Federal Register / Vol. 63, No. 75 / Monday, April 20, 1998 / Proposed Rules 19431

Comments also may be submitted

electronically at the following E-mail

address: rule-comments@sec.gov.

Comment letters should refer to File No.

S7–8–98; this file number should be

included on the subject line if E-mail is

used. All comments received will be

available for public inspection and

copying at the Commission’s Public

Reference Room, 450 Fifth Street, N.W.,

Washington, D.C. 20549. Electronically

submitted comment letters will be

posted on the Commission’s Internet

web site (http://www.sec.gov).

FOR FURTHER INFORMATION CONTACT: Jerry

W. Carpenter, Assistant Director, 202/

942–4187; Thomas C. Etter, Jr., Special

Counsel, 202/942–0178; or Jeffrey S.

Mooney, Special Counsel, 202/942–

4174, Division of Market Regulation,

Securities and Exchange Commission,

450 Fifth Street, N.W., Mail Stop 10–1,

Washington, D.C. 20549.

SUPPLEMENTARY INFORMATION: On March

5, 1998, the Commission proposed

temporary Rule 17Ad-18 under the

Securities Exchange Act of 1934. Rule

17Ad-18 would require all non-bank

registered transfer agents to file with the

Commission at least one report

regarding its Year 2000 readiness. The

initial report would be due no later than

45 days after the Commission adopts

this rule. The follow-up reports, which

would be due on August 31, 1998, and

on August 31, 1999, would include an

attestation by an independent public

accountant that would give the

independent public accountant’s

opinion whether there is a reasonable

basis for the transfer agent’s assertions

in the reports. Additionally, the release

contains a Commission advisory notice

on its transfer agent record retention

and recordkeeping requirements relating

to the Year 2000.

The Commission has recently

received requests from interested

persons to extend the comment period

for this release. The Commission

believes that extending the comment

period is appropriate in order to give the

public additional time to comment on

the matters the release addresses.

Therefore, the comment period is

extended until April 27, 1998.

By the Commission.

Dated: April 14, 1998.

Margaret H. McFarland,

Deputy Secretary.

[FR Doc. 98–10336 Filed 4–17–98; 8:45 am]

BILLING CODE 8010–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. 97N–0449]

RIN 0910–AB51

Revisions to the General Safety

Requirements for Biological Products;

Companion Document to Direct Final

Rule

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the biologics regulations by

adding cellular therapy products to the

list of products exempted from the

general safety test (GST) and by adding

an administrative procedure for

obtaining exemptions from the GST

requirements. This proposed rule is a

companion document to the direct final

rule published elsewhere in this issue of

the Federal Register. FDA is taking this

action because the GST may not be

relevant or necessary for many types of

biological products, including cellular

therapy products, currently in various

stages of development.

DATES: Comments must be received on

July 6, 1998. Submit written comments

on the information collection provisions

by June 19, 1998.

ADDRESSES: Submit written comments

on the proposed rule to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857.

FOR FURTHER INFORMATION CONTACT:

Dano B. Murphy, 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

This proposed rule is a companion to

the direct final rule published in the

final rules section of this issue of the

Federal Register. This companion

proposed rule will provide the

procedural framework to finalize the

rule in the event the direct final rule

receives any significant adverse

comment and is withdrawn. The

comment period for this companion

proposed rule runs concurrently with

the comment period for the direct final

rule. Any comments received under this

companion proposed rule will also be

considered as comments regarding the

direct final rule. FDA is publishing the

direct final rule because the rule

contains noncontroversial changes, and

FDA anticipates that it will receive no

significant adverse comment.

A significant adverse comment is

defined as a comment that explains why

the rule would be inappropriate,

including challenges to the rule’s

underlying premise or approach, or

would be ineffective or unacceptable

without a change. In determining

whether a significant adverse comment

is sufficient to terminate a direct final

rulemaking, FDA will consider whether

the comment raises an issue serious

enough to warrant a substantive

response in a notice-and-comment

process. Comments that are frivolous,

insubstantial, or outside the scope of the

rule will not be considered significant

or adverse under this procedure. For

example, a comment requesting

inclusion of additional product classes

in the exceptions paragraph of the GST

(§ 610.11(g)) will not be considered a

significant adverse comment because it

is outside the scope of this rule. A

comment recommending a rule change

in addition to the rule would not be

considered a significant adverse

comment, unless the comment states

why the rule would be ineffective

without additional change. In addition,

if a significant adverse comment applies

to part of a rule and that part can be

severed form the remainder of the rule,

FDA may adopt as final those parts of

the rule that are not subject of a

significant adverse comment.

