Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2739

(3) The term ‘‘product license

application,’’ as it is used in those

sections of parts 600 through 680 of this

chapter that are applicable to wellcharacterized biotechnology products,

shall include a biologics license

application for a well-characterized

biotechnology product.

(4) To the extent that the requirements

in this paragraph conflict with other

requirements in this subchapter, this

paragraph (c) shall supercede such other

requirements.

Dated: January 8, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 96–1582 Filed 1–25–96; 10:42 am]

BILLING CODE 4160–01–F

21 CFR Parts 314, 600, and 601

[Docket No. 95N–0329]

RIN 0910–AA57

Changes to an Approved Application

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the biologics regulations for

reporting changes to an approved

application in order to reduce

unnecessary reporting burdens on

applicants holding licenses approved in

the Center for Biologics Evaluation and

Research (CBER) under the Public

Health Service Act (the PHS Act) to

manufacture biological products. In

addition, FDA is proposing to amend

the corresponding drug regulations for

submitting supplements for and

reporting changes to an application

approved under the Federal Food, Drug,

and Cosmetic Act (the act) for wellcharacterized biotechnology products

reviewed in the Center for Drug

Evaluation and Research (CDER) to

harmonize the drug and biologics

regulations. These actions are part of

FDA’s continuing effort to achieve the

objectives of the President’s

‘‘Reinventing Government’’ initiatives.

DATES: Written comments on this

proposed rule by April 29, 1996. Submit

written comments on the information

collection requirements by February 28,

1996, but not later than March 29, 1996.

The agency proposes that any final rule

that may issue based on this proposal

become effective immediately upon its

date of publication in the Federal

Register.

ADDRESSES: Submit written comments

on this proposed rule to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Submit written comments on the

information collection requirements to

the Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Tracey H. Forfa or Timothy W. Beth,

Center for Biologics Evaluation and

Research (HFM–630), Food and

Drug Administration, 1401

Rockville Pike, suite 200N,

Rockville, MD 20852–1448, 301–

594–3074

or;

Yuan Yuan Chiu, Center for Drug

Evaluation and Research (HFD–

820), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–443–

3510.

SUPPLEMENTARY INFORMATION:

I. Introduction

A. Background

This proposed rule is issued in

accordance with the principles set forth

in the Regulatory Flexibility Act of 1990

(Pub. L. 96–354), Executive Order

12866; the President’s memorandum of

March 4, 1995, announcing the

‘‘Regulatory Reinvention Initiative;’’ the

President’s memorandum of April 21,

1995, entitled, ‘‘Regulatory Reform—

Waiver of Penalties and Reduction of

Reports;’’ the April 1995 Publication

‘‘Reinventing Drug and Medical Device

Regulations, and the November 1995,

Presidential National Performance

Review report ‘‘Reinventing the

Regulation of Drugs Made From

Biotechnology.’’ The Regulatory

Flexibility Act requires Federal agencies

to consider the burden a rule may have

on small business entities through a

regulatory flexibility analysis and to

periodically review its rules to

determine if regulatory burdens may be

reduced. Executive Order 12866 directs

Federal agencies and the Office of

Information and Regulatory Affairs

(OIRA) to implement measures that will

reform and make the regulatory process

more efficient.

Under Executive Order 12866, FDA

published a document in the Federal

Register on January 20, 1994 (59 FR

3043), that announced FDA’s plan to

review and evaluate all significant

regulations for their effectiveness in

achieving public health goals and in

order to avoid unnecessary regulatory

burden. FDA published two documents

in the Federal Register of June 3, 1994

(59 FR 28821 and 28822), that

announced the review of certain general

biologics and blood and blood product

regulations by CBER to identify those

regulations that are outdated,

burdensome, inefficient, duplicative, or

otherwise unsuitable or unnecessary.

The President’s memorandum of

March 4, 1995, entitled ‘‘Regulatory

Reinvention Initiative’’ sets forth four

steps toward regulatory reform, one of

which instructs agencies to revise those

regulations that are in need of reform.

FDA believes that this proposed

regulation is in keeping with these

principles without compromising the

agency’s duty and commitment to

protect the public health. The

President’s memorandum of April 21,

1995, directs Federal agencies to reduce

the frequency of regularly scheduled

reports that the public is required, by

rule or policy, to provide to the Federal

government. In addition, the November

1995, Presidential National Performance

Review report entitled ‘‘Reinventing the

Regulation of Drugs Made From

Biotechnology,’’ focused on FDA’s

efforts to reform the regulation of

biotech drugs used for therapy.

FDA also held a public meeting on

January 26, 1995, to discuss the

retrospective review effort. The public

meeting was a forum for the public to

voice its comments regarding the

retrospective review of regulations being

undertaken by CBER.

Many of the comments submitted to

the public docket regarding the CBER

retrospective regulations review were

requests to revise § 601.12 Changes to be

reported (21 CFR 601.12). Most of those

comments requested revision of the

regulation to reduce the burden on

applicants of reporting changes to an

approved application. As part of the

CBER regulatory review initiative, and

in response to the comments received,

FDA published in the Federal Register

of April 6, 1995 (60 FR 17535), a

document entitled, ‘‘Changes to Be

Reported for Product and Establishment

License Applications; Guidance.’’ The

guidance document set forth FDA’s

current interpretation of § 601.12 and

was intended to reduce the reporting

burden as well as facilitate the timely

implementation of certain changes by

manufacturers. The guidance document

was the first step in a reinventing

Government initiative outlined in the

April 1995 publication ‘‘Reinventing

Drug and Medical Device Regulations.’’

Concurrently, CBER’s Office of Blood

Research and Review (OBRR), in letters

to applicants and an industry trade

organization and in presentations at a

January 30 and 31, 1995, ‘‘Licensing

Blood Establishments’’ workshop,
2740 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

communicated FDA’s interpretation of

§ 601.12 as it applies to blood

establishments. OBRR discussed

categories of changes that blood

establishments could implement

without supplement submission and

FDA approval. These categories include

noncritical standard operating

procedures, certain personnel changes,

and some facility changes. During a 9-

month period (October 1994 to June

1995), CBER received over 850 such

submissions that were not required to

await FDA approval.

The agency is proposing to revise

§ 600.3 (21 CFR 600.3) and § 601.12 to

permit more substantial report

reduction as the second step in the

President’s reinvention initiative. FDA

is also proposing to add § 314.70(g) (21

CFR 314.70(g)) which would apply to

well-characterized biotechnology

products approved under the act to

harmonize CDER and CBER

postapproval reporting requirements.

FDA published a definition of a wellcharacterized therapeutic recombinant

deoxyribonucleic acid (DNA)-derived

and monoclonal antibody biotechnology

product in a document published in the

Federal Register of December 8, 1995,

(60 FR 63048), as follows:

A chemical entity(ies) whose identity,

purity, impurities, potency, and quantity can

be determined and controlled.

