Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2733

DEPARTMENT OF ENERGY

Federal Energy Regulatory

Commission

18 CFR Part 35

[Docket Nos. RM95–8–000 and RM94–7–

001]

Promoting Wholesale Competition

Through Open Access NonDiscriminatory Transmission Services

by Public Utilities; Recovery of

Stranded Costs by Public Utilities and

Transmitting Utilities

January 19, 1996.

AGENCY: Federal Energy Regulatory

Commission.

ACTION: Proposed rule; extension of time

for comments on Draft Environmental

Impact Statement (DEIS).

SUMMARY: On November 17, 1995, the

staff of the Federal Energy Regulatory

Commission issued a draft

environmental impact statement for the

proposed rule in this proceeding (60 FR

58304, November 27, 1995). On January

3, 1996, an extension of time for the

filing of comments on the DEIS was

granted because certain departments

and agencies of the Federal government

were closed for all but emergency

matters due to a lack of appropriated

funds.

DATES: Comments by all parties shall be

filed on or before February 2, 1996.

ADDRESSES: Federal Energy Regulatory

Commission, 888 First Street, N.E.,

Washington, D.C. 20426.

FOR FURTHER INFORMATION CONTACT:

Bill Meroney, Office of Economic

Policy, (202) 208–1069.

Lois D. Cashell,

Secretary.

[FR Doc. 96–1530 Filed 1–26–96; 8:45 am]

BILLING CODE 6717–01–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600 and 601

[Docket No. 95N–0411]

RIN 0910–AA68

Well-Characterized Biotechnology

Products; Elimination of Establishment

License Application

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the biologics regulations to

eliminate the establishment license

application (ELA) requirement for wellcharacterized biotechnology products

licensed under the Public Health

Service Act (PHS Act). The proposed

rule would also exempt wellcharacterized biotechnology products

licensed under the PHS Act from certain

biologics regulations and harmonize the

requirements applicable to these

products with those applicable to

similar drug products which are

approved under the Federal Food, Drug,

and Cosmetic Act (the act).

This action is part of FDA’s

continuing effort to achieve the

objectives of the President’s

‘‘Reinventing Government’’ initiatives,

and it is intended to reduce unnecessary

burdens for industry without

diminishing public health protection.

DATES: Written comments on this

proposed rule by February 28, 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 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.

FOR FURTHER INFORMATION CONTACT:

Tracey H. Forfa, Center for Biologics

Evaluation and Research (HFM–630),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, 301–594–3074.

SUPPLEMENTARY INFORMATION

I. Background

In the Federal Register of December 8,

1995 (60 FR 63048), the agency

announced its interim definition of a

well-characterized therapeutic

recombinant DNA-derived and

monoclonal antibody biotechnology

product, 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.

A well-characterized therapeutic

recombinant DNA-derived and monoclonal

antibody product requires proper raw

material controls, process validation and

controls, and sensitive and validated test

methods and specifications.

As announced in the Federal Register

of October 25, 1995 (60 FR 54695), FDA

held a scientific workshop on December

11, 12, and 13, 1995, to discuss the

definition of a well-characterized

therapeutic recombinant DNA-derived

and monoclonal antibody product and

to identify the information necessary to

characterize such products. FDA

intends to consider information

received at the workshop, as well as

comments received in response to this

proposed rule, to determine whether the

definition previously given in this

document should be expanded to

include other categories of products that

would be considered to be wellcharacterized, such as certain vaccines

and biologic devices, e.g., test kits for

screening blood.

FDA is proposing to use the phrase

‘‘well-characterized biotechnology

product,’’ to describe the products that

would be eligible for a single license

application so that the regulatory

language would accommodate such

additional categories of products. FDA

has not included a definition of a wellcharacterized biotechnology product in

the proposed regulations because the

agency intends to clarify the definition

in a guidance document that can be

more readily modified to reflect changes

that may be warranted as scientific

knowledge progresses. FDA specifically

invites public comment on whether a

definition of a well-characterized

biotechnology product should be

included in the regulations and, if so,

what the scope of such a definition

should be.

