[Code of Federal Regulations]

[Title 21, Volume 7]

[Revised as of April 1, 2019]
[CITE: 21CFR601]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER F--BIOLOGICS
  PART 601 LICENSING  

Subpart A--General Provisions

Sec. 601.2 Applications for biologics licenses; procedures for filing.

(a) General. To obtain a biologics license under section 351 of the Public

Health Service Act for any biological product, the manufacturer shall submit
an application to the Director, Center for Biologics Evaluation and Research
or the Director, Center for Drug Evaluation and Research (see mailing
addresses in 600.2(a) or (b) of this chapter), on forms prescribed for such
purposes, and shall submit data derived from nonclinical laboratory and
clinical studies which demonstrate that the manufactured product meets
prescribed requirements of safety, purity, and potency; with respect to each
nonclinical laboratory study, either a statement that the study was
conducted in compliance with the requirements set forth in part 58 of this
chapter, or, if the study was not conducted in compliance with such
regulations, a brief statement of the reason for the noncompliance;
statements regarding each clinical investigation involving human subjects
contained in the application, that it either was conducted in compliance
with the requirements for institutional review set forth in part 56 of this
chapter; or was not subject to such requirements in accordance with 56.104
or 56.105, and was conducted in compliance with requirements for informed
consent set forth in part 50 of this chapter. A full description of
manufacturing methods; data establishing stability of the product through
the dating period; sample(s) representative of the product for introduction
or delivery for introduction into interstate commerce; summaries of results
of tests performed on the lot(s) represented by the submitted sample(s);
specimens of the labels, enclosures, and containers, and if applicable, any
Medication Guide required under part 208 of this chapter proposed to be used
for the product; and the address of each location involved in the
manufacture of the biological product shall be listed in the biologics
license application. The applicant shall also include a financial
certification or disclosure statement(s) or both for clinical investigators
as required by part 54 of this chapter. An application for a biologics
license shall not be considered as filed until all pertinent information and
data have been received by the Food and Drug Administration. The applicant
shall also include either a claim for categorical exclusion under 25.30 or
25.31 of this chapter or an environmental assessment under 25.40 of this
chapter. The applicant, or the applicant's attorney, agent, or other
authorized official shall sign the application. An application for any of
the following specified categories of biological products subject to
licensure shall be handled as set forth in paragraph (c) of this section:
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
(b) [Reserved]
(c)(1) To obtain marketing approval for a biological product subject to
licensure which is a therapeutic DNA plasmid product, therapeutic synthetic
peptide product of 40 or fewer amino acids, monoclonal antibody product for
in vivo use, or therapeutic recombinant DNA-derived product, an applicant
shall submit a biologics license application in accordance with paragraph
(a) of this section except that the following sections in parts 600 through
680 of this chapter shall not be applicable to such products: 600.10(b) and
(c), 600.11, 600.12, 600.13, 610.53, and 610.62 of this chapter.
(2) To the extent that the requirements in this paragraph (c) conflict with
other requirements in this subchapter, this paragraph (c) shall supersede
other requirements.
(d) Approval of a biologics license application or issuance of a biologics
license shall constitute a determination that the establishment(s) and the
product meet applicable requirements to ensure the continued safety, purity,
and potency of such products. Applicable requirements for the maintenance of
establishments for the manufacture of a product subject to this section
shall include but not be limited to the good manufacturing practice
requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter.
(e) Any establishment and product license for a biological product issued
under section 351 of the Public Health Service Act (42 U.S.C. 201 et seq. )
that has not been revoked or suspended as of December 20, 1999, shall
constitute an approved biologics license application in effect under the
same terms and conditions set forth in such product license and such
portions of the establishment license relating to such product.
(f) Withdrawal from sale of approved biological products. A holder of a
biologics license application (BLA) must report to FDA, in accordance with
the requirements of 207.61 and 207.65, the withdrawal from sale of an
approved biological product. The information must be submitted to FDA within
30 working days of the biological product's withdrawal from sale. The
following information must be submitted: The holder's name; product name;
BLA number; the National Drug Code; and the date on which the product is
expected to be no longer in commercial distribution. The reason for the
withdrawal of the biological product is requested but not required to be
submitted.
[64 FR 56450, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005; 80 FR
18092, Apr. 3, 2015; 80 FR 37974, July 2, 2015; 81 FR 60221, Aug. 31, 2016]

Sec. 601.3 Complete response letter to the applicant.