Identity:

a. Recombinant DNA Biotechnology

Products

The primary structure is known (i.e.,

amino acid sequence), and

The secondary structure is known (e.g.,

disulfide linkage), and

Post-translational modifications are known

(e.g., glycosylation), or

b. Monoclonal Antibodies

The identity can be determined by rigorous

physicochemical and immunochemical

characterization without fully knowing its

chemical structure

Purity and impurities:

The purity is quantifiable.

The impurities are quantifiable, and

identified if feasible

Potency and quantity:

The biological activity is measurable.

The quantity is measurable.

Well-characterized therapeutic

recombinant DNA-derived or monoclonal

antibody biotechnology product require

proper raw materials controls, process

validation and controls, and sensitive and

validated test methods and specifications.

FDA plans to hold an open public

meeting that will be announced in a

future issue of the Federal Register

during the comment period of this

proposed rule to facilitate public

discussion.

B. Summary of the Proposed Rule

1. Summary of Changes to § 600.3—

Definitions

There has been much confusion

regarding the use of the words

‘‘supplement’’ and ‘‘amendment’’ in

relation to license applications for

biological products approved under

section 351 of the PHS Act. In order to

clarify the use of these terms, and to

facilitate a clearer understanding of the

proposed revision of § 601.12, FDA is

proposing to amend § 600.3 (21 CFR

600.3) to include definitions of

‘‘supplement’’ and ‘‘amendment.’’

Previously, a change submitted to an

approved biological product license

application (PLA) or establishment

license application (ELA) was termed an

‘‘amendment.’’ In order to achieve

consistency with CDER in implementing

the Prescription Drug User Fee Act of

1992 (PDUFA)(21 U.S.C. 301, et seq.),

CBER began using the term

‘‘amendment’’ to refer to a change

submitted to a pending license

application or supplement, and the term

‘‘supplement’’ to refer to a change

submitted to an approved license

application. A change to an unapproved

(pending) new drug application (NDA)

is also referred to as an ‘‘amendment’’

and a change submitted to an approved

NDA is also referred to as a

‘‘supplement.’’ Under this proposed

rule, § 600.3(ff) would define the term

‘‘amendment’’ as the submission of

information to an unapproved license

application or supplement. Such

information could include additional

information or reanalysis of data

previously submitted, to revise or

modify the application as originally

submitted. Section § 600.3(gg) would

define a ‘‘supplement’’ as a request to

the Director, CBER, to approve a change

to an approved license application. A

supplement would ordinarily contain a

description of the proposed change and

the data and information supporting the

change.

FDA believes that defining these

terms in the regulations will simplify

the approval process for applicants,

minimize misunderstanding between

CBER and the biologics industry, and

harmonize the use of the terms within

CBER and CDER.

2. Section 314.70—Changes to an

Approved Application

To ensure consistent treatment of

well-characterized biotechnologyderived products within CBER and

CDER, conforming amendments to

§ 314.70 are also being proposed.

Specifically, FDA is proposing an

exception in § 314.70(g) for wellcharacterized biotechnology products

that provides that manufacturing

changes to these products would be

handled as described in proposed

§ 601.12(b), (c), and (d) with regard to

preapproval, notification, and

submission in annual reports instead of

as described in § 314.70 (a), (b), (c), and

(d). However, labeling changes would

not be affected by the proposed change.

3. Summary of Proposed § 601.12—

Changes to an Approved Application

Section 601.12 currently requires that

important proposed changes in location,

equipment, management and

responsible personnel, or in

manufacturing methods and labeling, be

reported to the Director, CBER, not less

than 30 days in advance of the time

such changes are intended to be made.

Proposed changes in manufacturing

methods and labeling may not become

effective until notification of acceptance

is received from the Director, CBER.

In comments made to the public

docket and at the January 26, 1995,

public meeting, representatives from the

biologics industry requested that FDA

modify § 601.12 to be more flexible and

less burdensome. The representatives

also asked that a category system of

changes to be reported be implemented,

which would include changes that

could be made without prior approval

and those that would be required to be

described in an annual report. Several

comments requested that CBER make

the reporting process comparable to

§ 314.70 Supplements and other

changes to an approved application

which sets out three categories of

notification of changes that are reported

to FDA. These include: Supplements

requiring FDA approval before the

change is made, supplements for

changes that may be made before FDA

approval (changes being effected), and

changes described in an annual report.

Another comment stated that

regulations should not stand as a barrier

to manufacturing process improvement

by requiring the filing of a supplement

and CBER approval for even minor

changes and improvements in the

manufacturing process.

The regulatory scheme that the agency

is now proposing responds to these and

other requests from the public. In

response to the comments, FDA

undertook an informal review of the

types of changes that had historically

been subject to prior approval and the

impact such changes had on products

and establishments. FDA also examined

the existing requirements applicable to

drugs and devices approved under the

act; in particular, the regulations found

in §§ 314.70 and 814.39 (21 CFR
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2741

814.39). FDA used this information to

develop categories of reportable changes

and criteria for assigning a change to the

appropriate category.

FDA is now proposing a threecategory scheme for changes in the

product, production process,

equipment, facilities, or responsible

personnel that would eliminate FDA

approval of certain reportable changes

and create a category of changes that

would be described in an annual report.

In addition to these two categories, there

is a category of changes which would

require approval prior to distribution.

The agency believes that this proposed

rule reduces unnecessary reporting and

approval of changes for biologics

licensed under the PHS Act consistent

with the corresponding regulations

applicable to drugs and devices

approved under the act. These

categories would include: (1)

Supplement submission and approval

prior to distribution of a product made

using a proposed change that has a

substantial potential to have an adverse

effect on a product’s safety, purity,

potency, or effectiveness; (2)

notification not less than 30 days prior

to distributing a product made using a

change that has a moderate potential to

have an adverse effect on a product’s

safety, purity, potency, or effectiveness;

and (3) an annual report describing

changes that have minimal potential to

have an adverse effect on a product’s

safety, purity, potency, or effectiveness.

The agency does not intend that this

rule would apply to normal

maintenance and repair which would

continue to be documented as it is now

by firms under applicable current good

manufacturing practice (CGMP)

regulations (21 CFR parts 210, 211, 606,

and 820). The proposed revision also

includes new § 314.70(g) for wellcharacterized biotechnology products to

make the requirements for changes

made to such products consistent

within CBER and CDER.

The proposed revision also sets out a

separate, three-category reporting

system for biological product labeling

changes. This scheme differs slightly

from the scheme for proposed changes

in the product, production process,

equipment, facilities, or responsible

personnel, and is consistent with

requirements for labeling changes

applicable to drugs approved under the

act. A change to a product package

label, container label, or package insert

would require one of the following: (1)

Submission of a supplement with FDA

approval required prior to product

distribution; (2) submission of a

supplement with product distribution

allowed prior to FDA approval; or (3)

submission of the final printed label in

an annual report. Promotional labeling

and advertising would be required to be

submitted in accordance with the

requirements of § 314.81(b)(3)(i)(21 CFR

314.81((b)(3)(i)).