Well-characterized therapeutic

recombinant DNA-derived and

monoclonal antibody products that are

viruses, therapeutic sera, toxins,

antitoxins, vaccines, blood, blood

components or derivatives, allergenic

products, or analogous products

applicable to the prevention, treatment,

or cure of human diseases or injuries are

‘‘biologics’’ within the meaning of
2734 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

section 351 of the PHS Act (42 U.S.C.

262). They are also ‘‘drugs’’ as the term

is defined in section 201(g) of the act (21

U.S.C. 321(g)). Additional wellcharacterized biotechnology products

identified in the future may be

‘‘devices’’ as defined in section 201(h)

of the act (21 U.S.C. 321(h)). Therefore,

such products are subject to the

provisions of the act applicable to drugs

and/or devices, including, but not

limited to, the adulteration and

misbranding provisions (21 U.S.C. 351

and 352).

At the present time, these products

are regulated by either FDA’s Center for

Biologics Evaluation and Research

(CBER) or Center for Drug Evaluation

and Research (CDER). CBER and CDER

have entered into an intercenter

agreement announced in the Federal

Register of November 21, 1991 (56 FR

58760), with respect to the regulation of

drugs and biological products. The

intercenter agreement assigns

jurisdiction to CBER or CDER based on

product class. A product class is defined

as a distinct category of agents

recognizable by physical characteristics,

source materials, or pharmacologic

properties. Examples of product classes

include: antibiotics, vaccines,

hormones, and human blood

derivatives. Under the agreement, some

well-characterized biotechnology

products, such as recombinant insulin

and human growth hormone, are

assigned to CDER, while other similar

recombinant products, such as

erythropoietin, colony stimulating

factor, and interferon, are assigned to

CBER.

Currently, when approved under the

PHS Act as biological products, wellcharacterized biotechnology products

are reviewed like any other biologic;

that is, both a product license

application (PLA) and an ELA are

submitted to and approved by FDA

before the well-characterized

biotechnology product may be shipped.

When approved under the act as a drug

product, a well-characterized

biotechnology product must have an

approved new drug application (NDA)

in place of a PLA and ELA. Much of the

information provided in a PLA is

similar to that included in an NDA.

Some of the information provided in an

ELA is included in the chemistry,

manufacturing and controls section of

the NDA (see § 314.50(d)(1)(21 CFR

314.50(d)(1))); however, much of the

information concerning the

manufacturing facility that is included

in an ELA is not included in an NDA.

Technical advances over the last 15

years have greatly increased the ability

of manufacturers to control and analyze

the manufacture of many biotechnologyderived biological products. After over a

decade of experience with these

products, the agency has found that it

can review the safety, purity, potency,

and effectiveness of most wellcharacterized biotechnology products

without requiring submission of a

separate ELA. Accordingly, FDA is

proposing procedures under which

CBER would approve well-characterized

biotechnology products by requiring a

single biologics license application.

CDER would continue to approve NDA’s

for well-characterized biotechnology

products. The single biologics license

application and the NDA would have an

identical format and include the same

information. FDA would continue to

inspect manufacturing facilities for

compliance with good manufacturing

practice requirements before approving

either a biologics license application or

NDA.

FDA has determined that the review

standards for well-characterized

biotechnology products across the

agency are substantially identical,

notwithstanding that such standards

may be specified in separate regulations,

but the manner in which information is

submitted to FDA is more burdensome

when done through the ELA

mechanism. Accordingly, the agency

believes that the proposed procedures

will significantly reduce burdens

without reducing the safety or

effectiveness of these products.

