29552 Federal Register / Vol. 63, No. 104 / Monday, June 1, 1998 /Rules and Regulations

approval is discussed in the freedom of

information summary.

In accordance with the freedom of

information provisions of 21 CFR part

20 and 514.11(e)(2)(ii), a summary of

safety and effectiveness data and

information submitted to support

approval of this application may be seen

in the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857, between

9 a.m. and 4 p.m., Monday through

Friday.

The agency has determined under 21

CFR 25.33(d)(1) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

Under section 512(c)(2)(F)(ii) of the

Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 360b(c)(2)(F)(ii)), this

approval qualifies for 3 years of

marketing exclusivity beginning March

13, 1998, because the application

contains substantial evidence of the

effectiveness of the drug involved or

studies of target animal safety required

for approval of the application and

conducted or sponsored by the

applicant.

List of Subjects in 21 CFR Part 522

Animal drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs and redelegated to

the Center for Veterinary Medicine, 21

CFR part 522 is amended as follows:

PART 522—IMPLANTATION OR

INJECTABLE DOSAGE FORM NEW

ANIMAL DRUGS

1. The authority citation for 21 CFR

part 522 continues to read as follows:

Authority: 21 U.S.C. 360b.

2. Section 522.1289 is added to read

as follows:

§ 522.1289 Lufenuron suspension.

(a) Specifications. Each milliliter of

sterile aqueous suspension contains 10

milligrams of lufenuron.

(b) Sponsor. See No. 058198 in

§ 510.600(c) of this chapter.

(c) [Reserved]

(d) Conditions of use—(1) Cats—(i)

Amount. 10 milligrams per kilogram

(4.5 milligrams per pound) of body

weight every 6 months, subcutaneously.

(ii) Indications for use. For use in cats

6 weeks of age and older, for control of

flea populations. Lufenuron controls

flea populations by preventing the

development of flea eggs and does not

kill adult fleas. Concurrent use of

insecticides may be necessary for

adequate control of adult fleas.

(iii) Limitations. For subcutaneous use

in cats only. The safety of this product

in reproducing animals has not been

established. Do not use in dogs. Federal

law restricts this drug to use by or on

the order of a licensed veterinarian.

(2) [Reserved]

Dated: May 12, 1998.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 98–14298 Filed 5–29–98; 8:45 am]

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DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 801

[Docket No. 96N–0119]

Amended Economic Impact Analysis

of Final Rule Requiring Use of Labeling

on Natural Rubber Containing Devices

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule; amended economic

analysis statement.

SUMMARY: The Food and Drug

Administration (FDA) is issuing an

amended economic analysis statement

relating to a final rule that published in

the Federal Register of September 30,

1997 (62 FR 51021), requiring labeling

statements concerning the presence of

natural rubber latex in medical devices.

This rule was issued in response to

numerous reports of severe allergic

reactions and deaths related to a wide

range of medical devices containing

natural rubber. The final rule becomes

effective on September 30, 1998. In

order to allow further comment on the

economic impact of the September 30,

1997 final rule, FDA is publishing an

amended economic impact statement,

including an amended initial regulatory

flexibility analysis (IRFA) that it has

prepared under the Regulatory

Flexibility Act (RFA), as amended by

the Small Business Regulatory

Enforcement and Fairness Act

(SBREFA). FDA will respond to

comments to this amended economic

analysis statement, and publish in the

Federal Register an amended final

economic impact statement prior to the

effective date of the September 30, 1997

rule.

DATES: Submit written comments by

July 1, 1998 on this amended economic

analysis statement.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857.

Comments should be identified with the

docket numbers found in brackets in the

heading of this document.

FOR FURTHER INFORMATION CONTACT:

Donald E. Marlowe, Center for Devices

and Radiological Health (HFZ–100),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20850,

301–443–2444, FAX 301–443–2296.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September

30, 1997 (62 FR 51021), FDA published

a final rule (to be codified at 21 CFR

801.437), under its authority in section

505(a) and (f) of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 352(a) and

(f)), requiring certain labeling statements

on medical devices that contain or have

packaging that contains natural rubber.

