[Federal Register Volume 66, Number 199 (Monday, October 15, 2001)]
[Notices]
[Pages 52418-52420]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-25762]


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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.

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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