II. Legal Authority

This proposal would establish a

licensing scheme for well-characterized

biotechnology products that differs from

the current licensing scheme in four

fundamental ways. First, an applicant

seeking marketing approval of a wellcharacterized biotechnology product

would submit a single biologics license

application to CBER and be issued a

single license. Second, for these

products, many of the establishment

standards set forth in part 600 (21 CFR

part 600) would be exempted from

applicability and the current good

manufacturing practice requirements

found at parts 210 and 211 (21 CFR

parts 210 and 211) would constitute the

bulk of the applicable establishment

standards. Some of the product

standards set forth in part 610 (21 CFR

part 610) would also be eliminated for

these products. Third, in lieu of

submitting an ELA to CBER showing

compliance with establishment

standards, FDA would evaluate whether

establishment standards had been met

by reviewing information submitted in

the biologics license application and by

inspecting the facilities in which the

product is manufactured. Fourth, the

term ‘‘manufacturer’’ as it is used in

parts 600 through 680 (21 CFR parts 600

through 680) would be broadened to

include an applicant for a license for a

well-characterized biotechnology

product who may or may not own the

facilities engaged in significant

production steps. This would allow a

single license applicant to take

responsibility for compliance with the

requirements in parts 600 through 680

applicable to manufacturers and

eliminate the requirement that each

separate contract facility engaging in

significant manufacturing obtain a

separate license.

These licensing procedures for wellcharacterized biotechnology-derived

biological products are authorized by

section 351 of the PHS Act. The

proposed rule would establish an

administrative approach to enforce the

requirements in sections 351(a) and (d)

of the PHS Act appropriate for current

scientific and technological methods

applied in the manufacture of these

products.

FDA’s current regulations to

administer and enforce the statutory

requirements embody a dual licensing

scheme: Applicants must submit to

CBER an ELA and a PLA and obtain

agency approval of both applications

before they may distribute a biological

product. Parts 600 through 680 set out

establishment and product standards

that applicants must meet before FDA

issues an establishment or product

license. However, a dual licensing

scheme is not compelled by the PHS

Act.

Section 351(a) of the PHS Act restricts

the interstate sale, barter, and exchange

of biologics to products manufactured in

establishments that have been licensed.

Section 351(a) requires that a biologic

product be ‘‘propagated or

manufactured and prepared at an

establishment holding an unsuspended

and unrevoked license.’’ Section 351(d)

authorizes the agency to prescribe

regulations for the issuance, suspension,

and revocation of licenses: ‘‘Licenses for

the maintenance of establishments for

the propagation or manufacture and

preparation of [biological] products

* * * may be issued only upon a

showing that the establishment and the

products for which a license is desired

meet standards, designed to insure the

continued safety, purity, and potency of

such products, prescribed in

regulations, and licenses for new

products may be issued only upon a

showing that they meet such

standards.’’ The sole limitation on the

agency’s discretion to issue biologic

licenses is that licenses may only be
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2735

issued upon a showing that both the

establishment in which the product is

prepared and the product meet

regulatory standards designed to insure

the continued safety, purity, and

potency of such products.

The PHS Act does not prescribe

requirements for the format or content

of license applications. Nor does it

direct that there be two forms of license.

The clear import of section 351(a) is that

the entity responsible for the product

and its manufacture should be licensed.

The agency believes that the single

biologics license application scheme

that FDA is proposing for wellcharacterized biotechnology products is

authorized by the PHS Act because

licenses would continue to be issued

only after the agency has made a

determination that the product and the

establishment(s) in which it is

manufactured meet applicable

regulatory standards. FDA would make

its determination as to whether the

product and establishment(s) meet

applicable regulatory standards after

reviewing the information submitted in

the biologics license application and

after inspecting the manufacturing

facilities.

FDA believes that a license holder

need not be the legal owner of each

facility in which the product is

manufactured as long as he or she is

responsible for assuring FDA that the

product and establishment standards are

met. Accordingly, the proposed rule

would permit a single license holder to

assume control of the production of a

well-characterized biotechnology

product regardless of whether he or she

owns the manufacturing facilities.

FDA also believes that its

administrative approach to enforcing

the PHS Act can and should change to

respond to changing knowledge and

experience in reviewing the safety,

purity, and potency of biological

products.

III. Summary of Proposed Rule

A. Biologics License Application.

The proposed rule would be

applicable to applicants seeking

marketing approval of wellcharacterized biotechnology products

that are currently licensed under the

provisions of the PHS Act.