(a) Complete response letter. The Food and Drug Administration will send the
biologics license applicant or supplement applicant a complete response
letter if the agency determines that it will not approve the biologics
license application or supplement in its present form.
(1) Description of specific deficiencies. A complete response letter will
describe all of the deficiencies that the agency has identified in a
biologics license application or supplement, except as stated in paragraph
(a)(2) of this section.
(2) Inadequate data. If FDA determines, after a biologics license
application or supplement is filed, that the data submitted are inadequate
to support approval, the agency might issue a complete response letter
without first conducting required inspections, testing submitted product
lots, and/or reviewing proposed product labeling.
(3) Recommendation of actions for approval. When possible, a complete
response letter will recommend actions that the applicant might take to
place its biologics license application or supplement in condition for
approval.
(b) Applicant actions. After receiving a complete response letter, the
biologics license applicant or supplement applicant must take either of the
following actions:
(1) Resubmission. Resubmit the application or supplement, addressing all
deficiencies identified in the complete response letter.
(2) Withdrawal. Withdraw the application or supplement. A decision to
withdraw the application or supplement is without prejudice to a subsequent
submission.
(c) Failure to take action. (1) FDA may consider a biologics license
applicant or supplement applicant's failure to either resubmit or withdraw
the application or supplement within 1 year after issuance of a complete
response letter to be a request by the applicant to withdraw the application
or supplement, unless the applicant has requested an extension of time in
which to resubmit the application or supplement. FDA will grant any
reasonable request for such an extension. FDA may consider an applicant's
failure to resubmit the application or supplement within the extended time
period or request an additional extension to be a request by the applicant
to withdraw the application.
(2) If FDA considers an applicant's failure to take action in accordance
with paragraph (c)(1) of this section to be a request to withdraw the
application, the agency will notify the applicant in writing. The applicant
will have 30 days from the date of the notification to explain why the
application or supplement should not be withdrawn and to request an
extension of time in which to resubmit the application or supplement. FDA
will grant any reasonable request for an extension. If the applicant does
not respond to the notification within 30 days, the application or
supplement will be deemed to be withdrawn.
[73 FR 39611, July 10, 2008]

Sec. 601.4 Issuance and denial of license.

(a) A biologics license shall be issued upon a determination by the

Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research that the establishment(s) and the
product meet the applicable requirements established in this chapter. A
biologics license shall be valid until suspended or revoked.
(b) If the Commissioner determines that the establishment or product does
not meet the requirements established in this chapter, the biologics license
application shall be denied and the applicant shall be informed of the
grounds for, and of an opportunity for a hearing on, the decision. If the
applicant so requests, the Commissioner shall issue a notice of opportunity
for hearing on the matter pursuant to 12.21(b) of this chapter.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR
19142, Apr. 12, 1977; 64 FR 56450, Oct. 20, 1999; 70 FR 14983, Mar. 24,
2005]

Sec. 601.5 Revocation of license.