This rule becomes effective on

September 30, 1998. The agency issued

this rule because medical devices

composed of natural rubber may pose a

significant health risk to some

consumers and health care providers

who are sensitized to natural latex

proteins. FDA has received numerous

reports about adverse effects related to

reactions to natural latex proteins

contained in medical devices, including

16 deaths following barium enemas.

These deaths were associated with

anaphylactic reactions to the natural

rubber latex cuff on the tip of barium

enema catheters. Scientific studies and

case reports have documented

sensitivity to natural latex proteins

found in a wide range of medical

devices. It is estimated that 5 to 17

percent of health care workers are

sensitive to latex proteins (Refs. 1

through 5).

The September 30, 1997 rule

(hereinafter referred to as the final rule)

specifically requires that devices that

contain natural rubber that is intended

to contact or is likely to contact the

health care worker or patient bear one

or more of four labeling statements,

depending on the type of natural rubber

in the device and depending on whether

the natural rubber is in the device itself

or in its packaging. These statements are

as follows: ‘‘This Product Contains Dry

Natural Rubber.’’; ‘‘Caution: This

Product Contains Natural Rubber Latex

Which May Cause Allergic Reactions.’’;

‘‘The Packaging of This Product

Contains Dry Natural Rubber.’’; and

‘‘The Packaging of This Product

Contains Natural Rubber Latex Which
Federal Register / Vol. 63, No. 104 / Monday, June 1, 1998 /Rules and Regulations 29553

May Cause Allergic Reactions.’’ The

final rule also prohibits the use of the

word ‘‘hypoallergenic’’ on devices that

contain natural rubber latex.

FDA, in response to a comment on the

proposed latex labeling regulation (61

FR 32618, June 24, 1996) concerning the

application of the rule to combination

products, stated in the preamble to the

final rule that it intended to require

combination products (i.e., drug/device

and biologic/device combinations) that

contain natural rubber device

components to be labeled in accordance

with the final rule (62 FR 51021 at

51026).

After publication of the final rule, the

agency received numerous inquiries

about, and objections to the application

of the natural rubber labeling

requirements to combination drug/

device products, and combination

biologic/device products that currently

are regulated under drug and biologic

authorities. In the Federal Register of

May 6, 1998 (63 FR 24934), FDA issued

a notice stating that upon consideration

of these comments, and the need to

provide a uniform labeling approach for

all drug and biological products,

including combination products, FDA

had decided that further opportunity for

public comment should be provided on

how natural rubber labeling

requirements should be applied to all

products regulated as drugs and

biologics. Accordingly, FDA announced

that it does not intend to apply the final

rule to combination products currently

regulated as drugs or biologics, and

instead intends to initiate a separate

proceeding to propose rulemaking

requirements for labeling statements on

natural rubber-containing products

regulated as drugs and biologics,

including combination products,

currently regulated under drug or

biologic authorities.

In the June 24, 1996 proposed rule,

FDA stated that it did not believe that

the proposed rule would be a significant

regulatory action as defined by

Executive Order 12866, and certified

under the Regulatory Flexibility Act (5

U.S.C. 601–602) that the rule would not

have a significant economic impact on

a substantial number of small entities.

FDA stated that it believed the rule’s

proposed effective date 180 days after

publication would allow manufacturers

to exhaust their existing labeling

supplies.

FDA received comments concerning

the economic impact of the proposed

rule stating that the requirement would

have a major impact on multinational

companies, costing at least $15,000 per

device for labeling. Another comment

stated that the agency underestimated

the impact of the proposed rule, as each

manufacturer will need to draft, review,

and relabel primary and secondary

packages of hundreds, if not thousands

of devices.