Although the proposed decrease in

reporting and approval requirements

and the corresponding reduction in the

agency’s role in reviewing changes

before they are implemented does

present some risks to product safety,

purity, potency, and effectiveness, the

agency believes that these risks are

minimal. Under the proposed rule the

applicant would be required to

document that each change has no

adverse effect on the safety, purity,

potency, or effectiveness of the product.

Such documentation would include

appropriate validation and/or other

studies. In some cases clinical data

would be necessary and in other cases

it would not. Applicants would be

required to maintain records of the

validation and study data under existing

CGMP requirements. For those changes

no longer requiring supplement

approval, FDA review would shift to

postmarketing review including

inspections of manufacturing facilities.

The proposed rule includes some

specific examples of changes that fall

into a particular category, but does not

attempt to set out a comprehensive list

of the changes included in each

category. The agency recognizes that

scientific and technological advances

may change the need for supplement

approval and/or reporting of many types

of changes. Moreover, the potential for

a particular change to adversely affect a

product’s safety, purity, potency, or

effectiveness may differ for different

products. FDA recognizes that a change

made to a less well-characterized

product could fall into a different

reporting category than the same change

made to a product that was adequately

characterized using analytical and

functional tests. For example, scale up

of a purification process may have a

greater impact on a live virus vaccine

than it may on a well-characterized

recombinant DNA-derived purified

protein. The agency believes that it can

more readily respond to advances in

technology, differences among products,

and knowledge gained from experience

by creating a rule that sets out general

categories of changes. FDA recognizes,

however, that applicants need clear

guidance on how the agency intends to

interpret the rule in order to efficiently

produce products and adhere to

regulatory requirements. Accordingly,

FDA intends to make available guidance

documents to describe the agency’s

current interpretation of specific

changes falling into each category and to

modify the documents as needed to

reflect changes in science and

technology. Notices of availability for

drafts of guidance documents for

reporting changes to most biological

products and to well-characterized

recombinant DNA-derived and

monoclonal antibody biotechnology

products are published elsewhere in

this issue of the Federal Register. FDA

is seeking comment on the use of

guidance documents in conjunction

with a final rule that may result from

this proposal. FDA is also soliciting

comment on the appropriate

categorization of specific changes

enumerated in this proposal and the

guidance documents. In the Federal

Register of October 25, 1995, (60 FR

54695), FDA announced that a

workshop would be held on December

11 through 13, 1995, to discuss the

definition of a well-characterized

biotechnology product. Information

from this workshop will help FDA to

refine its definition of a wellcharacterized biotechnology product.

FDA also anticipates that applicants

could consult with the office which has

product or establishment responsibility

in CBER, or the Office of New Drug

Chemistry in CDER, regarding

appropriate objectives and design of

studies to validate and document the

potential for adverse effect of a

proposed change for a particular

product prior to committing the

resources for such studies. Guidance on

the appropriate reporting mechanism

would also be available from these

offices.

The proposed rule would authorize

the Directors of CBER and CDER, or

their designees under 21 CFR part 5, to

make decisions under the provisions of

the rule as they apply to their respective

centers.

The agency expects that applicants

would update their marketing

applications in an annual report to

assure that they accurately reflect

current conditions. FDA is seeking

comments on mechanisms that industry

and the public believe may be

appropriate for the periodic update of

marketing applications. This proposed

rule would require that some changes in

manufacturing be submitted annually.

CBER does not currently require, nor

would this proposed rule require, that

the annual report include additional

information that is submitted for a drug

approved under the act under

§ 314.81(b)(2). FDA requests comment

on whether the annual report for a

biological product licensed under the
2742 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

PHS act should include the information

described in § 314.81(b)(2).

The proposed rule does not address

requirements for submitting changes to

a pending license application or

supplement. Applicants currently

submit amendments to pending

applications in order to comply with the

requirement in the PHS Act that a

biologic product distributed for sale,

barter, or exchange in interstate

commerce must be manufactured in

accordance with its license, and the

regulations in § 601.2 that set out the

information and data that must be

submitted in such license applications.

FDA intends to consider whether

specific requirements for submitting

amendments to pending applications

should be included when the agency

undertakes a review of the licensing

requirements in part 601 (21 CFR part

601).

4. Analysis of § 601.12—Changes to An

Approved Application

a. Changes requiring supplement

submission and approval prior to

distribution of product made using the

change. Currently, all important

proposed changes made by applicants

must be reported not less than 30 days

in advance of the time such changes are

intended to be made. Such changes in

manufacturing methods and labeling

may not become effective until

notification of acceptance is received

from the Director, CBER. Accordingly,

CBER requires approval of all important

changes in manufacturing methods and

labeling before such changes are

implemented. FDA continues to believe

that it is important that the agency

review data regarding any change that

has a substantial potential to have an

adverse effect on the safety, purity,

potency, or effectiveness of the product,

prior to distribution of the product

made using the change, to assess

whether the change will have a

detrimental impact on the licensed

product with regard to its safety, purity,

potency, effectiveness, and consistency

in biological and clinical characteristics.

Proposed § 601.12(b)(1) would require

an applicant to submit a supplement for

approval to the Director, CBER, for any

proposed change in the product,

production process, equipment, or

facilities that has a substantial potential

to have an adverse effect on the

product’s safety, purity, potency, or

effectiveness. These changes have the

highest probability to adversely affect

the product’s safety, purity, potency, or

effectiveness, and, in most instances, are

integral to the manufacturing process or

product production equipment.

Proposed § 601.12(b)(1) would require

the applicant to submit a supplement

containing a detailed description of the

proposed change, the products

involved, the manufacturing sites or

areas affected, a description of the

methods used and studies performed to

evaluate the effect of the change on the

product’s safety, purity, potency, and

effectiveness, the data derived from

clinical and/or nonclinical laboratory

studies, relevant validation protocols

and data, and a reference list of the

relevant standard operating procedures

(SOP’s). Approval of the supplement by

the Director, CBER, would be required

prior to distributing product made using

the change.

FDA proposes to enumerate the

following changes that have a

substantial potential to have an adverse

effect on a product’s safety, purity,

potency, or effectiveness: A new

indication, route of administration,

dosing schedule, dosage form, or

formulation; the addition, removal, or

reordering of the step(s) of the licensed

production process; and the conversion

of a single product manufacturing area

to a multiproduct manufacturing area.

The agency believes that the need for

FDA premarket approval of these

significant changes is unlikely to vary

with technological advances or due to

differences among products, and that

these changes should be enumerated in

the rule.

