[Federal Register Volume 62, Number 109 (Friday, June 6, 1997)]
[Notices]
[Pages 31118-31121]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14750]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97D-0191]


Medical Devices; Guidance for Industry; Premarket Notification 
(510(k)) Guidance Document for Contact Lens Care Products; Revised; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a revised guidance entitled, ``Guidance for Industry; 
Premarket Notification (510(k)) Guidance Document for Contact Lens Care 
Products.'' The revised guidance sets forth the types of tests the 
Center for Devices and Radiological Health (CDRH), FDA, believes are 
necessary to provide reasonable assurance of the safety and 
effectiveness of contact lens care products. The revised guidance 
accompanies a final rule, which appears elsewhere in this issue of the 
Federal Register, reclassifying rigid gas permeable contact lens 
solution; soft (hydrophilic) contact lens solution; and contact lens 
heat disinfecting units from class III (premarket approval) to class II 
(special controls).

DATES: Written comments may be submitted at any time.
ADDRESSES: Submit written requests for single copies of the revised 
guidance entitled, ``Guidance for Industry Premarket Notification 
(510(k)) Guidance Document for Contact Lens Care Products'' (shelf 
number 674) to the Division of Small Manufacturers Assistance (HFZ-
220), Center for Devices and Radiological Health, Food and Drug 
Administration, 1350 Piccard Dr., Rockville, MD 20850, 301-443-6597 
(outside MD 1-800-638-2041). Send two self-addressed adhesive labels to 
assist that office in processing your requests. Submit written comments 
on the revised guidance to the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, 
MD 20857. Requests and comments should be identified with the docket 
number found in brackets in the heading of this document. Comments may 
be submitted at any time and will be used to determine whether to 
revise the guidance further.

FOR FURTHER INFORMATION CONTACT: James F. Saviola, Center for Devices 
and Radiological Health (HFZ-460), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-1744.

SUPPLEMENTARY INFORMATION:

I. The Statutory Requirements

    The Safe Medical Devices Act (the SMDA) (Pub. L. 101-629), which 
amended the medical device provisions of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 321 et. seq.), contains specific 
provisions on transitional devices (i.e., those devices regulated as 
new drugs before the Medical Device Amendments of 1976 (Pub. L. 94-295) 
became law) (see section 520(l) of the act (21 U.S.C. 360j(l)). In 
1976, Congress classified into class III all transitional devices 
(i.e., those devices previously regulated as drugs). The legislative 
history of the SMDA reflects congressional concern that many 
transitional devices were being overregulated in class III (H. Rept. 
808, 101st Cong., 2d sess. 26-27 (1990); S. Rept. 513, 101st Cong., 2d 
sess. 26-27 (1990)). Congress amended section 520(l) of the act to 
direct FDA to collect certain safety and effectiveness information from 
the manufacturers of transitional devices that still remain in class 
III to determine whether the devices should be reclassified into class 
II (special controls) or class I (general controls).
    Under section 520(l)(5)(B) of the act, FDA was to publish 
regulations by December 1, 1992, either leaving the transitional class 
III devices in class III or revising their classification down to class 
I or class II. However, as permitted by section 520(l)(5)(C) of the 
act, in the Federal Register of November 30, 1992 (57 FR 56586), the 
agency published a notice extending the period for issuing such 
regulations until December 1, 1993. Due to limited resources, FDA was 
unable to publish the regulations before the December 1, 1993, 
deadline. In the Federal Register of April 1, 1996 (61 FR 14277), FDA 
published a proposed rule to reclassify from class III (premarket 
approval) to class II (special controls) the rigid gas permeable 
contact lens solution; the soft (hydrophilic) contact lens solution; 
and the contact lens heat disinfecting unit. FDA also announced the 
availability of a premarket notification (510(k)) draft guidance 
document for contact lens care products (61 FR 14330, April 1, 1996). 
Interested persons were invited to comment on the guidance document by 
May 31, 1996.
    Elsewhere in this issue of the Federal Register, FDA is issuing a 
final rule reclassifying from class III (premarket approval) to class 
II (special controls) all transitional contact lens care products. In 
conjunction with the final rule, FDA is announcing the availability of 
the revised guidance for premarket notification for the reclassified 
contact lens care products entitled, ``Guidance for Industry; Premarket 
Notification (510(k)) for Contact Lens Care Products.''