Based on FDA’s information, the

agency responded that it did not agree

that the regulation would require the

relabeling of hundreds or thousands of

devices, and that agency estimates of

relabeling costs were between $1,000 to

$2,000 for each type of device. The

agency also noted that the extended 1

year effective date should allow most

manufactures to exhaust their current

labeling stock prior to the effective date

of the regulation. On this basis, the

agency stated that the final rule was not

a significant regulatory action under the

Executive Order, and certified that

although a substantial number of small

entities would be affected by the rule,

the estimated $1,000 to $2,000 cost of

implementing the final rule would not

have a significant economic impact on

those entities.

On October 7, 1997, the Office of the

Chief Counsel for Advocacy of the U.S.

Small Business Administration

submitted a comment stating that the

agency had not supplied data in the

preamble to the final rule to support its

cost estimates. The agency also received

information from industry, subsequent

to the issuance of the final rule,

identifying additional products that

would be subject to the final rule. On

the basis of this information, FDA has

decided to issue an amended economic

impact analysis, including an Initial

Regulatory Flexibility Analysis (IRFA),

and offer opportunity for further

comment before the implementation of

the rule. If comments received persuade

the agency that the conclusions of its

amended economic analysis are

erroneous, FDA will decide whether to

issue the rule on its current effective

date, to stay the effective date of the

final rule, and/or repropose the rule. In

any event, FDA will respond, in the

Federal Register, to comments received

in response to this amended economic

impact statement.

II. Federal Rules that May Duplicate,

Overlap, or Conflict with the Final Rule

FDA does not believe that the final

rule duplicates, overlaps, or conflicts

with any existing Federal rules.

Although 21 CFR 801.5 defines

adequate directions for use, and lists

certain situations where directions for

use may be considered inadequate, there

is no regulation requiring a specific

labeling statement that reduces the risks

associated with natural rubber products

by informing consumers about the

presence natural rubber. Without the

final regulation, manufacturers may

provide a wide variety of information

about natural rubber that may not be

adequate to provide consumer

protection, or may provide no

information at all. FDA believes that

this regulation will assure that

necessary safety information is provided

to the public, and that standardized

information is the best method to inform

the public about risks presented by

natural rubber containing products.

III. Public Outreach

Each of the Federal Register

documents concerning these products is

available to small businesses on FDA’s

website. In addition to the publication

in the Federal Register of the proposed

rule, the final rule, and this amended

economic analysis, FDA has conducted

extensive outreach to a wide audience,

including small businesses, on labeling

requirements for products containing

natural rubber.

Prior to the issuance of any proposal,

FDA has discussed agency concerns

about latex allergies and the need for

labeling on products containing natural

rubber at numerous public meetings,

including several meetings of the

American Society for Testing Materials

(ASTM), a major consensus standards

development organization in the United

States. After the proposal was

published, FDA continues a public

dialogue on the labeling regulations at a

variety of meetings, including meetings

with the U.S. Pharmacopeia, the ASTM,

and representatives of the Health

Industry Manufacturers Association

(HIMA), a trade association representing

medical device manufacturers,

including many that qualify as small

businesses. FDA’s Division of Small

Manufacturers Assistance (DSMA)

handled numerous telephone inquiries

from businesses that were interested in

obtaining information about the

proposal.

At the same time the final labeling

regulation was published, DSMA faxed

correspondence to 100 industry

organizations for further broadcast to

their membership. That correspondence

provided information about the labeling

requirements as well as agency contacts

who would handle inquiries and

comments about the regulation. FDA

then held further meetings concerning

the rule with standards setting

organizations whose membership

includes small businesses as well as

additional meetings with HIMA

members. FDA also sponsored a

national conference devoted to latex

issues that reached the largest audience

of any teleconference previously

produced by FDA. Interested
29554 Federal Register / Vol. 63, No. 104 / Monday, June 1, 1998 /Rules and Regulations

individuals and businesses at 5,000

downlinks had an opportunity at that

teleconference to exchange views with

agency staff and industry experts on the

subject of latex allergies and the

implementation and impact of FDA’s

labeling requirements.

IV. Analysis of Impacts

FDA has examined the impacts of the

rule under Executive Order 12866, the

Regulatory Flexibility Act (5 U.S.C.

601–612), and the Unfunded Mandates

Reform Act (2 U.S.C 1501 et. seq.).

