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

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.

[[Page 31121]]

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