II. The Revised Guidance

    The revised guidance sets forth the types of testing that FDA 
believes will provide reasonable assurance of the continued safety and 
effectiveness of transitional contact lens care products. It also 
provides comprehensive

[[Page 31119]]

directions for manufacturers of contact lens care products to follow in 
submitting a 510(k) premarket notification submission demonstrating 
substantial equivalence of their device to a legally marketed contact 
lens care product (predicate device). Information on the battery of 
preclinical testing that may demonstrate substantial equivalence is 
included in the guidance. If the results of preclinical testing 
demonstrate that the device will have new characteristics, clinical 
performance data may be needed to establish substantial equivalence. If 
clinical performance data are needed, the guidance document suggests 
methodologies (e.g., size and scope of the study) to be included in the 
investigational protocol.
    Other elements of the guidance include: (1) General information on 
the regulations and requirements for labeling contact lens care 
products; (2) information about 510(k) submission requirements relating 
to modifying a marketed contact lens care product; and (3) guidance for 
submitting a 510(k) notification for contact lens cases and contact 
lens accessories (i.e., mechanical cleaning aids and accessory cleaning 
pads).
    In the event that clinical trials are necessary, FDA emphasizes 
that manufacturers are required to conduct the trials in accordance 
with the investigational device exemption regulations in 21 CFR part 
812. At this time, FDA considers clinical studies of most contact lens 
care products to be nonsignificant risk investigations. For 
nonsignificant risk investigations, approval of an institutional review 
board (IRB) is necessary before initiating a clinical study, and an 
investigational plan and informed consent document must be presented to 
an IRB for review and approval. Prior FDA approval is not required.
    However, FDA considers some clinical studies of solutions that 
contain new active ingredients for ophthalmic use and that are intended 
for use directly in the eye to be significant risk investigations that 
would require both IRB and FDA review and approvals. Examples of 
significant risk investigations requiring FDA and IRB review and 
approval include investigations of solutions intended for repeated use 
directly in the eye that contain new types of ingredients that have no 
history of ophthalmic use, that may require different testing than the 
preclinical tests in the guidance, that may contain ingredients that 
can perfuse through the cornea, or that may involve overlapping 
concerns with other FDA Centers, such as products or studies 
incorporating a biologic or a pharmaceutical compound. Sponsors 
proposing to conduct such studies should contact James F. Saviola 
(address above) concerning the risk status of the proposed 
investigation prior to implementing their studies.
    Comments received from the public on the draft guidance were 
summarized at the July 26, 1996, meeting of the Ophthalmic Devices 
Panel of the Medical Devices Advisory Committee.

III. Summary and Analysis of Comments and FDA's Response

    Separate comments were received from four individuals and a single 
set of comments from industry via the Contact Lens Institute. Comments 
were generally categorized as editorial, clarification, and 
substantive. The guidance document has been revised to address most of 
the editorial, providing clarification and substantive comments.
    Comments pertaining to policy and clinical information are 
summarized as follows:
    1. One comment suggested that FDA change the wording in the 
guidance which states that clinical studies of contact lens care 
products are nonsignificant risk investigations. The current wording in 
the guidance states that this is the case unless the device contains 
new active ingredients for ophthalmic use and is intended to be used 
directly in the eye.
    FDA agrees in part with this comment. However, investigations of 
some in-eye products are significant risk investigations (e.g., 
investigations of solutions intended for repeated use directly in the 
eye that contain new types of ingredients that have no history of 
ophthalmic use, that may require different testing than the preclinical 
tests in the guidance, that may contain ingredients that can perfuse 
through the cornea, or that may involve overlapping concerns with other 
FDA Centers, such as products or studies incorporating a biologic or a 
pharmaceutical compound). The guidance has been revised to clarify when 
a contact lens care product investigation is considered significant 
risk and to recommend that sponsors contact FDA for guidance concerning 
risk status of such proposed investigations prior to beginning clinical 
studies.
    2. One comment stated that discard dates alone will not necessarily 
reduce the risk of eye infections caused by contamination during use 
and suggested that the statement in the General Manufacturing section 
stating that, whenever possible, manufacturers should consider the use 
of discard dates after opening, be revised to be more consistent with 
21 CFR 800.10(b).
    FDA agrees that the guidance should reflect the regulation and has 
revised the guidance accordingly. However, FDA believes that discard 
dates would help to minimize contamination of lens care products and 
that responsible manufacturers should work in this direction.
    3. A few comments were received pertaining to recommendations for 
clinical trials (e.g., size and scope, study design, and testing 
matrix). One comment stated that the studies are too short and may not 
uncover complications such as different levels of patient 
hypersensitivity. That comment stated that clinical studies for all new 
lens care formulations should be, at a minimum, 3 months in length with 
at least 100 patients. Also, for products that are substantially the 
same as one already on the market with the same indication, clinical 
studies would still be necessary.
    FDA has designed the guidance to include preclinical testing as the 
primary evidence for establishing substantial equivalence, with 
supplemental clinical testing as additional confirmatory information. 
The clinical recommendations include minimum patient numbers. Sample 
sizes are similar to those used in the daily wear contact lens 
guidance. FDA has revised the guidance to clarify that a 30 patient/1-
month study is appropriate in certain matrices for products with active 
ingredients within marketed concentrations, as well as for higher or 
lower concentrations. Under study design, FDA has clarified the 
statement that a crossover design with an in vitro analysis is an 
example of a method that may be used for clearer effectiveness studies, 
rather than stating that it may be the best method to use. The guidance 
has been revised to include suggestions for sponsors choosing to 
include data from a patient population greater than the minimum size 
recommended.
    In Appendix B for protocol considerations, FDA has revised the 
visit schedule to delete the 2-week visit for trials conducted longer 
than 1 month, provided for the use of other suitable well-defined 
grading scales (e.g., International Standards Organization Scale), and 
revised the investigator-patient ratio section to provide additional 
guidance for the number of patients per study site.
    4. One comment suggested that the title of the ``Adverse Reaction 
Section'' be changed to ``Serious Adverse Reaction.'' Another comment 
suggested that the discontinued eye summary