A detailed rationale for the rule is set

forth in the preamble to the direct final

rule and in section I of this document.

If no significant adverse comment is

received in response to the direct final

rule, no further action will be taken

related to this proposed rule. Instead,

FDA will publish a confirmation

document within 30 days after the

comment period ends confirming that

the direct final rule will go into effect

on September 2, 1998. Additional

information about FDA’s direct final

rulemaking procedures is set forth in a

guidance published in the Federal

Register of November 21, 1997 (62 FR

62466).

If FDA receives any significant

adverse comment regarding this rule,

FDA will publish a document

withdrawing the direct final rule within

30 days after the comment period ends.

FDA then will proceed to respond to all

of the comments received regarding this

rule and, if appropriate, the rule will be

finalized under this proposed rule using

usual notice-and-comment procedures.
19432 Federal Register / Vol. 63, No. 75 / Monday, April 20, 1998 / Proposed Rules

Requests to add other products to the

named exceptions will be considered

separately by FDA. If FDA agrees that

other products should be excepted from

the GST, it will propose those

exceptions under other independent

rulemaking actions. Any parties

interested in commenting on this

document should do so at this time.

This action is part of FDA’s continuing

effort to achieve the objectives of the

President’s ‘‘Reinventing Government’’

initiative, and is intended to reduce the

burden of unnecessary regulations on

biological products without diminishing

the protection of the public health.

Under § 610.11 (21 CFR 610.11), a test

for general safety shall be performed on

biological products intended for

administration to humans. A GST is one

of several tests in part 610, General

Biological Product Standards (21 CFR

part 610), that are intended to help

ensure the safety, purity, and potency of

biological products administered to

humans. The test is used to detect

extraneous toxic contaminants that may

be present in a particular biological

product. As outlined in § 610.11, an

amount of the final container product is

injected into the peritoneum of guinea

pigs and mice. The GST is satisfactory

when the criteria in § 610.11(d) are met,

i.e., injected animals survive the test

period, they do not exhibit an

unexpected or non-specific response

that may indicate a difference in quality

of the product, and they weigh no less

at the end of the test period than they

did at the time of injection. Section

610.11(g) identifies the biological

products for which the GST is not

required.

The requirement for a GST was

originally intended as a means by which

harmful extraneous toxins could be

detected that published in a document

in the Federal Register of March 15,

1976 (41 FR 10888). The source of such

toxins may be bacterial toxins that

persist even after the bacteria producing

the toxins had been removed by

filtration or killed by sterilization, or

formulation errors that result in harmful

levels of certain substances, e.g.,

preservatives. The test continues to

serve as a safety net to detect harmful

contaminants that may enter or be

introduced into the final container

through undetected failures in the

manufacture of biological products.

In the last 15 years, technological

advances have increased the ability of

manufacturers to control and analyze

the manufacture of many biotechnology

derived biological products. After more

than a decade of experience with these

products, FDA found that it could

evaluate many aspects of a biological

product’s safety, purity, or potency with

tests other than those prescribed in part

610. In response to these developments,

FDA published in the Federal Register

of May 14, 1996 (61 FR 24227), a final

rule exempting certain biotechnology

and synthetic biological products from,

among other things, specified

regulations applicable to biological

products, including the GST (§ 601.2).

Recent scientific advances have

dramatically increased the diversity of

biological products regulated under

section 351 of the Public Health Service

Act (the PHS Act). In particular,

cellular-based therapies intended for the

diagnosis, cure, mitigation, treatment, or

prevention of disease in man have been

the subject of much biomedical research

and are used with increasing frequency.