In an effort to further harmonize the

manner in which well-characterized

biotechnology products are regulated,

the agency is proposing in new

§ 601.2(c) to eliminate the requirement

for a separate ELA for wellcharacterized biotechnology products

licensed under the PHS Act. This

proposed regulation would require that

an applicant seeking marketing approval

of a well-characterized biotechnology

product file a single application on a

form prescribed by CBER. The form will

include a section that is the same as the

chemistry, manufacturing, and controls

(CMC) section found in an NDA. (See

§ 314.50(d)(1)). CBER and CDER have

prepared a draft form that has been

made available for comment. This draft

form may be used in the interim until

a final form is available. Both CBER and

CDER intend to prepare and use the

same guidance documents to aid in the

preparation of the chemistry,

manufacturing, and controls section of

an application for a well-characterized

biotechnology product. FDA intends

that this guidance will be made

available to the public by the time of

issuance of any final rule resulting from

this proposal.

The CMC section of a license

application for a well-characterized

biotechnology product, like an NDA for

a well-characterized biotechnology

product, would include the following

elements, at a minimum: A full

description and characterization of the

well-characterized biotechnology

product; the names, addresses, and

responsibilities of all manufacturers

involved in the manufacture and testing

of the product; the method of

manufacture, including raw materials,

solvents, and reagents; process controls

and tests; reference standards;

specifications and analytical methods; a

description of the container and closure

system and its compatibility with the

well-characterized biotechnology

product drug substance; a description of

the storage conditions, stability study

protocols, and results; a tabulated list of

all components; specifications and

methods for the drug product’s

ingredients; methods of manufacturing

and packaging of the well-characterized

drug product including a floor plan

which designates rooms in the

manufacturing facilities and operations

in each room; specifications and

methods for the drug product; any

microbiology and drug product stability

data; description of any investigational

formulation; environmental assessment

and method validation.

This proposal would also expand the

definition in § 600.3(t) of

‘‘manufacturer’’ to include a license

applicant for a well-characterized

biotechnology product regardless of

whether the applicant is personally

engaged in significant manufacturing

steps.

These proposed changes would

facilitate a company’s ability to contract

out manufacture of its wellcharacterized biotechnology products.

The proposed rule would eliminate the

requirement that each separate contract

facility engaging in significant

production steps submit an ELA and a

PLA. Instead, a well-characterized

biotechnology product would be

covered by a single biologics license

application, which lists all

manufacturing locations, regardless of

how many separate companies are

involved in its manufacture. FDA is

seeking comment on whether the

definition of ‘‘manufacturer’’ in

§ 600.3(t) should also be expanded to

include license applicants for products

other than well-characterized

biotechnology products.

B. Good Manufacturing Practice

Requirements.

The establishment standards for wellcharacterized biotechnology products

would continue to include the CGMP

regulations found in parts 210 and 211

(21 CFR parts 210 and 211). FDA would

review compliance with good

manufacturing practice requirements

upon inspection and applicants would

be required to demonstrate such

compliance in order to obtain approval

of a biologics license application.

Should well-characterized devices

licensed under the PHS Act be

identified and be eligible for the new

procedures, applicable CGMP

regulations would include parts 606 and

820 (21 CFR parts 606 and 820) (for

blood and blood components). FDA

requests comments on whether a

specific reference to part 820 should be

included in the rule.

Under section 501(a)(2)(B) of the act,

the methods used in, and the facilities

or controls used for the manufacture,

processing, packing, or holding of a

drug must conform to current good

manufacturing practice. Because the

bulk drug substance, drug component,

and bulk drug product meet the

definition of ‘‘drug’’ in section 201(g)(1)

of the act (21 U.S.C. 321(g)(1)), their

manufacture also must conform to good

manufacturing practice. The CGMP

regulations set forth in parts 210 and

211 are intended to apply to the

preparation of a finished dosage form,

whether or not in packaged form. (See

§ § 210.3(b)(4) and 211.1(a).) Although

these CGMP regulations are not applied

to the manufacture of bulk drug

components, there are numerous

instances where good manufacturing

practice for bulk drug substances and

bulk drug product components would

parallel the requirements set forth in

part 211. (See 43 FR 45076.) Because

well-characterized biotechnology

products can be susceptible to

contamination, adequate control over
2736 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

bulk manufacturing is important. FDA

intends to use the standards of part 211

as guidelines during inspections of

manufacturers of bulk drug substance

and bulk drug product components,

under the jurisdiction of the act, to help

ensure that a well-characterized

biotechnology product will have the

proper raw materials controls, process

validation and controls, and sensitive

and validated test methods and

specifications that are necessary to

assure the safety, purity, potency, and

effectiveness of the product.