[[Page 31120]]

table be deleted. FDA disagrees with both of these comments. The first 
comment invites subjectivity of reporting adverse events. 
Discontinuation information could provide important safety or efficacy 
information and should be reported.
    Comments pertaining to preclinical information are summarized as 
follows:
    Concerning microbiology, most comments submitted for clarification 
or minor changes in test methods have been included in the revised 
guidance. Many of these comments addressed preparation of the microbial 
challenge used to conduct the test. Substantive comments on the 
disinfection efficacy tests, which are the stand alone and regimen 
tests, addressed the panel of test organisms, the methodology, and the 
performance criteria.
    Concerning test organisms, one comment recommended that FDA add to 
the current panel of microorganisms used for evaluating antimicrobial 
efficacy.
    This comment was rejected. FDA believes the current panel is 
adequate for determining the substantial equivalence of newly marketed 
products. Manufacturers may choose to test products against additional 
microorganisms during product evaluation; however, FDA's current policy 
is that labeling claims may not highlight product efficacy against 
individual microorganisms.
    Concerning methodology, comments addressed the need to include 
organic load and biofilm in the test procedures.
    FDA's position remains unchanged regarding the inclusion of organic 
load to establish the substantial equivalence of disinfecting 
solutions. FDA did not incorporate two separate comments on organic 
load (i.e., one that suggested inclusion of a mild organic load in the 
stand alone test procedure and one that recommended elimination of 
organic load in the regimen test). Stand alone disinfecting products 
are labeled with cleaning instructions to remove organic load. For lens 
care regimens with milder disinfecting agents, it is necessary to 
include removal of simulated lens deposits during cleaning and rinsing 
steps.
    FDA rejected a comment to evaluate biofilm in the lens case. The 
issue of biofilm formation can be adequately addressed through labeling 
recommendations for daily cleaning and frequent lens case replacement.
    Concerns were raised on the currently recommended performance 
regimen criteria of less than three colony forming units to determine 
substantial equivalence of disinfecting regimens.
    FDA agrees that manufacturers should have alternative performance 
criteria due to limited experience with the revised regimen test 
procedure. Therefore, the guidance has been revised to include an 
option based on directly comparing regimen test results for the device 
with those obtained for a predicate device.
    FDA revised the guidance to include the experimental error (+/-0.5 
log) in the performance criteria requiring stasis on yeast and mold 
counts.
    Based on the comments received concerning the bacteriostasis test, 
the following revisions have been made in the guidance:
    1. A correction to eliminate a microbial rechallenge in the 
bacteriostasis test.
    2. Including bacteriostasis testing outside of the actual product 
container.
    FDA has incorporated most suggested clarifications for chemistry 
and manufacturing. Revisions include the following for chemistry:
    1. A solution compatibility test has been included in all product 
test matrices.
    2. A wetting angle test is recommended for all conditioning 
solutions in the test matrix.
    3. The following example has been added as a modification not 
requiring a 510(k): Nonsignificant manufacturing changes made in 
accordance with 21 CFR 807.81 that meet good manufacturing practice 
requirements.
    Comments on the protocol for establishing shelf-life concerned 
microbiology and chemistry testing.
    1. FDA rejected the suggestion that sponsors should submit and/or 
reference data from identically packaged contact lens care products to 
support shelf-life sterility since a product formulation may affect 
microbial growth during storage.
    2. FDA has added the statement that manufacturing changes to 
smaller bottle sizes from identical materials, using an approved shelf-
life protocol, is an example of a change not requiring a 510(k).
    3. FDA has deleted the recommendation for disinfection efficacy 
testing at the end of the recommended shelf life.
    4. FDA has included container inversion as one example for 
maximally testing the container/closure system as clarification, and 
not as a specific recommendation.
    5. FDA has reevaluated the recommendation for accelerated testing 
for establishing shelf life beyond 2 years and the recommendation for 6 
months ambient temperature data prior to marketing. The recommendation 
that any shelf-life request beyond 2 years should be based on real time 
data has been eliminated. The guidance recommends that companies 
provide their shelf-life protocol in their 510(k) and certify that they 
will have shelf-life data sufficient to support their labeled 
expiration date prior to marketing their device.
    Toxicology comments received on the product specific test matrices 
include:
    1. Replacing the current 3-day acute ocular irritation test with a 
5-day test.
    2. Adding an additional battery of toxicology tests for the higher 
than marketed concentrations.
    3. Including cytotoxicology and an ocular irritation toxicology 
screening test for active ingredients within marketed concentrations 
and for lower than marketed concentrations.
    FDA's response to these comments are as follows:
    1. The suggested 3-day acute ocular irritation test currently in 
the guidance is based on historical evidence that if adverse events 
occur, they will generally manifest themselves during the 3-day time 
period. If a sponsor prefers the 5-day test, this is acceptable.
    2. While the additional battery of tests for the higher than 
marketed concentrations may be appropriate in some cases depending on 
the ingredients, they are not generally appropriate for all product 
specific matrices.
    3. FDA agrees that toxicology screening is appropriate and the 
guidance has been revised accordingly.
    Several comments were received concerning labeling. Many of these 
suggested editorial changes which have been incorporated in the revised 
guidance. The following four labeling comments were rejected:
    1. FDA has not deleted the warning, ``To Avoid Contaminating Your 
Solution, Do Not Transfer to Other Bottles or Containers.'' This 
warning was recommended by the Ophthalmic Devices Panel as one means of 
helping to minimize contamination. FDA believes that, at a minimum, 
this warning should be on larger-sized bottles.
    2. Company phone numbers to which adverse reactions should be 
reported is still included as a means of encouraging device reporting 
back to the manufacturer.
    3. Boxed warnings were included in the ``Write-it-Right'' labeling 
example to provide an example of labeling developed according to 
specific principles. These warnings remain in the guidance because they 
are examples and not specific recommendations.