Typically, cellular therapies use

autologous or allogeneic cells, often

lymphocyte subpopulations, but other

cell types may be used, obtained from

a donor and manipulated ex vivo to

varying degrees before use in the

recipient patient. The ex vivo

manipulation may consist of, for

example, growing a small number of

cells to increase their number (cellular

expansion), selective enrichment of a

specific cell subpopulation, or the

addition of specific cell factors or

genetic sequences. A common

characteristic of cellular therapies is the

need for a relatively short turn-around

time between first obtaining the cells

and their final infusion as a cellular

therapy product into the patient. In

many cases, cells used in the final

cellular therapeutic are obtained only

hours before they must be used and

turn-around times of several days or less

are presently typical. A test, such as the

GST, that requires 7 days to complete is

not compatible with such products and

such a requirement would make it

impossible to use many of these

products. Furthermore, because the

procedures and materials used to

produce cellular therapy products are

stringently controlled and monitored,

the likelihood of an extraneous toxic

component contaminating a final

product is greatly reduced.

In the Federal Register of June 3, 1994

(59 FR 28821 and 28822), FDA

announced that the Center for Biologics

Evaluation and Research (CBER) would

review certain biologics regulations to

identify regulations that are outdated,

burdensome, inefficient, duplicative, or

otherwise unsuitable or unnecessary.

FDA included § 610.11 in the review.

On January 26, 1995, FDA held a public

meeting to discuss the retrospective

review of regulations applicable to

biological products and to provide a

forum for the public to voice its

comments regarding the retrospective

review. At the meeting, only one

comment addressed whether § 610.11

should be retained unchanged,

modified, or deleted. The comment

acknowledged the utility of the GST for

products that have a high degree of

intrinsic variability. However, despite

its recognized value in some specific

cases, the comment questioned the

rationale for requiring the GST for all

biological products intended for

administration to humans. The

comment noted that the amount of final

container product administered to

animals for the GST may not have any

correlation with the human dose, that

some biological products possess

extensive documented histories of no

GST failure, and that each run of the test

requires the use of at least four animals.

The comment suggested that FDA revise

§ 610.11 to grant exemptions from the

GST when the test is unnecessary to

evaluate the safety of a specific product.

FDA received several comments from

the public regarding issues raised at the

January 26, 1995, meeting. Two

comments agreed with the suggestion

made at the public meeting that § 610.11

be amended to include a provision that

would allow certain products to be

exempted from the GST upon approval

of the Director, CBER. Another comment

suggested that exemptions be permitted

for appropriate biological products by

the Director, CBER, after a suitable

qualification period was met without

any failure of the GST, such as 1 year

of production or after 10 consecutive

production lots pass the GST. The

comment suggested that a demonstrated

record of GST compliance also be

supported by well-documented inprocess safety controls, long-term

compliance with current good

manufacturing practices (CGMP)

regulations (21 CFR parts 210 and 211),

and the use of sophisticated analytical

techniques capable of adequately

characterizing the final product and

validating its safety.

On March 17, 1997, FDA held a

public meeting to discuss the agency’s

proposed approach to the regulation of

human cellular and tissue-based

products. The meeting was attended by

FDA, members of industry,

representatives from accrediting

organizations, and interested members

of the public. During the meeting, two

attendees addressed the use of the GST

with cellular therapy products. The

comments regarded the 7-day

incubation time of the test as an

unworkable requirement for many

cellular therapy products and suggested

that such products be exempted from
Federal Register / Vol. 63, No. 75 / Monday, April 20, 1998 / Proposed Rules 19433

the test, including allogeneic and

autologous cell therapy products.

II. Highlights of the Proposed Rule

FDA agrees with the comments

received that cellular therapy products

should be exempt from the GST

requirement. FDA is proposing this rule

to expand the exceptions in § 610.11(g)

to include ‘‘cellular therapy products.’’

In addition, FDA is adding an

administrative procedure for

manufacturers of other biological

products to request and obtain

exemptions from the GST. Many

biological products are currently

manufactured, or will be manufactured

in the future, under highly controlled

and rigorously monitored conditions.