C. Applicability of Current Regulations

(Parts 600–680).

In order to harmonize the regulatory

standards applied by CBER and CDER in

their review of applications for wellcharacterized biotechnology products,

FDA is proposing to exempt wellcharacterized biotechnology products

licensed under the PHS Act from certain

requirements found in parts 600 through

680. The regulations that have not been

excluded in this proposed rule are those

that FDA believes are necessary to

ensure the safety, purity, and potency of

well-characterized biotechnology

products; are essentially the same as

those found in comparable regulations

governing drug products; may not be

applicable by their terms to wellcharacterized biotechnology products;

or are ones that are targeted for revision.

FDA requests comments on whether

well-characterized biotechnology

products should be exempted from

requirements in parts 600 through 680

not identified for exclusion in this

proposal, or whether certain regulations

exempted in this proposed rule should

remain applicable. FDA also requests

comments on whether wellcharacterized devices licensed under

the PHS Act, should such products be

identified, would need to be exempted

from the same or different requirements

in parts 600 through 680.

The following lists set forth those

provisions that FDA proposes would

remain applicable, those that FDA

proposes to exempt from applicability to

well-characterized biotechnology

products, and those that would not be

applicable by their terms to wellcharacterized biotechnology products.

The following sections would remain

applicable to well-characterized

biotechnology products: § § 600.3,

600.10(a), 600.14, 600.20, 600.21,

600.22, 600.80, 600.81, 600.90, 601.2,

601.3(b), 601.4, 601.5, 601.6, 601.7,

601.8, 601.9, 601.12, 601.20, 601.21,

601.22, 601.33, 601.40, 601.41, 601.42,

601.43, 601.44, 601.45, 601.46, 601.50,

601.51, 610.1, 610.2 (Lot-by-lot release

eliminated for licensed wellcharacterized therapeutic recombinant

DNA-derived and monoclonal antibody

products per letters to manufacturers

and notice in the Federal Register of

December 8, 1995, (60 FR 63048.)),

610.9, 610.10, 610.11a, 610.12

(Equivalent methods or processes

possible under § 610.9.), 610.13, 610.14,

610.15, 610.17, 610.18, 610.30, 610.40,

610.41, 610.45 (Sections 610.40 through

610.45 apply to blood and blood

components used in the manufacture of

a well-characterized biotechnology

product.), 610.50, 610.60, 610.61,

610.63, 610.64, 610.65, and parts 606

(potential applicability to blood and

blood components only); 640 (potential

applicability to blood and blood

products only); and 680 (would apply

only to a well-characterized

biotechnology allergenic product).

The following sections would be

exempted from applicability to wellcharacterized biotechnology products:

§§ 600.10(b) and (c), 600.11, 600.12,

600.13, 601.1, 601.30, 601.31, 601.32,

610.11, 610.53, and 610.62.

The following sections by their terms

would not be applicable to wellcharacterized biotechnology products:

§§ 600.15, 601.3(a), 601.10, 601.25,

601.26, 610.16, 610.19, 610.20, 610.21,

and parts 607, 620, 630, 650, and 660.

FDA is proposing to exempt wellcharacterized biotechnology products

from the requirements of § 610.11,

which sets out procedures for a general

safety test for biological products. FDA

believes that a general safety test

requirement is not necessary to ensure

the safety, purity, and potency of a wellcharacterized biotechnology product.

With in-process control and process

validation and product testing, the

identity of the well-characterized

biotechnology product can be

determined, its purity can be controlled

and quantified, its activity and quantity

can be measured, and the end-product

release specifications can be validated.

The agency believes that specific

analytical tests that are available for

these products will provide a better

assessment of safety than the general

safety test.

FDA is also proposing to exempt wellcharacterized biotechnology products

from § 610.62, which sets out

requirements for position and

prominence of the proper name of the

product on the package label. FDA

believes that the requirements in

§ 201.10(g) are adequate to assure the

appropriate identification of these

products.