(a) A biologics license shall be revoked upon application of the

manufacturer giving notice of intention to discontinue the manufacture of
all products manufactured under such license or to discontinue the
manufacture of a particular product for which a license is held and waiving
an opportunity for a hearing on the matter.
(b)(1) The Commissioner shall notify the licensed manufacturer of the
intention to revoke the biologics license, setting forth the grounds for,
and offering an opportunity for a hearing on the proposed revocation if the
Commissioner finds any of the following:
(i) Authorized Food and Drug Administration employees after reasonable
efforts have been unable to gain access to an establishment or a location
for the purpose of carrying out the inspection required under 600.21 of this
chapter,
(ii) Manufacturing of products or of a product has been discontinued to an
extent that a meaningful inspection or evaluation cannot be made,
(iii) The manufacturer has failed to report a change as required by 601.12
of this chapter,
(iv) The establishment or any location thereof, or the product for which the
license has been issued, fails to conform to the applicable standards
established in the license and in this chapter designed to ensure the
continued safety, purity, and potency of the manufactured product,
(v) The establishment or the manufacturing methods have been so changed as
to require a new showing that the establishment or product meets the
requirements established in this chapter in order to protect the public
health, or
(vi) The licensed product is not safe and effective for all of its intended
uses or is misbranded with respect to any such use.
(2) Except as provided in 601.6 of this chapter, or in cases involving
willfulness, the notification required in this paragraph shall provide a
reasonable period for the licensed manufacturer to demonstrate or achieve
compliance with the requirements of this chapter, before proceedings will be
instituted for the revocation of the license. If compliance is not
demonstrated or achieved and the licensed manufacturer does not waive the
opportunity for a hearing, the Commissioner shall issue a notice of
opportunity for hearing on the matter under 12.21(b) of this chapter.
[64 FR 56451, Oct. 20, 1999]

Sec. 601.6 Suspension of license.

(a) Whenever the Commissioner has reasonable grounds to believe that any of
the grounds for revocation of a license exist and that by reason thereof
there is a danger to health, the Commissioner may notify the licensed
manufacturer that the biologics license is suspended and require that the
licensed manufacturer do the following:
(1) Notify the selling agents and distributors to whom such product or
products have been delivered of such suspension, and
(2) Furnish to the Center for Biologics Evaluation and Research or the
Center for Drug Evaluation and Research, complete records of such deliveries
and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either:
(1) Proceed under the provisions of 601.5(b) of this chapter to revoke the
license, or
(2) If the licensed manufacturer agrees, hold revocation in abeyance pending
resolution of the matters involved.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

Sec. 601.7 Procedure for hearings.

(a) A notice of opportunity for hearing, notice of appearance and request

for hearing, and grant or denial of hearing for a biological drug pursuant
to this part, for which the exemption from the Federal Food, Drug, and
Cosmetic Act in 310.4 of this chapter has been revoked, shall be subject to
the provisions of 314.200 of this chapter except to the extent that the
notice of opportunity for hearing on the matter issued pursuant to 12.21(b)
of this chapter specifically provides otherwise.
(b) Hearings pursuant to 601.4 through 601.6 shall be governed by part 12 of
this chapter.
(c) When a license has been suspended pursuant to 601.6 and a hearing
request has been granted, the hearing shall proceed on an expedited basis.
[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR
19143, Apr. 12, 1977]

Sec. 601.8 Publication of revocation.

The Commissioner, following revocation of a biologics license under 21 CFR

601.5(b), will publish a notice in the Federal Register with a statement of
the specific grounds for the revocation.
[74 FR 20585, May 5, 2009]

Sec. 601.9 Licenses; reissuance.

(a) Compliance with requirements. A biologics license, previously suspended

or revoked, may be reissued or reinstated upon a showing of compliance with
requirements and upon such inspection and examination as may be considered
necessary by the Director, Center for Biologics Evaluation and Research or
the Director, Center for Drug Evaluation and Research.
(b) Exclusion of noncomplying location. A biologics license, excluding a
location or locations that fail to comply with the requirements in this
chapter, may be issued without further application and concurrently with the
suspension or revocation of the license for noncompliance at the excluded
location or locations.
(c) Exclusion of noncomplying product(s). In the case of multiple products
included under a single biologics license application, a biologics license
may be issued, excluding the noncompliant product(s), without further
application and concurrently with the suspension or revocation of the
biologics license for a noncompliant product(s).
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

Subpart B [Reserved]

Subpart C--Biologics Licensing

Sec. 601.12 Changes to an approved application.