Other examples of changes that have

caused detrimental effects on the safety,

purity, potency, or effectiveness of

products, even where applicants

performed validation or other studies,

include process changes or changes in

analytical methods that result in a

change of specification limits and

addition of a new location for

manufacture. FDA believes that the

agency’s continued prior review and

approval of such changes is currently

necessary to protect the public from

products whose safety, purity, potency,

or effectiveness may be compromised.

However, FDA is proposing to describe

these, and additional, specific examples

of changes that CBER currently believes

have substantial potential to adversely

affect the product, in guidance, rather

than enumerate them in the rule. FDA

anticipates that scientific advances and

future experience may reduce the need

for premarket approval of certain

changes and believes that the agency

will be able to respond readily to

changed circumstances by revising

guidance that interprets the rule.

b. Changes requiring notification not

less than 30 days prior to distributing

product made using the change. FDA

believes that the public health can be

adequately protected by eliminating

agency approval of changes that have

only a moderate potential to have an

adverse effect on the safety, purity,

potency, or effectiveness of a product.

Changes that have moderate potential to

affect a product’s safety, purity,

potency, or effectiveness are changes

that do not have as high a probability for

causing an adverse effect as those for

which the agency proposes to require

supplement approval. Under current

§ 601.12, the agency requires FDA

approval of all important proposed

changes to a product, and requires that

all important proposed changes in

manufacturing methods and labeling

await such approval before they may be

distributed. FDA is now proposing to

require that applicants notify the agency

not less than 30 days prior to

distributing a product made with a

change in the product, production

process, equipment, facilities, or

responsible personnel that has moderate

potential to have an adverse effect on

the product, but to permit a product to

be distributed after the 30-day period

has elapsed without awaiting FDA

approval. These notifications would not

be considered supplements requiring

approval. Thus, many changes that now

require FDA approval as supplements

could be implemented rapidly through

the notification process without the

prior submission of a supplement. For

example, based on FDA’s experience in

reviewing submissions, the agency

currently believes that minor changes in

fermentation batch size using the same

equipment and resulting in no change in

specifications of the bulk or final

product, and increases or decreases in

the purification scale, not associated

with a process change or different

equipment, have moderate potential to

have an adverse effect on the product.

In the notification, an applicant

would be required to provide the agency

with a clear description of the change,

the product or products involved, the

manufacturing sites or areas involved, a

brief description of the validation and/

or other clinical and/or nonclinical

laboratory studies conducted to analyze

the effect of the change on the safety,

purity, potency, and effectiveness of the

product, the dates of any such studies,

reference to any SOP’s used to complete

the studies, and a summary of the

relevant data or information. During the

30-day period, FDA would review the

notification to determine if it was

properly submitted as a notification. If

FDA agreed that the change described

was of the type that had moderate

potential to adversely affect the safety,

purity, potency, or effectiveness of the

product, and the notification included
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2743

all of the required information, the

applicant could begin distribution of a

product made using the change 30 days

after FDA’s receipt of the notification.

Under the proposed rule, FDA would

ordinarily contact the applicant before

the expiration of the 30-day period if the

agency determined that the change was

improperly submitted as a notification.

If FDA informed the applicant within

the 30-day period that the submission

did not meet the requirements for a

notification, the applicant would be

required to correct the deficiencies in

the information submitted before

distributing the product. Depending on

the problem, FDA would respond in one

of two ways: (1) If the change was of the

type that presented a substantial

potential to adversely affect the safety,

purity, potency, or effectiveness of the

product, the agency would inform the

applicant that the change should be

submitted as a supplement and the

applicant would be required to await

FDA approval before product produced

with the change could be distributed; or

(2) if the change was of the type that

could properly be submitted as a

notification, but the required

information was incomplete, the

applicant would be required to supply

the missing information and wait until

FDA determined compliance with this

section before distributing the product.

FDA intends, during the 30 days, to

focus its review on determining whether

the applicant reported the change under

the appropriate mechanism, and, if so,

whether any of the required information

was missing. Under the proposed rule,

FDA would not ordinarily contact the

applicant if the notification was

properly submitted in accordance with

§§ 601.12(c) or 314.70(g)(2). FDA

anticipates that applicants would use a

method of delivery for notifications that

would allow confirmation of the

submission having been received by

FDA.

FDA would also ordinarily review the

substantive information contained in a

notification and request the applicant to

clarify the submission if necessary. If

the agency’s review determined that

additional studies or information were

necessary to document the lack of an

adverse effect on the safety, purity,

potency, or effectiveness of the product,

the agency could request that additional

data be collected. Failure to comply

with the proposed requirements and

existing CGMP requirements to properly

validate the change could result in

enforcement action. Following the

agency’s review, FDA would send to the

applicant a stamped copy of the cover

letter for the notification indicating that

FDA had placed the submission in the

applicant’s license application file. FDA

anticipates that the agency could

conduct a more extensive review of data

supporting the notification during

inspections if necessary.

FDA believes that a notification

process, as described above, for changes

that have a moderate potential to affect

the safety, purity, potency, or

effectiveness of the product would

protect against the distribution of unsafe

or ineffective products while speeding

the availability of improved products.

Under the proposed rule, applicants

would be required to demonstrate,

through appropriate validation or other

studies, that a change has no adverse

effect on the safety, purity, potency, and

effectiveness of the product. Applicants

would be required to briefly describe

the studies and data in the notification.

While a full description of the studies

would not be required to be submitted

in a notification, as it generally would

be in a supplement, applicants would be

required to maintain the data in records

that are available for FDA inspection

under existing CGMP’s. The 30-day

period that would be required to elapse

before products made using the change

could be distributed would permit the

agency to redirect submissions for

changes that could substantially affect

product safety, purity, potency, or

effectiveness to the supplement

approval process before the product

entered the market. In addition, the

agency could identify applicants that,

through an incomplete submission,

failed to establish that they had

followed the necessary steps to validate

and implement a change. Applicants

would be required to submit the missing

information before they could distribute

the product.

c. Changes to be described in an

annual report. FDA recognizes that

there are changes in the product,

production processes, equipment,

facilities, and responsible personnel that

have minimal potential to have an

adverse effect on the product’s safety,

purity, potency, or effectiveness. Under

the current § 601.12, the agency has

required many of these changes to await

supplement approval before they could

be implemented. FDA believes that

prior agency approval of these changes

is unnecessary, and is proposing in

§ 601.12(d) that such changes would not

be required to be approved by the

agency. FDA continues to believe that it

is important that such changes be

documented and validated so that there

is a mechanism for assessing the

consequences of the change. FDA is

therefore proposing that changes that

have minimal potential to have an

adverse effect on the product’s safety,

purity, potency, or effectiveness be

required to be described by the

applicant in an annual report. The

annual report would be required to be

submitted each year within 60 days of

the anniversary date of approval of the

application. FDA believes that the

agency can effectively assess

compliance with this section and CGMP

requirements for changes that have

minimal potential to adversely affect the

product’s safety, purity, potency, or

effectiveness by having ready access to

information regarding such changes

through the submission of an annual

report and by inspection. Applicants

would be required to include in the

annual report a listing of all products

involved, a brief description of and

reason(s) for the change, the

manufacturing sites or areas involved,

the date each change was made, and a

cross-reference to any validation

protocols and/or SOP’s. Both the

applicant and FDA could use this

information to assess whether problems

which may arise with products are

related to such changes. Under

proposed § 601.12(a), the applicant

would be required to perform

appropriate validation or other studies

to demonstrate the lack of adverse effect

on the safety, purity, potency, and

effectiveness of the product. Applicants

would maintain records of such studies

under existing CGMP requirements.

