a substitute for the animal caries
reduction test if adequate data were submitted demonstrating that an
alternative testing procedure provides results of equivalent accuracy.
In 1996, FDA granted a petition (Refs. 1 and 2) that included the
results of a study conducted in humans wearing an IOA with attached
enamel chips as a substitute for the animal caries reduction test.
Although the agency had initial concerns about the design and results
of this IOA test, the data were considered sufficient to accept the
test as an alternative to the animal caries model to demonstrate the
effectiveness of the tested dentifrice formulation.
The petition also requested that the results of the IOA test be
accepted as evidence of the effectiveness of the petitioner's other
formulations. However, because these formulations contain different
abrasives and flavorings, the agency determined that all other
formulations must be tested individually (Ref. 2). The agency also
recommended that protocols for any further IOA tests be submitted for
review prior to conducting the tests.
IOA models employ small pieces of tooth enamel, mounted in the
acrylic flanges of dentures worn by subjects that have been randomized
to the various treatments to be investigated. The enamel chips are
examined for demineralization or remineralization using various test
methods. Proponents of the IOA model argue that, when compared with the
animal caries reduction test, the IOA test is more
[[Page 52419]]
sensitive, reliable, and accurate, and that the testing does not
require the sacrificing of animals.
Proponents add that a potential advantage of the IOA model is
comparability to normal dentifrice use. In the animal caries reduction
test, rats are superinfected with cariogenic bacteria and, unlike
clinical subjects, swallow the fluoride toothpaste. Thus, it may be
difficult to determine if the caries reduction is confounded by
systemic absorption of fluoride. Further, the use of a removable
appliance containing multiple enamel specimens offers a number of
advantages. Most importantly, this method provides a sufficient number
of specimens for several different analyses to be used: (1)
Microradiography demonstrates the occurrence and extent of
remineralization, (2) fluoride uptake measures in-situ bioavailability
of fluoride, and (3) microhardness and acid-resistance testing measure
the stability of remineralized enamel lesions. Multiple specimens also
ensure that sufficient samples are available even if some are damaged
during wearing or analysis.
In 1989, the Council on Dental Therapeutics (the Council) of the
American Dental Association (ADA) accepted a new, modified fluoride
dentifrice based largely upon data from IOA models, thus acknowledging
that IOA models could be used as a potential indicator of clinical
effectiveness. This marked an important departure from the Council's
past practice of accepting modified anticaries agents only when
conventional clinical trials had demonstrated a statistically
significant benefit. Subsequently, the Council concluded that further
consideration should be given to statistical issues related to IOA
models and recommended that guidelines be developed concerning the
validity and reliability of these models for use in approval of product
claims (Ref. 3).
The animal caries reduction test has a long history of reliability
in demonstrating the effectiveness of fluoride dentifrices. This test
directly measures the effectiveness of a fluoride dentifrice in an
animal model in vivo after limited brushing and gives a more complete
assessment of tested formulations compared with the two in vitro tests
(fluoride enamel uptake and enamel solubility reduction). This test has
been a requirement of the OTC anticaries final monograph since it was
published in 1995. The anticaries final monograph provides general
guidance on appropriate statistical analyses for the animal caries
model.
In 1996, when FDA granted the petition to accept an IOA study as a
substitute for the animal caries reduction test, the agency did not
anticipate many similar requests. However, since that time, several
citizen petitions (Refs. 4, 5, and 6) requested substitution of an IOA
model for the animal caries test. Based on information in these
petitions, the agency believes that a well-conducted IOA study can
provide a measure of both remineralization and demineralization of
tooth structure and potentially may provide results that, when compared
to the animal caries model, are of equivalent accuracy.
The agency also received a citizen petition opposing these requests
(Ref. 7). The petition presented two major criticisms of the IOA model:
(1) It measures demineralization but not remineralization, and (2) it
does not adequately mimic realistic caries challenges.
Thus, there is disagreement within the dental research community
about whether IOA studies provide sufficient evidence of both
demineralization and remineralization. There is also disagreement about
whether the potential advantages of the IOA model, which uses human
teeth, outweigh the predictability and the experience of the animal
model.
II. The Current Request for Data and Information
Because of the lack of consensus within the dental community
regarding the IOA test and the apparent increased interest among
manufacturers to rely on this test in lieu of animal studies to
demonstrate the effectiveness of new fluoride formulations, the agency
has determined that it is appropriate to address these issues in a
public forum where experts can debate the usefulness and acceptability
of alternate biological testing methods such as the IOA model. The
agency is publishing this notice to gather information concerning IOA
models and whether and how they can be used in lieu of the animal
caries models in meeting the biological testing requirements for OTC
anticaries drug products. This information would include various study
designs, the parameters measured, methods for measuring these
parameters, and the statistical methods employed to analyze the data.