(a) General. (1) As provided by this section, an applicant must inform the

Food and Drug Administration (FDA) (see mailing addresses in 600.2 of this
chapter) about each change in the product, production process, quality
controls, equipment, facilities, responsible personnel, or labeling
established in the approved license application(s).
(2) Before distributing a product made using a change, an applicant must
assess the effects of the change and demonstrate through appropriate
validation and/or other clinical and/or nonclinical laboratory studies the
lack of adverse effect of the change on the identity, strength, quality,
purity, or potency of the product as they may relate to the safety or
effectiveness of the product.
(3) Notwithstanding the requirements of paragraphs (b), (c), and (f) of this
section, an applicant must make a change provided for in those paragraphs in
accordance with a regulation or guidance that provides for a less burdensome
notification of the change (for example, by submission of a supplement that
does not require approval prior to distribution of the product or in an
annual report).
(4) The applicant must promptly revise all promotional labeling and
advertising to make it consistent with any labeling change implemented in
accordance with paragraphs (f)(1) and (f)(2) of this section.
(5) A supplement or annual report must include a list of all changes
contained in the supplement or annual report. For supplements, this list
must be provided in the cover letter.
(b) Changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes). (1) A
supplement shall be submitted for any change in the product, production
process, quality controls, equipment, facilities, or responsible personnel
that has a substantial potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they may relate to
the safety or effectiveness of the product.
(2) These changes include, but are not limited to:
(i) Except as provided in paragraphs (c) and (d) of this section, changes in
the qualitative or quantitative formulation, including inactive ingredients,
or in the specifications provided in the approved application;
(ii) Changes requiring completion of an appropriate human study to
demonstrate the equivalence of the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness of
the product;
(iii) Changes in the virus or adventitious agent removal or inactivation
method(s);
(iv) Changes in the source material or cell line;
(v) Establishment of a new master cell bank or seed; and
(vi) Changes which may affect product sterility assurance, such as changes
in product or component sterilization method(s), or an addition, deletion,
or substitution of steps in an aseptic processing operation.
(3) The applicant must obtain approval of the supplement from FDA prior to
distribution of the product made using the change. Except for submissions
under paragraph (e) of this section, the following 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 identity, strength, quality, purity, or potency
of the product as they may relate to the safety or effectiveness of the
product;
(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).
(4) An applicant may ask FDA to expedite its review of a supplement for
public health reasons or if a delay in making the change described in it
would impose an extraordinary hardship on the applicant. Such a supplement
and its mailing cover should be plainly marked: "Prior Approval Supplement-
Expedited Review Requested.
(c) Changes requiring supplement submission at least 30 days prior to
distribution of the product made using the change. (1) A supplement shall be
submitted for any change in the product, production process, quality
controls, equipment, facilities, or responsible personnel that has a
moderate potential to have an adverse effect on the identity, strength,
quality, purity, or potency of the product as they may relate to the safety
or effectiveness of the product. The supplement shall be labeled
"Supplement--Changes Being Effected in 30 Days" or, if applicable under
paragraph (c)(5) of this section, "Supplement--Changes Being Effected."
(2) These changes include, but are not limited to:
(i) [Reserved]
(ii) An increase or decrease in production scale during finishing steps that
involves different equipment; and
(iii) Replacement of equipment with that of similar, but not identical,
design and operating principle that does not affect the process methodology
or process operating parameters.
(iv) Relaxation of an acceptance criterion or deletion of a test to comply
with an official compendium that is consistent with FDA statutory and
regulatory requirements.
(3) Pending approval of the supplement by FDA, and except as provided in
paragraph (c)(5) of this section, distribution of the product made using the
change may begin not less than 30 days after receipt of the supplement by
FDA. The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of
this section shall be contained in the supplement.
(4) If within 30 days following FDA's receipt of the supplement, FDA informs
the applicant that either:
