[Federal Register Volume 61, Number 19 (Monday, January 29, 1996)]
[Proposed Rules]
[Pages 2739-2748]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1580]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
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.
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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 well-
characterized 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
Sec. 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 Sec. 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,
[[Page 2740]]
communicated FDA's interpretation of Sec. 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 Sec. 600.3 (21 CFR 600.3) and
Sec. 601.12 to permit more substantial report reduction as the second
step in the President's reinvention initiative. FDA is also proposing
to add Sec. 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 well-characterized 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 Sec. 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 Sec. 601.12, FDA is proposing
to amend Sec. 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, Sec.
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 Sec. 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 biotechnology-
derived products within CBER and CDER, conforming amendments to
Sec. 314.70 are also being proposed. Specifically, FDA is proposing an
exception in Sec. 314.70(g) for well-characterized biotechnology
products that provides that manufacturing changes to these products
would be handled as described in proposed Sec. 601.12(b), (c), and (d)
with regard to preapproval, notification, and submission in annual
reports instead of as described in Sec. 314.70 (a), (b), (c), and (d).
However, labeling changes would not be affected by the proposed change.
3. Summary of Proposed Sec. 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 Sec. 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 Sec. 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 Secs. 314.70 and 814.39 (21 CFR
[[Page 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 three-category 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
Sec. 314.70(g) for well-characterized 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 Sec. 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 well-characterized 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 Sec. 314.81(b)(2). FDA requests comment on whether
the annual report for a biological product licensed under the
[[Page 2742]]
PHS act should include the information described in Sec. 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
Sec. 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 Sec. 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 Sec. 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
Sec. 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
Sec. 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
[[Page 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
Secs. 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 Sec. 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 Sec. 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
Sec. 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 Sec. 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
[[Page 2744]]
labeling changes. The regulations in Sec. 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 Sec. 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 Sec. 601.12(e) would significantly decrease the
number of labeling submissions that currently require approval prior to
use of the labeling.
Under proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 601.12(f) that in
the event of repeated failure of the applicant to comply with
Sec. 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 Sec. 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 Sec. 601.12(g) provides that an
applicant may request a review of FDA employee decisions made pursuant
to section Sec. 601.12 in accordance with Sec. 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 Sec. 10.75 in
Sec. 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
[[Page 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
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Number of Number of Responses Per
Regulation (21 CFR) Respondents Hours Per Response Responses Respondent Total Operating and Maintenance Costs Total 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
[[Page 2746]]
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:
Sec. 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
Sec. 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
[[Page 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:
Sec. 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:
Sec. 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
[[Page 2748]]
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 Sec. 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 Sec. 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