As a result of FDA’s experience in

reviewing changes, the agency believes

that changes that have a minimal

potential to have an adverse effect on

the product would include such

changes as a change in storage

conditions of in-process intermediates

based on data derived from studies

following a protocol in the approved

license application; modifications in

analytical procedures with no change in

the basic test methodology or existing

release specifications; relocation of

analytical testing laboratories within a

licensed facility; and area upgrades such

as the installation of improved finishes

on floors or walls.

d. Labeling. Under the current

§ 601.12, all important proposed

labeling changes are required to be

submitted for FDA approval before they

may be implemented. The agency

recognizes, however, that some labeling

changes may not have a substantial

impact on the safe and effective use of

the product. For other changes, such as

updates of important safety information,

it is important that prescribers and

patients have access to current

information as soon as it becomes

available. Therefore, the agency is

proposing to revise the biological

products reporting requirements for
2744 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

labeling changes. The regulations in

§ 314.70(b), (c), and (d), governing how

labeling changes are reported for

products regulated by CDER, are not

affected by the proposal. In fact, the

proposed revision of § 601.12(e) is

consistent with requirements for

labeling changes applicable to drugs

approved under the act.

Changes to labeling would be

submitted to CBER in one of the

following ways: (1) A supplement

requiring FDA approval prior to

distribution of product with the revised

labeling, (2) a supplement requiring

FDA approval but permitting the

distribution of product with the

accompanying revised labeling prior to

such approval, or (3) submission of final

printed labeling in an annual report. It

is expected that proposed § 601.12(e)

would significantly decrease the

number of labeling submissions that

currently require approval prior to use

of the labeling.

Under proposed § 601.12(e)(2), an

applicant would be required to submit

a supplement, but could disseminate the

revised labeling with the product, at the

time the supplement was submitted.

Such revisions to the labeling would

include any information that adds or

strengthens a contraindication, warning,

precaution, or adverse reaction; adds or

strengthens a statement about abuse,

dependence, psychological effect, or

overdosage; adds or strengthens an

instruction about dosage and

administration that is intended to

increase the safe use of the product; or

deletes false, misleading, or

unsupported indications for use or

claims for effectiveness.

FDA believes that permitting these

labeling changes to be effected and

product distributed prior to FDA

approval would facilitate labeling

changes intended to adequately inform

prescribers and patients of the risks and

benefits of a biological product and

thereby allow prescribers and patients

earlier access to important new

information on the safe use of the

product. Proposed § 601.12(e)(2) would

require that the supplement clearly

identify any changes being made and

include necessary supporting data.

Under the proposed rule, the changes

identified in § 601.12(e)(2) could be

implemented prior to agency approval.

FDA could, however, deny approval of

a supplement for a labeling change that

has already been disseminated with the

product. In assessing an applicant’s

plans to correct a problem, FDA would

consider the applicant’s reasons for

making the change and the alternatives

available to the applicant. If the

circumstances warranted, FDA could

require the labeling change to be

immediately discontinued. However,

when circumstances permit, the agency

would allow the applicant to correct a

problem with minimal expense and

without unnecessary waste.

Under proposed § 601.12(e)(3), an

applicant making editorial or other

minor changes, or a change in the

information on how the biologic is

supplied that does not involve a change

in the dosage strength or dosage form,

would be required to submit a

description of the changes and all final

printed labeling incorporating the

changes in an annual report to be

submitted to the Director, CBER. For all

changes in the package insert, package

label, and container label that would not

fall under § 601.12(e)(2) or (e)(3), an

applicant would be required to submit

a supplement supporting the proposed

change and await FDA approval prior to

distribution.

Under proposed § 601.12(e)(4),

promotional labeling and advertising

would be submitted in accordance with

21 CFR 314.81(b)(3)(i), which requires

that an applicant submit specimens of

mailing pieces and any other labeling or

advertising devised for promotion of the

product at the time of initial

dissemination of the labeling and at the

time of initial publication of the

advertisement for a prescription

product.

e. Failure to comply. FDA is

proposing in § 601.12(f) that in the event

of repeated failure of the applicant to

comply with § 601.12, the Director,

CBER, may require that the applicant

submit a supplement for any proposed

change and obtain CBER approval prior

to distributing the product made using

the change. This measure would be in

addition to other remedies available in

applicable laws and regulations,

including suspension or revocation of

licenses, seizure of products, and

injunction, among others. With this

proposed rule, FDA is undertaking to

significantly reduce the number of

changes that are reported, reviewed, and

approved by the agency. Continued

protection of the public from products

with compromised safety, purity,

potency, or effectiveness will depend on

applicants’ adherence to the proposed

requirements to conduct validation and/

or other studies to document the lack of

adverse effect on the product and

utilization of the appropriate

mechanism to inform the agency of such

changes. In determining repeated failure

to comply with the § 601.12 and

whether an applicant would be required

to file future submissions as

supplements, the agency would

consider, among other things, the

applicant’s compliance history and the

significance of the deficiencies.

f. Administrative review. Proposed

§ 601.12(g) provides that an applicant

may request a review of FDA employee

decisions made pursuant to section

§ 601.12 in accordance with § 10.75 (21

CFR 10.75). Section 10.75 provides a

mechanism for internal agency review

of decisions. FDA proposes to include

the reference to § 10.75 in § 601.12(g) so

that applicants who wish agency review

of a decision made under the provisions

of the rule are made aware of the

mechanism for such review. The

internal agency review of a decision

would be based on the information in

the administrative file. FDA believes

that it is important for the agency to

apply regulations affecting regulated

products consistently and fairly, and

believes that agency review should be

available to resolve a disputed issue.