(i) The change requires approval prior to distribution of the product in
accordance with paragraph (b) of this section; or
(ii) Any of the information required under paragraph (c)(3) of this section
is missing; the applicant shall not distribute the product made using the
change until FDA determines that compliance with this section is achieved.
(5) In certain circumstances, FDA may determine that, based on experience
with a particular type of change, the supplement for such change is usually
complete and provides the proper information, and on particular assurances
that the proposed change has been appropriately submitted, the product made
using the change may be distributed immediately upon receipt of the
supplement by FDA. These circumstances may include substantial similarity
with a type of change regularly involving a "Supplement--Changes Being
Effected" supplement or a situation in which the applicant presents evidence
that the proposed change has been validated in accordance with an approved
protocol for such change under paragraph (e) of this section.
(6) If the agency disapproves the supplemental application, it may order the
manufacturer to cease distribution of the products made with the
manufacturing change.
(d) Changes to be described in an annual report (minor changes). (1) Changes
in the product, production process, quality controls, equipment, facilities,
or responsible personnel that have a minimal potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the product
as they may relate to the safety or effectiveness of the product 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
Director, Center for Biologics Evaluation and Research or the Director,
Center for Drug Evaluation and Research, may approve a written request for
an alternative date to combine annual reports for multiple approved
applications into a single annual report submission.
(2) These changes include, but are not limited to:
(i) Any change made to comply with a change to an official compendium,
except a change described in paragraph (c)(2)(iv) of this section, that is
consistent with FDA statutory and regulatory requirements.
(ii) The deletion or reduction of an ingredient intended only to affect the
color of the product, except that a change intended only to affect Blood
Grouping Reagents requires supplement submission and approval prior to
distribution of the product made using the change in accordance with the
requirements set forth in paragraph (b) of this section;
(iii) An extension of an expiration dating period based upon full shelf life
data on production batches obtained from a protocol approved in the
application;
(iv) A change within the container closure system for a nonsterile product,
based upon a showing of equivalency to the approved system under a protocol
approved in the application or published in an official compendium;
(v) A change in the size and/or shape of a container containing the same
number of dosage units for a nonsterile solid dosage form product, without a
change from one container closure system to another;
(vi) The addition by embossing, debossing, or engraving of a code imprint to
a solid dosage form biological product other than a modified release dosage
form, or a minor change in an existing code imprint; and
(vii) The addition or revision of an alternative analytical procedure that
provides the same or increased assurance of the identity, strength, quality,
purity, or potency of the material being tested as the analytical procedure
described in the approved application, or deletion of an alternative
analytical procedure.
(3) The following information for each change shall be contained in the
annual report:
(i) A list of all products involved; and
(ii) A full description of the manufacturing and controls changes including:
the manufacturing site(s) or area(s) involved; the date the change was made;
a cross-reference to relevant validation protocols and/or SOP's; and
relevant data from studies and tests performed to evaluate the effect of the
change on the identity, strength, quality, purity, or potency of the product
as they may relate to the safety or effectiveness of the product.
(iii) A statement by the holder of the approved application or license that
the effects of the change have been assessed.
(4) 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 paragraph for each change made during the annual
reporting interval which ends on the anniversary date in the order in which
they were implemented.
(e) An applicant may submit one or more protocols describing the specific
tests and validation studies and acceptable limits to be achieved to
demonstrate the lack of adverse effect for specified types of manufacturing
changes on the identity, strength, quality, purity, or potency of the
product as they may relate to the safety or effectiveness of the product.
Any such protocols, or change to a protocol, shall be submitted as a
supplement requiring approval from FDA prior to distribution of the product
which, if approved, may justify a reduced reporting category for the
particular change because the use of the protocol for that type of change