D. Transition Issues.

Any well-characterized biotechnology

product for which a PLA and an ELA

are pending on the effective date of

these regulations would be reviewed as

submitted. No new submission would

be necessary to implement this rule

change for these products. If found

acceptable for licensure, FDA would

issue a biologics license in lieu of

issuing both a product and

establishment license. Any company

planning to file a PLA or an ELA prior

to April 1996 should contact the agency

for guidance. FDA specifically asks for

comments on how transition issues

should be handled.

FDA anticipates that applicants

already holding an approved ELA and

PLA for a well-characterized

biotechnology product would not be

required to file supplements to comply

with the new requirements. The

approved PLA for a well-characterized

biotechnology product, together with

the limited portions of the approved

ELA relevant to the new requirements

for the biologics license application,

would be deemed to constitute an

approved biologics license application

under the new regulations.

IV. Proposed Effective Date

FDA proposes that a final rule

resulting from this proposal become

effective upon its date of publication in

the Federal Register. As provided under

5 U.S.C. 553(d) and 21 CFR 10.40(c)(4),

the effective date of a final rule may not

be less than 30 days after publication,

except for, among other things, ‘‘a

regulation that grants an exemption or

relieves a restriction’’ (§ 10.40(c)(4)(i)).

Because, as described below, this rule

would decrease the regulatory burdens

for well-characterized biotechnology

products, FDA believes that an

immediate effective date is appropriate.

V. Analysis of Impacts

A. Reduction in Burden

The proposed harmonization of the

requirements would reduce burden on

industry because companies

manufacturing well-characterized

biotechnology products that are

regulated by both CBER and CDER

would be able to submit applications for

products in a consistent format.

Companies developing and

manufacturing well-characterized

biotechnology products regulated by

CBER would no longer have to prepare

an ELA to submit to the agency for

approval. The amount of information

that applicants would need to provide

in a biologics license application would

be less than that currently required in a

PLA and ELA. These proposed changes

would enable companies to devote more

resources to ensuring that
Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules 2737

manufacturing processes are properly

validated and fewer resources to

submitting documentation to the

agency. These changes would especially

benefit biotechnology companies that

lack experience preparing ELA’s and

PLA’s. According to the biotechnology

industry, preparation and submission of

an ELA may add substantially to the

cost of obtaining approval of a wellcharacterized biotechnology product.

The inclusion of parts 210 and 211 in

the proposed rule as establishment

standards would not impose any

additional burden on industry. Human

drugs, including well-characterized

biotechnology products, are already

subject to the CGMP’s in parts 210 and

211.

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 regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impact; and equity). The agency

believes that this proposed rule is

consistent with the regulatory

philosophy and principles identified in

the Executive Order. In addition, 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 burdens on

applicants filing for approval of a wellcharacterized biotechnology product. In

addition, FDA anticipates that the

proposed rule would facilitate

applicants’ ability to improve their

licensed products and methods of

manufacture by decreasing the burden

and cost associated with filing an

application.

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 previously,

the overall result of the proposed rule

would be a substantial reduction of the

regulatory and reporting burdens, the

agency certifies that the proposed rule

would not have a significant negative

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 collection requirements

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

for the 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: Well-characterized

Biotechnology Products; Elimination of

Establishment License Application.

Description: FDA is proposing to

eliminate the requirement that an ELA

be submitted and approved by FDA for

those well-characterized biotechnology

products that are licensed by CBER. For

these products, in place of the ELA, a

company would be required to prepare

and submit additional information for

inclusion in a single biologics license

application, which would be the same

as the information included in the

‘‘Chemistry, manufacturing, and

controls’’ (CMC) section of a NDA. This

proposed regulation would harmonize

the approval and other regulatory

requirements for all well-characterized

biotechnology product under the PHS

Act or approved as a drug under the

new drug provisions of the act.

Description of Respondents: All

applicants for a biological product

license to be approved under the Public

Health Service Act.