Executive Order 12866 directs agencies

to assess all costs and benefits of

available regulatory alternatives and,

when regulation is necessary, to select

regulatory approaches that maximize

net benefits (including potential

economic, environmental, public health

and safety, and other advantages;

distributive impacts; and equity). Under

the Regulatory Flexibility Act, if a rule

has a significant impact on a substantial

number of small entities, an agency

must analyze regulatory options that

would minimize any significant impact

of the rule on small entities. Title II of

the Unfunded Mandates Reform Act (21

U.S.C. 1532) requires that agencies

prepare a written assessment of

anticipated costs and benefits before

proposing any rule that may result in an

expenditure in any 1 year by State,

local, and tribal governments, in the

aggregate, or by the private sector of

$100 million (adjusted annually for

inflation).

The agency believes that this rule is

consistent with the regulatory

philosophy and principles identified in

Executive Order 12866 and in these two

statutes. The purpose of this rule is to

add labeling statements that will help

ensure the safe and effective use by

health care workers and patients of

natural rubber devices. Potential

benefits include early recognition of

symptoms that could develop into

severe natural latex allergies, and the

prevention of severe allergic reactions

and death that may occur if persons

who are allergic to natural rubber

inadvertently use natural rubber

devices. The agency contracted with

Eastern Research Group, Inc., (ERG),

Lexington, MA, to conduct an economic

analysis of this rule. The substantive

portions of the ERG analysis are

reproduced in their entirety in

Appendix 1.

Based on other information referenced

in this document, and on the analysis

performed by the ERG, FDA has

prepared an amended economic

analysis statement, including an

amended IRFA. Since the rule does not

impose any mandates on State, local or

tribal governments, or the private sector

that will result in an expenditure in any

1 year of $100 million or more, FDA is

not required to perform a cost-benefit

analysis according to the Unfunded

Mandates Reform Act. The rule is not a

significant regulatory action as defined

by the Executive Order.

The ERG analysis estimated that this

rule will affect approximately 1,110

small businesses. Total annualized

compliance costs for small businesses

are estimated at $1.3 million, which

represent 0.04 percent of revenues for

small medical device manufacturers.

Although this economic analysis

indicates that this rule will not have a

significant economic impact on a

substantial number of small entities, the

agency is soliciting comments on this

IRFA. In the event that FDA, after

receiving further comments to this

amended analysis, determines that the

rule does have a significant effect on a

substantial number of small entities,

FDA is providing the following

discussion and analysis of alternatives

that minimize effects on small

businesses.

V. Alternatives

A. Voluntary Compliance

FDA could have issued guidance

stating that FDA considered statements

about the presence of natural rubber

necessary to comply with existing

general statutory and regulatory

prohibitions against false and

misleading labeling (21 U.S.C. 352(a)),

and failure to provide adequate

directions for use (21 U.S.C. 352(f)).

Given the significant health risks

associated with natural rubber products,

FDA does not believe that existing

general statutory labeling authority and

regulations provide adequate protection

to ensure that health care workers and

patients are warned about the risks

associated with natural rubber.

Without the final regulation,

manufacturers may not provide any

information at all. The ERG report and

FDA’s own experience indicate that

some manufacturers never voluntarily

revise their labeling. Even if it could be

assumed that all manufacturers would

voluntarily provide some labeling

information about the presence of

natural rubber, such information is

likely to be presented in a variety of

ways that may confuse consumers and

limit the effectiveness of the natural

rubber statement. FDA believes that the

provision of consistent, accurate

information to consumers is critical.

FDA believes that this regulation, which

provides accurate, consistent

information in a standardized manner,

will assure that the safety information is

communicated effectively to the public.

B. Implementation Periods

FDA considered various

implementation periods for the effective

date after the issuance of the final rule.

The June 24, 1996, proposed rule

proposed an effective date 6 months

after the publication of the final rule.

The final rule has reduced the impact

on small businesses by extending the

effective date to 1 year after issuance of

the final rule. Based on the ERG report

figures, the total industry cost of

compliance for this rule with a 1 year

implementation period is $48.7 million.