reduces the potential risk of an adverse effect.
(f) Labeling changes. (1) Labeling changes requiring supplement submission--
FDA approval must be obtained before distribution of the product with the
labeling change. Except as described in paragraphs (f)(2) and (f)(3) of this
section, an applicant shall submit a supplement describing a proposed change
in the package insert, package label, container label, or, if applicable, a
Medication Guide required under part 208 of this chapter, and include the
information necessary to support the proposed change. An applicant cannot
use paragraph (f)(2) of this section to make any change to the information
required in 201.57(a) of this chapter. An applicant may report the minor
changes to the information specified in paragraph (f)(3)(i)(D) of this
section in an annual report. The supplement shall clearly highlight the
proposed change in the labeling. The applicant shall obtain approval from
FDA prior to distribution of the product with the labeling change.
(2) Labeling changes requiring supplement submission--product with a
labeling change that may be distributed before FDA approval. (i) An
applicant shall submit, at the time such change is made, a supplement for
any change in the package insert, package label, or container label to
reflect newly acquired information, except for changes to the package insert
required in 201.57(a) of this chapter (which must be made under paragraph
(f)(1) of this section), to accomplish any of the following:
(A) To add or strengthen a contraindication, warning, precaution, or adverse
reaction for which the evidence of a causal association satisfies the
standard for inclusion in the labeling under 201.57(c) of this chapter;
(B) To add or strengthen a statement about abuse, dependence, psychological
effect, or overdosage;
(C) To add or strengthen an instruction about dosage and administration that
is intended to increase the safety of the use of the product; and
(D) To delete false, misleading, or unsupported indications for use or
claims for effectiveness.
(E) Any labeling change normally requiring a supplement submission and
approval prior to distribution of the product that FDA specifically requests
be submitted under this provision.
(ii) Pending approval of the supplement by FDA, 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 shall be plainly marked: "Special
Labeling Supplement--Changes Being Effected."
(3) Labeling changes requiring submission in an annual report. (i) An
applicant shall submit any final printed package insert, package label,
container label, or Medication Guide required under part 208 of this chapter
incorporating the following changes in an annual report submitted to FDA
each year as provided in paragraph (d)(1) of this section:
(A) Editorial or similar minor changes;
(B) A change in the information on how the product is supplied that does not
involve a change in the dosage strength or dosage form;
(C) A change in the information specified in 208.20(b)(8)(iii) and (b)(8)
(iv) of this chapter for a Medication Guide; and
(D) A change to the information required in 201.57(a) of this chapter as
follows:
(1 ) Removal of a listed section(s) specified in 201.57(a)(5) of this
chapter; and
(2 ) Changes to the most recent revision date of the labeling as specified
in 201.57(a)(15) of this chapter.
(E) A change made pursuant to an exception or alternative granted under
201.26 or 610.68 of this chapter.
(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 to the Center for Biologics Evaluation and
Research or Center for Drug Evaluation and Research in accordance with the
requirements set forth in 314.81(b)(3)(i) of this chapter.
(5) The submission and grant of a written request for an exception or
alternative under 201.26 or 610.68 of this chapter satisfies the
requirements in paragraphs (f)(1) through (f)(2) of this section.
(6) For purposes of paragraph (f)(2) of this section, information will be
considered newly acquired if it consists of data, analyses, or other
information not previously submitted to the agency, which may include (but
are not limited to) data derived from new clinical studies, reports of
adverse events, or new analyses of previously submitted data (e.g., meta-
analyses) if the studies, events or analyses reveal risks of a different
type or greater severity or frequency than previously included in
submissions to FDA.
(g) 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, FDA may require that the applicant submit a supplement
for any proposed change and obtain approval of the supplement by FDA prior
to distribution of the product made using the change.
(h) Administrative review. Under 10.75 of this chapter, an applicant may
request internal FDA review of FDA employee decisions under this section.
[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998.
Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766, Apr.
8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72 FR 73600,
Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008; 73 FR 68333, Nov. 18, 2008; 80 FR
18092, Apr. 3, 2015]