The agency would also like to have information concerning the
statistical analyses that have been applied to the data generated by
animal caries studies conducted to support monograph status for
currently-marketed dentifrices.
In terms of study design, the agency is seeking information on both
short-term and long-term IOA models. In the short-term study, the test
product is used only once and the treatment phase lasts anywhere from 1
to 6 hours. In long-term studies, subjects wear the appliance for 2 to
8 weeks, using the test product several times a day. Because one of the
criticisms of IOA models is their inability to measure
remineralization, the agency seeks discussion regarding the ability of
short-term and long-term studies to measure demineralization and
remineralization.
Currently, the literature cites several ways of calculating the
extent of mineralization or demineralization in these studies. Two
common methods of measuring the percent mineral change in enamel are
microradiographic analysis and microhardness testing. The agency
requests detailed explanations of these methods, as well as others that
are being proposed for this use. The agency also encourages discussion
of the validity of substituting examination of mineral changes in the
enamel chips in the IOA model for caries in the animal model. Further,
the agency requests information on the validity of accelerating mineral
changes in enamel both by soaking the chips in a sucrose solution and
placing gauze over the chips to attract additional plaque.
Adequate demonstration of bioavailability in the biological testing
models for fluoride dentifrices requires that the test product be
significantly superior to the placebo, and noninferior to the reference
standard performance. In the June 15, 1988, tentative final monograph
for OTC anticaries drug products (53 FR 22430 at 22440), the agency
discussed equivalence testing for the biological tests as follows:
``The more general statement `not significantly lower than the score
for the reference formulation' allows the application of appropriate
statistical criteria to laboratory data to demonstrate that fluoride
dentifrices achieve scores in the biological tests that are not
significantly lower than the scores for the reference formulations.''
The use of the appropriate statistical analysis is further emphasized
in the next paragraph of that section where it states: ``Further, as
stated in Sec. 211.165(d) [21 CFR 211.165(d)], appropriate statistical
quality control criteria must be used for drug products.''
Recent petitions requesting that the agency accept the IOA model in
lieu of the animal caries reduction test have interpreted the phrase
``not significantly lower than the scores for the reference
formulation'' as allowing the use of
[[Page 52420]]
hypothesis testing as an acceptable statistical method. Although FDA
considers computing p-values to be the correct method to test the
hypothesis that a difference exists between the test product and
placebo, the agency does not consider this method appropriate for
demonstrating noninferiority of the test product to the reference
standard. Failure to demonstrate a difference can result from several
factors, including a small sample size, inappropriate adjustment, or
poor study design. However, it is incorrect to infer from hypothesis
testing that two products are equivalent or that one is not inferior to
the other. For the comparison between the test product and the
reference standard, the agency believes that noninferiority testing, a
subset of equivalence testing, is necessary.
The agency is seeking comment on statistical analyses that can be
used to support the comparison between the test product and the
reference standard. Because statistical testing for demonstrating
superiority of a test dentifrice to a placebo dentifrice is generally
straightforward, the agency is particularly interested in the
statistical testing that would support either equivalence or
noninferiority comparisons. Coupled with this, the agency is requesting
information on whether the IOA models would require larger sample sizes
than the animal caries models.
The agency anticipates that this information-gathering process will
be followed by an advisory committee meeting at which the various
models and the appropriate statistical analyses will be discussed.
III. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written or electronic comments regarding this notice by
January 14, 2002. Three copies of all written comments are to be
submitted. Individuals submitting written comments or anyone submitting
electronic comments may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document and may be accompanied by a supporting memorandum or brief.
Received comments may be seen in the Dockets Management Branch between
9 a.m. and 4 p.m., Monday through Friday.
IV. References
The following references are on display in the Dockets Management
Branch (address above) under Docket No. 80N-0042 and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Comment No. CP5.
2. Comment No. LET35.
3. Proskin, H. M., N. W. Chilton, and A. Kingman, ``Interim
Report of the Ad Hoc Committee for the Consideration of Statistical
Concerns Related to the Use of Intra-oral Models in Submissions for
Product Claims Approval to the American Dental Association,''
Journal of Dental Research, 71:949-952, 1992.
4. Comment No. CP7.
5. Comment No. CP9.
6. Comment No. AMD3.
7. Comment No. CP8.
Dated: September 28, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-25762 Filed 10-12-01; 8:45 am]
BILLING CODE 4160-01-S