II. Analysis of Impacts

A. Method of Analysis

To determine the impact of the

proposed rule, CBER undertook an

analysis of changes approved as

supplements during the 9-month period

between October 1, 1994, and June 1,

1995. CBER has determined that the

proposed rule as currently written

would result in an overall 32 percent

reduction in submissions requiring prior

agency approval before an applicant

could commence distributing product

made using the change. The extent of

the reduction would be greater for

certain products. Under the proposed

regulation, 88 of 175 submissions

reviewed as supplements under the

current regulation (for changes to

biological products other than blood

products and blood component

products) would be supplements

requiring prior approval, 62 would be

notifications to CBER not requiring FDA

approval, and 25 would be described in

an annual report. For blood and blood

components, of 177 supplements

approved in a 2-month portion of the 9-

month period, 128 would be

supplements requiring prior approval

under the proposed rule, 36 would be

notifications, and 13 would be

described in an annual report.

B. Review Under Executive Order 12866

and the Regulatory Flexibility Act

FDA has examined the impact of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(Pub. L. 96–354). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select the regulatory
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2745

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The agency

believes that this proposed rule is

consistent with the regulatory

philosophy and principles identified in

the Executive Order. The proposed rule

is a significant regulatory action as

defined by the Executive Order and is

subject to review under the Executive

Order because it deals with a novel

policy issue.

In accordance with the principles of

Executive Order 12866, the overall

result of the proposed rule would be a

substantial reduction in reporting

burden for applicants and in review

burden for the agency. In addition, FDA

anticipates that the proposed rule would

encourage applicants to improve their

licensed products and methods of

manufacture.

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact of a rule on small

entities. Because, as stated above, the

overall result of the proposed rule

would be a substantial reduction of the

regulatory and reporting burden, the

agency certifies that the proposed rule

will not have a significant economic

impact on a substantial number of small

entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is

required.

C. Review under the Paperwork

Reduction Act of 1995

This proposed rule contains

information collections which are

subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995.

The title, description, and respondent

description of the information collection

are shown below with an estimate of the

annual reporting burden. Included in

the estimate is the time for reviewing

instructions, gathering and maintaining

the data needed, and completing and

reviewing the collection of information.

With respect to the following

collection of information, FDA invites

comments on: (1) Whether the proposed

collection of information is necessary to

for proper performance of FDA’s

functions, including whether the

information will have practical utility;

(2) the accuracy of FDA’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) ways to enhance the quality, utility,

and clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: 21 CFR 601.12—Changes to an

Approved Application and 21 CFR

314.70(g) Exception.

Description: This proposed rule would

change the requirements for

respondents to report to FDA changes in

the product, labeling, production

process, equipment, facilities, or

responsible personnel established in an

approved application for a biological

product or for a well-characterized

biotechnology product. The respondent

would report the change to FDA in one

of the three following ways depending

on the potential for the change to have

an adverse effect on the safety, purity,

potency or effectiveness of the product:

(1) Changes that have a significant

potential to have an adverse effect on

the product would be submitted in a

supplement requiring prior approval by

FDA before distribution of a product

made using the change; (2) changes that

have a moderate potential to have an

adverse effect on the product would be

submitted to FDA in a notification not

less than thirty days prior to

distribution of the product made using

the change; and (3) Changes that have a

minimal potential to have an adverse

effect on the product would be

submitted by the respondent in an

annual report.

Labeling changes for a biological

product would also be submitted in one

of the following ways: (1) A supplement

requiring FDA approval prior to

distribution of product with the revised

labeling; (2) a supplement requiring

FDA approval but permitting the

distribution of product with the

accompanying revised labeling prior to

such approval; or (3) submission of final

printed labeling in an annual report.

Promotional labeling and advertising

would be submitted in accordance with

314.81(b)(3)(i). Labeling changes for

well-characterized biotechnology

products would not be affected by this

proposed rule.

Description of Respondents: All

manufacturers and applicants holding a

biological license approved under

section 351 of the Public Health

Services Act and all manufacturers and

applicants of well-characterized

biotechnology products holding an

approved NDA would report (Business

or other for-profit).

These estimates are an approximation

of the average time expected to be

necessary for a collection of

information. They are based on such

information as is available to FDA.

There are no capital costs associated

with this information collection. It is

estimated that 20 percent of all reports

required under these proposed

regulations are being prepared by

contractors. The burden hours in the

chart below therefore reflect a 20

percent reduction per regulation

because these burden hours will not be

expended by the affected industry rather

they will be expended by the

contractors. It is estimated that a

contractor will charge $40 per hour for

the service of preparing these reports.

The 20 percent burden hours multiplied

by $40 per hour are reflected in the

column labeled ‘‘Operating and

Maintenance Costs.’’

The agency seeks comments on these

estimates, particularly the industry’s

view of the number of firms and

products affected by the collections of

information contained in this proposed

rule.

Estimated Annual Burden

Regulation (21

CFR)

Number of

Respondents

Hours Per

Response

Number of

Responses

Number of Responses

Per Respondent

Total Operating and Maintenance CostsTotal Hours Per Regulation

601.12(b) 391 80 610 1.56 $390,400 39,040

601.12(c) 391 40 280 0.72 $89,600 8,960

601.12(d) 391 10 110 0.28 $8,800 880

601.12(e)(1) 391 40 200 0.51 $64,000 6,400

601.12(e)(2) 391 20 20 0.05 $3,200 320

601.12(e)(3) 391 10 220 0.56 $17,600 1,760

601.12(e)(4) 391 10 110 0.28 $8,000 800
2746 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

Estimated Annual Burden

Regulation (21

CFR)

Number of

Respondents

Hours Per

Response

Number of

Responses

Number of Responses

Per Respondent

Total Operating and Maintenance CostsTotal Hours Per Regulation

314.70(g)(1) 4 80 50 12.5 $32,000 3,200

314.70(g)(2) 2 40 3 1.5 $960 96

314.70(g)(3) 6 10 20 3.33 $1,600 160

Totals Total O&M Costs = $616,160 Total Hours = 61,616

The agency has submitted a copy of

this proposed rule to OMB for its review

and approval of these information

collections. Interested persons are

requested to send comments regarding

this information collection, including

suggestions for reducing this burden to

the Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA. Submit written

comments on the information collection

by February 28, 1996, but not later than

March 29, 1996.

D. Review Under the National

Environmental Policy Act

The agency has determined under 21

CFR 25.24(a)(8) 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.

Interested persons may, on or before

April 29, 1996, submit to the Dockets

Management Branch (address above)

written comments regarding the

proposal. Two copies of any comments

are to 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. Received

comments may be seen in the office

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

Monday through Friday. Submit

comments on the information collection

requirements to the Office of

Information and Regulatory Affairs,

OMB, (address above).

As stated previously, FDA plans to

hold an open public meeting during the

comment period to facilitate public

comment on this proposed rule. The

time and location of this meeting will be

announced in a future issue of the

Federal Register.

List of Subjects

21 CFR Part 314

Administrative practice and

procedure, Confidential business

information, Drugs, Reporting and

recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and

recordkeeping requirements.