Estimated Annual Reporting Burden

CFR Section Number of

Respondents

Frequency of Responses Total Annual Responses Hours per Response Total Hours

601.2(c) 1 1 1 40 40

Reporting or Disclosure: 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 or operating and maintenance

costs associated with this information

collection. The number of respondents

is dependent in part, on the definition

of ‘‘well-characterized biotechnology

products,’’ now under review by the

agency. At the present time, FDA

estimates the number of respondents at

one a year. The agency seeks comment

on these estimates, particularly the

industry’s view of the number of firms

and products affected by the collections

of information requirements contained

in this proposed rule.

The agency has submitted a copy of

this proposed rule to OMB for its review

of these information collections.

Interested persons are requested to send
2738 Federal Register / Vol. 61, No. 19 / Monday, January 29, 1996 / Proposed Rules

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. Environmental Impact

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

February 28, 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. Two copies

of all comments are to be submitted,

except that individuals may submit one

copy. The comments received are

available for public examination in the

Dockets Management Branch between 9

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

Friday. Submit written comments on the

information collection requirements to

the Office of Information and Regulatory

Management, OMB (address above).

List of Subjects

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 authority

delegated to the Commissioner of Food

and Drugs, it is proposed that 21 CFR

parts 600 and 601 be amended as

follows:

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

revising paragraph (t) to read as follows:

§ 600.3 Definitions.

* * * * *

(t) Manufacturer means any legal

person or entity engaged in the

manufacture of a product subject to

license under the act; ‘‘Manufacturer’’

also includes an applicant for a license

for a well-characterized biotechnology

product.

* * * * *

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 601.2 is amended by

adding a sentence at the end of

paragraph (a) and by adding a new

paragraph (c) to read as follows:

§ 601.2 Applications for establishment and

product licenses; procedures for filing.

(a) * * * In lieu of the procedures

described in this paragraph,

applications for well-characterized

biotechnology products shall be

handled as set forth in paragraph (c) of

this section.

* * * * *

(c) Well-characterized biotechnology

products. (1) To obtain marketing

approval for a well-characterized

biotechnology product, an applicant

shall submit to the Director, Center for

Biologics Evaluation and Research, a

biologics license application on a form

prescribed by the Director, Center for

Biologics Evaluation and Research. For

such well-characterized biotechnology

products, a separate establishment

license application shall not be

required. An application for a license

for a well-characterized biotechnology

product shall include: Data derived

from nonclinical laboratory and clinical

studies that demonstrate that the

manufactured product meets prescribed

standards of safety, purity, and potency;

with respect to each nonclinical

laboratory study, either a statement that

the study was conducted in compliance

with the requirements set forth in part

58 of this chapter, or, if the study was

not conducted in compliance with such

regulations, a brief statement of the

reason for the noncompliance;

statements regarding each clinical

investigation involving human subjects

contained in the application, that it

either was conducted in compliance

with the requirements for institutional

review set forth in part 56 of this

chapter or was not subject to such

requirements in accordance with

§§ 56.104 or 56.105 of this chapter, and

was conducted in compliance with

requirements for informed consent set

forth in part 50 of this chapter; a full

description of manufacturing methods;

data establishing stability of the product

through the dating period; sample(s)

representative of the product to be sold,

bartered, or exchanged or offered, sent,

carried or brought for sale, barter, or

exchange; summaries of results of tests

performed on the lot(s) represented by

the submitted samples; and specimens

of the labels, enclosures, and containers

proposed to be used for the product. An

application for license shall not be

considered as filed until all pertinent

information and data have been

received from the applicant by the

Center for Biologics Evaluation and

Research. The applicant shall also

include either a claim for categorical

exclusion under § 25.24 of this chapter

or an environmental assessment under

§ 25.31 of this chapter.

(2) Approval of the biologics license

application and issuance of the

biologics license shall constitute a

determination that the establishment

and the product meet applicable

standards established in this chapter to

ensure the continued safety, purity, and

potency of such products. Applicable

standards for the maintenance of

establishments for the manufacture of

well-characterized biotechnology

product shall include the good

manufacturing practice requirements set

forth in parts 210 and 211 of this

chapter. The following sections in parts

600 through 680 of this chapter shall not

be applicable to well-characterized

biotechnology products: § § 600.10(b)

and (c), 600.11, 600.12, 600.13, 601.1,

601.30, 601.31, 601.32, 610.11, 610.53,

and 610.62 of this chapter.
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,