The total annualized costs are

calculated at $3.2 million per year. The

costs for a 1 year effective date are 28

percent lower than a 6 month effective

date. Allowing a 24 month

implementation date would reduce

costs by 40 percent. FDA rejected the 6

month implementation period and

extended the implementation period to

1 year to allow manufacturers of

products containing natural rubber

latex, including small businesses, to

reduce costs by depleting existing

inventories and coordinating this

labeling change with other planned

labeling changes. Although costs could

further be reduced by allowing a 24

month implementation period, FDA

believes that the public need for this

information about devices that pose

serious risks justifies rejecting this

alternative.

C. Exempting Small Businesses

FDA has considered the option of

exempting small businesses from the

final regulation. The ERG report

estimates that approximately 83 percent

of the manufacturers of natural rubber

latex products are small businesses.

FDA believes that given that the large

majority of manufacturers of products

containing natural rubber latex are small

businesses, and given the risks

associated with these devices,

exempting small businesses from this

regulation would result in a significant

decrease of consumer protection.

Accordingly, FDA does not believe that

small businesses should be exempt from

this regulation.

D. Allowance of Supplementary

Labeling

FDA could have chosen a regulatory

alternative that would require that all

labeling be directly printed on the

existing packaging and labeling. Such a

regulatory provision would decrease the

possibility that the required statement

would become dislodged during

distribution. Instead, the final rule
Federal Register / Vol. 63, No. 104 / Monday, June 1, 1998 /Rules and Regulations 29555

allows the use of supplementary

labeling (stickers) to provide the

required labeling information. As noted

in the ERG report, this will allow a

number of firms, including small

businesses, to reduce costs by avoiding

extensive repackaging of existing

product inventory that will not be sold

prior to the end of the regulatory

implementation period. FDA decided to

include this option in the final rule.

E. Requiring a Labeling Statement on

Only One Level of Labeling

Under the provisions of the final rule,

FDA estimates that most devices

covered under the rule will bear the

required natural rubber statement on

two or three levels of labeling. FDA

considered requiring labeling statements

on only one level of labeling. This

alternative was rejected because of the

importance of the information contained

in the required labeling statements.

Users may not have the necessary

opportunity to read the statement if it is

included only on some levels of

labeling. For some products, especially

those with multiple users, some labeling

may be discarded prior to use by

subsequent consumers. The inclusion of

the statement on each level of labeling

increases the likelihood that consumers

will be aware of the risks posed by the

natural rubber in the product.

VI. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Kibby, T., and M. Akl, ‘‘Prevalence of

Latex Sensitization in a Hospital Employee

Population,’’ Annals of Allergy, 78:41–44,

1997.

2. Kaczmarek, R., B. Silverman, T. Gross,

et al., ‘‘Prevalence of Latex-specific IgE

Antibodies in Hospital Personnel,’’ Annals of

Allergy, Asthma & Immunology, 76:51–56,

1996.

3. Arellano, R., J. Bradley, and G. Sussman,

‘‘Prevalence of Latex Sensitization Among

Hospital Employees Occupationally Exposed

to Latex Gloves,’’ Anesthesiology, 77:905–

908, 1992.

4. Lagier, F., D. Vervloet, I. Lhermet, et

al.,‘‘Prevalence of Latex Allergy in Operating

Room Nurses,’’ Journal of Allergy and

Clinical Immunology, 90:319–322, 1992.

5. Yassin, M., M. Lierl, T. Fischer, et. al.,

‘‘Latex Allergy in Hospital Employees,’’

Annals of Allergy, 72:245–249, 1994.

VII. Requests for Comments

Interested persons may, on or before

July 1, 1998 submit to the Dockets

management Branch (address above)

written comments regarding this

amended economic analysis statement

on issues relating to natural rubber

devices. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket numbers found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

Dated: May 26, 1998.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

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[FR Doc. 98–14311 Filed 5–29–98; 8:45 am]

BILLING CODE 4160–01–C