21 CFR Part 601

Administrative practice and

procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and the Public

Health Service Act, and under the

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR parts 314, 600, and 601 be

amended as follows:

PART 314—APPLICATIONS FOR FDA

APPROVAL TO MARKET A NEW DRUG

OR AN ANTIBIOTIC DRUG

1. The authority citation for 21 CFR

part 314 continues to read as follows: Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 701, 704, 721 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374,

379e). 2. Section 314.70 is amended by

adding new paragraph (g) as follows:

§ 314.70 Supplements and other changes

to an approved application.

* * * * *

(g) Exception. An applicant proposing

to make a change in a well-characterized

biotechnology product of the type

described in § 314.70(a), (b)(1), (b)(2),

(c)(1), (c)(3), (d)(1), and (d)(4) through

(d)(9) shall comply with the following:

(1) Changes requiring supplement

submission and approval prior to

distribution of product made using the

change. (i) A supplement shall be

submitted for any proposed change in

the product, production process,

equipment, or facilities that has

substantial potential to have an adverse

effect on the safety, purity, potency, or

effectiveness of the product. These

changes include but are not limited to:

(A) A new indication, route of

administration, dosage form, dosing

schedule or formulation;

(B) Addition, removal, or reordering

of the step(s) of the production process;

and

(C) Change from production of a

single product to production of multiple

products at a facility.

(ii) The applicant shall obtain FDA

approval of the supplement prior to

distribution of the product made using

the change. The following information

shall be contained in the supplement:

(A) A detailed description of the

proposed change;

(B) The product(s) involved;

(C) The manufacturing site(s) or

area(s) affected;

(D) A description of the methods used

and studies performed to evaluate the

effect of the change on the product’s

safety, purity, potency, and

effectiveness;

(E) The data derived from such

studies;

(F) Relevant validation protocols and

data; and

(G) A reference list of relevant

standard operating procedures (SOP’s).

(2) Changes requiring notification not

less than 30 days prior to distributing

product made using the change. (i) An

applicant shall inform FDA, in a written

notification labeled ‘‘Notification—

Changes being effected in 30 days,’’ of

any change in the product, production

process, equipment, facilities, or

responsible personnel that has moderate

potential to have an adverse effect on

the safety, purity, potency, or

effectiveness of the product.

Distribution of the product

manufactured after the change was

instituted may not begin until 30 days

after FDA notification. The following

information shall be contained in the

notification:

(A) A clear, brief description of the

change;

(B) The products(s) involved;

(C) The manufacturing site(s) or

area(s) involved;

(D) A brief description of the

validation and/or other studies
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2747

conducted to analyze the effect of the

change on the safety, purity, potency,

and effectiveness of the product;

(E) The dates of the studies;

(F) Reference to relevant SOP’s used

to complete the studies; and

(G) A summary of the relevant data or

information.

(ii) If within 30 days following FDA’s

receipt of the notification FDA informs

the applicant that either:

(A) The change requires supplement

submission in accordance with

paragraph (g)(1) of this section; or

(B) Any of the information required

under paragraph (g)(2)(i) of this section

is missing, the applicant shall not

distribute the product made with the

change until FDA determines that

compliance with this section is

achieved.

(3) Changes to be described in an

annual report. Changes in the product,

production process, equipment,

facilities, or responsible personnel that

have minimal potential to have an

adverse effect on the product’s safety,

purity, potency, or effectiveness, shall

be documented by the applicant in an

annual report submitted each year

within 60 days of the anniversary date

of approval of the application. The

annual report shall contain the

following information for each change:

(i) A list of all products involved;

(ii) A brief description of and

reason(s) for the change;

(iii) The manufacturing sites or areas

involved;

(iv) The date each change was made;

and

(v) A cross-reference to relevant

validation protocol(s) and/or SOP’s.

* * * * *

PART 600—BIOLOGICAL PRODUCTS:

GENERAL

3. The authority citation for 21 CFR

Part 600 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 519, 701, 704 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 351, 352,

353, 355, 360, 360i, 371, 374); secs. 215, 351,

352, 353, 361, 2125 of the Public Health

Service Act (42 U.S.C. 216, 262, 263, 263a,

264, 300aa–25).

4. Section 600.3 is amended by

adding new paragraphs (ff) and (gg) to

read as follows:

§ 600.3 Definitions.

(ff) Amendment is the submission of

information to a pending license

application or supplement, to revise or

modify the application as originally

submitted.

(gg) Supplement is a request to the

Director, Center for Biologics Evaluation

and Research, to approve a change in an

approved license application.

PART 601—LICENSING

5. The authority citation for 21 CFR

part 601 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 513–516, 518–520, 701, 704, 721, 801,

of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 321, 351, 352, 353, 355, 360, 360c–

360f, 360h–360j, 371, 374, 379e, 381); secs.

215, 301, 351, 352, of the Public Health

Service Act (42 U.S.C. 216, 241, 262, 263);

secs. 2–12 of the Fair Packaging and Labeling

Act (15 U.S.C. 1451–1461).

6. Section 601.12 is revised to read as

follows:

§ 601.12 Changes to an approved

application.

(a) General. As provided in this

section, an applicant shall inform the

Director, Center for Biologics Evaluation

and Research (CBER), about each change

in the product, labeling, production

process, equipment, facilities, or

responsible personnel established in the

approved license application(s). Before

distributing a product made using a

change, an applicant shall demonstrate

through appropriate validation and/or

other clinical and/or nonclinical

laboratory studies the lack of adverse

effect of the change on the safety, purity,

potency, and effectiveness of the

product. Single copies of Food and Drug

Administration (FDA) guidance

describing FDA’s current interpretation

of this regulation may be obtained from

the Congressional and Consumer Affairs

Branch (HFM–12), Center for Biologics

Evaluation and Research, Food and

Drug Administration, 1401 Rockville

Pike, Rockville, MD 20852–1448.

(b) Changes requiring supplement

submission and approval prior to

distribution of product made using the

change.

(1) A supplement shall be submitted

to the Director, CBER, for any proposed

change in the product, production

process, equipment, or facilities that has

substantial potential to have an adverse

effect on the safety, purity, potency, or

effectiveness of the product. These

changes include but are not limited to

the following:

(i) A new indication, route of

administration, dosage form, dosing

schedule or formulation;

(ii) Addition, removal, or reordering

of the step(s) of the licensed production

process; and

(iii) Change from production of a

single product to production of multiple

products at a licensed facility;

(2) The applicant shall obtain

approval of the supplement from the

Director, CBER, prior to distribution of

the product made using the change. The

following information shall be

contained in the supplement:

(i) A detailed description of the

proposed change;

(ii) The product(s) involved;

(iii) The manufacturing site(s) or

area(s) affected;

(iv) A description of the methods used

and studies performed to evaluate the

effect of the change on the product’s

safety, purity, potency, and

effectiveness;

(v) The data derived from such

studies;

(vi) Relevant validation protocols and

data; and

(vii) A reference list of relevant

standard operating procedures (SOP’s).