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    4. FDA has revised the labeling examples to make product-specific 
warnings more direct.
    FDA will continue to evaluate and amend the guidance in the future 
if changes are necessary to assure the continued safety and 
effectiveness of contact lens care products.

IV. Significance of a Guidance

    In the past, guidances have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidances to state procedures or standards of general applicability 
that are not legal requirements, but that are acceptable to FDA. The 
agency is now in the process of revising Sec. 10.90(b). Therefore, this 
guidance is not being issued under the authority of Sec. 10.90(b). This 
guidance document represents the agency's current thinking on the tests 
the agency believes necessary to provide reasonable assurance of the 
safety and effectiveness of transitional contact lens care products. It 
does not create or confer any 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.

V. Requests for Comments

    Interested persons may, at any time, submit to the Dockets 
Management Branch and to the contact person (addresses above) comments 
on the revised guidance. Two copies of any comments should be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. The revised guidance and received comments may be 
seen in the office above between 9 a.m. and 4 p.m., Monday through 
Friday. Comments received will be considered in future revisions of the 
guidance.
    FDA/CDRH maintains an entry on the World Wide Web (WWW) for easy 
access to information including text, graphics, and files that may be 
downloaded to a PC with access to the Web. Updated on a regular basis, 
the CDRH home page includes the ``Guidance for Industry; Premarket 
Notification (510(k)) for Contact Lens Care Products,'' device safety 
alerts, Federal Register reprints, information on premarket submissions 
(including lists of approved applications and manufacturers' 
addresses), small manufacturers' assistance, information on video 
conferencing and electronic submissions, mammography matters, and other 
device-oriented information. The CDRH home page may be accessed at 
http://www.fda.gov/cdrh. ``Guidance for Industry Premarket Notification 
(510(k)) Guidance Document for Contact Lens Care Products'' will be 
available on the Ophthalmic Guidance Document page at: http://
www.fda.gov/cdrh/ode/ed-op.html. A text-only version of the 
CDRH Web site is also available from a computer or VT-100 compatible 
terminal by dialing 1-800-222-0185 (terminal settings are 8/1/N). Once 
the modem answers, press Enter several times and then select menu 
choice 1: FDA Bulletin Board Service. From there follow instructions 
for logging in, and at BBS Topics Page, arrow down to the FDA home page 
(do not select the first CDRH entry). Then select Medical Devices and 
Radiological Health for general information, or arrow down for specific 
topics.

    Dated: May 28, 1997.
Joseph A. Levitt,
Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 97-14750 Filed 6-5-97; 8:45 am]
BILLING CODE 4160-01-F