Therefore, under the amended rule,

manufacturers of biological products

that employ appropriate production

controls and quality assurance

safeguards would be permitted to apply

for an exemption from the GST

requirement. Such manufacturers will

be required to provide supporting

documentation to the Director, CBER, as

to why a product should not be subject

to the GST requirement. The request

shall include an explanation of why the

GST is unnecessary or cannot be

performed due to the mode of

administration, the method of

preparation, or the special nature of the

product and shall describe alternate

procedures, if any, to be employed. The

Director, CBER, may grant an exemption

if she finds that the manufacturer’s

submission justifies an exemption.

The value of the GST as a final assay

for the presence of extraneous toxins

may be diminished for certain biological

products, such as vaccines containing

recombinant or purified protein

antigens. Recombinant protein antigens

are not produced from infectious

bacteria or virus and antigens derived

from infectious pathogens may undergo

many production steps that kill or

neutralize the pathogen or inactivate

toxic materials. Therefore, for these

kinds of products, the risk is extremely

low that viable pathogenic or toxic

materials will persist through

production to the final filling. The

effectiveness of such steps can be

validated by specific in-process tests

and controls which can be used to alert

manufacturers to potential problems. To

further reduce the possibility that an

undetected extraneous toxin could

contaminate the product just before or

during the final fill stage, a

manufacturer may use production

facilities and final fill equipment that

can detect or enable the detection of any

loss in the integrity of the production

and fill processes. In addition, a method

of production and detailed product

characterization able to meet

requirements similar to those set out in

§ 601.2(c) could be used to demonstrate

the safety, purity, and potency of a

biological product without the use of

the GST. Each manufacturer will be

responsible for identifying the product

or products that are produced in such a

manner that makes the GST unnecessary

to ensure the safety, purity, and potency

of the biological product. Manufacturers

wishing to obtain an exemption to the

GST for a particular product would

contact the appropriate product division

of CBER for specific information

regarding how to apply and what

information should be included in the

application or supplemental

application.

III. Analysis of Impacts

A. Review Under Executive Order 12866

and the Regulatory Flexibility Act

FDA has examined the impact of the

proposed rule under Executive Order

12866, the Regulatory Flexibility Act (5

U.S.C. 601–612), and the Unfunded

Mandates Reform Act of 1995 (Pub. L.

104–4). 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). 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 result of the

proposed rule will be a substantial

reduction in burdens on applicants

filing for approval of certain biological

products.

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact of a rule on small

business entities. Because, as stated

previously, the overall result of the

proposed rule will be a substantial

reduction of the regulatory and

reporting burdens, the agency certifies

that the proposed rule will 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. This proposed rule also does

not trigger the requirement for a written

statement under section 202(a) of the

Unfunded Mandates Reform Act

because it does not impose a mandate

that results in an expenditure of $100

million or more by State, local, and

tribal governments in the aggregate, or

by the private sector, in any one year.

B. Environmental Impact

The agency has determined under 21

CFR 25.31(j) 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.

IV. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection provisions that

are subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(the PRA) (44 U.S.C. 3501–3520). The

title, description, and respondent

description of the information collection

provisions are shown below with an

estimate of the annual reporting burden.

Included in the estimate is the time for

reviewing the instructions, searching

existing data sources, gathering and

maintaining the data needed, and

completing and reviewing each

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: Requests for Exemptions from

the General Safety Testing Requirements

for Biological Products.

Description: FDA is proposing to

revise the requirements for general

safety testing (GST) set forth in § 610.11.

The test serves as a safety net to detect

harmful contaminants that may enter or

be introduced into the final container

through undetected failures in the

manufacture of biological products. The

revision would add ‘‘cellular therapy

products’’ to the list of products

excepted from the GST, and add an

administrative procedure for obtaining
19434 Federal Register / Vol. 63, No. 75 / Monday, April 20, 1998 / Proposed Rules

exemptions from the GST requirements

for other biological products. FDA is

proposing the new administrative

procedure because the GST may not be

feasible or appropriate for some

biological products. FDA anticipates

that manufacturers requesting

exemptions would have a demonstrated

record of GST compliance supported by

long-term compliance with CGMP’s,

well-documented in-process safety

controls, and use sophisticated

analytical techniques to adequately

characterize the final product and

validate its safety. Manufacturers would

submit their request and documentation

to the Director, CBER, who may grant

the exemption if it is determined that

the manufacturer’s submission justifies

an exemption.