(c) Changes requiring notification not

less than 30 days prior to distributing

product made using the change. (1) An

applicant shall inform the Director,

CBER, in a written notification labeled

‘‘Changes being effected in 30 days,’’ of

any change in the product, production

process, equipment, facilities, or

responsible personnel that has moderate

potential to have an adverse effect on

the safety, purity, potency, or

effectiveness of the product.

Distribution of the product

manufactured after the change was

instituted may not begin until 30 days

after receipt of the notification by CBER.

The following information shall be

contained in the notification:

(i) A clear, brief description of the

change;

(ii) The product(s) involved;

(iii) The manufacturing site(s) or

area(s) involved;

(iv) A brief description of the

validation and/or other studies

conducted to analyze the effect of the

change on the safety, purity, potency, or

effectiveness of the product;

(v) The dates of the studies;

(vi) Reference to relevant SOP’s used

to complete the studies; and

(vii) A summary of the relevant data

or information.

(2) If within 30 days following FDA

receipt of the notification, the Director,

CBER informs the applicant that either:

(i) The change requires supplement

submission in accordance with

paragraph (b) of this section; or

(ii) Any of the information required

under paragraph (c)(1) of this section is

missing, the applicant shall not

distribute the product made with the

change until compliance with this

section is achieved.

(d) Changes to be described in an

annual report. (1) Changes in the

product, production process,

equipment, facilities, or responsible

personnel that have minimal potential
2748 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

to have an adverse effect on the

product’s safety, purity, potency, or

effectiveness, shall be documented by

the applicant in an annual report

submitted each year within 60 days of

the anniversary date of approval of the

application. The annual report shall

contain the following information for

each change:

(i) A list of all products involved;

(ii) A brief description of and

reason(s) for the change;

(iii) The manufacturing sites or areas

involved;

(iv) The date each change was made;

and

(v) A cross-reference to relevant

validation protocol(s) and/or SOP’s.

(2) The applicant shall submit the

report to the FDA office responsible for

reviewing the application. The report

shall include all the information

required under this section obtained for

each change made during the annual

reporting interval which ends on the

anniversary date.

(e) Labeling changes—(1) Label

changes requiring supplement

submission—distribution of a product

with a label change must await FDA

approval. An applicant shall submit to

CBER a supplement describing a

proposed change in the package insert,

package label, or container label, except

those described in paragraphs (e)(2) and

(e)(3) of this section, and include the

information necessary to support the

proposed change. The supplement shall

clearly highlight the proposed change in

the label. The applicant shall obtain

approval from the Director, CBER, prior

to distributing a product with the label

change.

(2) Label changes requiring

supplement submission; product with a

label change may be distributed before

FDA approval. (i) An applicant shall

submit to CBER, at the time such change

is made, a supplement for any change in

the package insert, package label, or

container label to accomplish any of the

following:

(A) To add or strengthen a

contraindication, warning, precaution,

or adverse reaction;

(B) To add or strengthen a statement

about abuse, dependence, psychological

effect, overdosage;

(C) To add or strengthen an

instruction about dosage and

administration that is intended to

increase the safe use of the product; or

(D) To delete false, misleading, or

unsupported indications for use or

claims for effectiveness.

(ii) The applicant may distribute a

product with a package insert, package

label, or container label bearing such

change at the time the supplement is

submitted. The supplement shall clearly

identify the change being made and

include necessary supporting data. The

supplement and its mailing cover

should be plainly marked: ‘‘Special

Labeling Supplement—Changes Being

Effected.’’

(3) Label changes requiring

submission in an annual report. (i) An

applicant shall submit any final printed

package insert, package label, or

container label incorporating the

following changes to CBER in an annual

report submitted each year within 60

days of the anniversary date of approval

of the application:

(A) Editorial or similar minor

changes; or

(B) A change in the information on

how the drug is supplied that does not

involve a change in the dosage strength

or dosage form.

(ii) The applicant may distribute a

product with a package insert, package

label, or container label bearing such

change at the time the change is made.

(4) Advertisements and promotional

labeling.

Advertisements and promotional

labeling shall be submitted in

accordance with the requirements set

forth in § 314.81(b)(3)(i) of this chapter,

except that Form FDA–2567 shall be

used in lieu of Form FDA–2253.

(f) Failure to comply. In addition to

other remedies available in law and

regulations, in the event of repeated

failure of the applicant to comply with

this section, the Director, CBER, may

require that the applicant submit a

supplement for any proposed change to,

and obtain approval of the supplement

from, the Director, CBER, prior to

distributing a product made using the

change.

(g) Administrative review. Under

§ 10.75 of this chapter, an applicant may

request internal FDA review of CBER

employee decisions under this section.

Dated: January 16, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 96–1580 Filed 1–25–96; 10:41 am]

BILLING CODE 4160–01–F

21 CFR Parts 600 and 601

[Docket No. 95D–0415]

Draft Guidance; Changes To An

Approved Application for WellCharacterized Therapeutic

Recombinant DNA-Derived and

Monoclonal Antibody Biotechnology

Products; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule; notice of

availability.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of a draft guidance

document entitled ‘‘Draft Guidance;

Changes to An Approved Application

for Well-Characterized Therapeutic

Recombinant DNA-Derived and

Monoclonal Antibody Biotechnology

Products.’’ This draft guidance is

intended to assist applicants in

determining how they should report

changes to an approved license

application for well-characterized

therapeutic recombinant DNA-derived

and monoclonal antibody biotechnology

products under the proposed revision to

the biologics regulations issued

elsewhere in this issue of the Federal

Register. In a separate document also

published in this issue of the Federal

Register, FDA is announcing the

availability of a guidance document to

assist applicants in determining how

they should report changes to an

approved license application for

biologic products other than wellcharacterized therapeutic recombinant

DNA-derived and monoclonal antibody

biotechnology products under the

proposed rule. FDA does not intend for

these draft guidance documents to be

used at this time. The agency is

providing these guidance documents for

public comment only.

DATES: Written comments by April 29,

1996.

ADDRESSES: Submit written requests for

single copies of the draft guidance

entitled ‘‘Draft Guidance; Changes to An

Approved Application for WellCharacterized Recombinant DNADerived and Monoclonal Antibody

Biotechnology Products’’ to the

Congressional and Consumer Affairs

Branch (HFM–12), Center for Biologics

Evaluation and Research, Food and

Drug Administration, 1401 Rockville

Pike, Rockville, MD 20852–1448, 301–

594–1800 or call FDA’s automated

information system at 800–835–4709.

Send two self-addressed adhesive labels

to assist that office in processing your

requests. Submit written comments on

the draft guidance to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Two copies of any comments are

to be submitted, except that individuals

may submit one copy. Requests and

comments should be identified with the

docket number found in brackets in the

heading of this document. A copy of the

draft guidance and received comments

are available for public examination in