Description of Respondents:

Manufacturers of biological products.

The proposed rule would require only

those manufacturers requesting an

exemption from the GST under

§ 610.11(g)(2) to submit additional

information as part of a license

application or supplement to an

approved license application.

Manufacturers of ‘‘cellular therapy

products’’ would be excepted from the

GST under § 610.11(g)(2) and thus,

would not have to submit an exemption

request. In fact, manufacturers of

cellular therapy products would be

relieved of significant burdens because

they would no longer be required to

perform the GST and report the results

to FDA. FDA estimates that annually it

will receive approximately 10 requests

for administrative exemption from the

GST under 21 CFR 610.11(g)(2). FDA

estimates that 40 hours will be required

for an applicant to complete and submit

the appropriate information for the

exemption request. Since that

information is ordinarily compiled and

organized by the manufacturer while

performing the GST, FDA anticipates

that the additional time needed to

submit an exemption request will be

minimal.

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

610.11(g)(2) 10 1 10 40 400

Total 10 1 10 40 400

1There are no capital costs or operating and maintenance costs associated with this collection of information.

For consistency with the direct final

rule to which this proposed rule is a

companion, FDA is following the PRA

comment procedures for direct final

rules in this proposed rule. As provided

in 5 CFR 1320.5(c)(1), collection of

information in a direct final is subject to

the procedures set forth in 5 CFR

1320.10. Interested persons and

organizations may submit comments on

the information collection requirements

of this direct final rule by June 19, 1998

to the Dockets Management Branch

(address above).

At the close of the 60-day comment

period, FDA will review the comments

received, revise the information

collection provisions as necessary, and

submit these provisions to OMB for

review. FDA will publish a notice in the

Federal Register when the information

collection provisions are submitted to

OMB, and an opportunity for public

comment to OMB will be provided at

that time. Prior to the effective date of

the direct final rule, FDA will publish

a notice in the Federal Register of

OMB’s decision to approve, modify, or

disapprove the information collection

provisions. An agency may not conduct

or sponsor, and a person is not required

to respond to, a collection of

information unless it displays a

currently valid OMB control number.

V. Request for Comments

Interested persons may, on or before

July 6, 1998, submit to the Docket

Management Branch (address above)

written comments regarding this

proposal. This comment period runs

concurrently with the comment period

for the direct final rule. 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. All

comments received will be considered

as comments regarding this companion

proposed rule and the direct final rule.

In the event the direct final rule is

withdrawn, all comments received

regarding the direct final rule and this

companion proposed rule, will be

considered under this proposed rule.

List of Subjects in 21 CFR Part 610

Biologics, Labeling, Reporting and

recordkeeping requirements.

Therefore under the Federal Food,

Drug, and Cosmetic Act, the Public

Health Service Act, and the authority

delegated by the Commissioner of Food

and Drugs, 21 CFR part 610 is amended

as follows:

PART 610—GENERAL BIOLOGICAL

PRODUCTS STANDARDS

1. The authority citation for 21 CFR

part 610 continues to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353,

355, 360, 371; 42 U.S.C. 216, 262, 263, 263a,

264.

2. Section 610.11 is amended by

revising paragraph (g) to read as follows:

§ 610.11 General safety.

* * * * *

(g) Exceptions—(1) The test

prescribed in this section need not be

performed for Whole Blood, Red Blood

Cells, Cryoprecipitated AHF, Platelets,

Plasma or Cellular Therapy Products.

(2) For products other than those

identified in paragraph (g)(1) of this

section, a manufacturer may request

from the Director, CBER, an exemption

from the general safety test. The

manufacturer shall submit information

as part of a license application

submission or supplement to an

approved license application

establishing that because of the mode of

administration, the method of

preparation, or the special nature of the

product a test of general safety is

unnecessary to assure the safety, purity,

and potency of the product or cannot be

performed. The request shall include

any alternate procedures, if any, to be

performed. The Director, CBER, upon

finding that the manufacturer’s request

justifies an exemption, may exempt the

product from the general safety test

subject to any condition necessary to

assure the safety, purity, and potency of

the product.

Dated: April 10, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98–10313 Filed 4–17–98; 8:45 am]

BILLING CODE 4160–01–F