Sec. 601.14 Regulatory submissions in electronic format.

(a) General. Electronic format submissions must be in a form that FDA can

process, review, and archive. FDA will periodically issue guidance on how to
provide the electronic submission (e.g., method of transmission, media, file
formats, preparation and organization of files.)
(b) Labeling. The content of labeling required under 201.100(d)(3) of this
chapter (commonly referred to as the package insert or professional
labeling), including all text, tables, and figures, must be submitted to the
agency in electronic format as described in paragraph (a) of this section.
This requirement is in addition to the provisions of 601.2(a) and 601.12(f)
that require applicants to submit specimens of the labels, enclosures, and
containers, or to submit other final printed labeling. Submissions under
this paragraph must be made in accordance with part 11 of this chapter
except for the requirements of 11.10(a), (c) through (h), and (k), and the
corresponding requirements of 11.30.
[68 FR 69020, Dec. 11, 2003]

Sec. 601.15 Foreign establishments and products: samples for each

importation.

Random samples of each importation, obtained by the District Director of

Customs and forwarded to the Director, Center for Biologics Evaluation and
Research or the Director, Center for Drug Evaluation and Research (see
mailing addresses in 600.2(c) of this chapter) must be at least two final
containers of each lot of product. A copy of the associated documents which
describe and identify the shipment must accompany the shipment for
forwarding with the samples to the Director, Center for Biologics Evaluation
and Research or the Director, Center for Drug Evaluation and Research (see
mailing addresses in 600.2(c)). For shipments of 20 or less final
containers, samples need not be forwarded, provided a copy of an official
release from the Center for Biologics Evaluation and Research or Center for
Drug Evaluation and Research accompanies each shipment.
[70 FR 14983, Mar. 24, 2005, as amended at 80 FR 18092, Apr. 3, 2015]

Sec. 601.20 Biologics licenses; issuance and conditions.

(a) Examination--compliance with requirements. A biologics license

application shall be approved only upon examination of the product and upon
a determination that the product complies with the standards established in
the biologics license application and the requirements prescribed in the
regulations in this chapter including but not limited to the good
manufacturing practice requirements set forth in parts 210, 211, 600, 606,
and 820 of this chapter.
(b) Availability of product. No biologics license shall be issued unless:
(1) The product intended for introduction into interstate commerce is
available for examination, and
(2) Such product is available for inspection during all phases of
manufacture.
(c) Manufacturing process--impairment of assurances. No product shall be
licensed if any part of the process of or relating to the manufacture of
such product, in the judgment of the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research, would impair the assurances of continued safety, purity, and
potency as provided by the regulations contained in this chapter.
(d) Inspection--compliance with requirements. A biologics license shall be
issued or a biologics license application approved only after inspection of
the establishment(s) listed in the biologics license application and upon a
determination that the establishment(s) complies with the standards
established in the biologics license application and the requirements
prescribed in applicable regulations.
(e) One biologics license to cover all locations. One biologics license
shall be issued to cover all locations meeting the establishment standards
identified in the approved biologics license application and each location
shall be subject to inspection by FDA officials.
[64 FR 56451, Oct. 20, 1999, as amended at 70 FR 14983, Mar. 24, 2005]

Sec. 601.21 Products under development.

A biological product undergoing development, but not yet ready for a

biologics license, may be shipped or otherwise delivered from one State or
possession into another State or possession provided such shipment or
delivery is not for introduction or delivery for introduction into
interstate commerce, except as provided in sections 505(i) and 520(g) of the
Federal Food, Drug, and Cosmetic Act, as amended, and the regulations
thereunder (21 CFR parts 312 and 812).
[64 FR 56451, Oct. 20, 1999]

Sec. 601.22 Products in short supply; initial manufacturing at other than

licensed location.
A biologics license issued to a manufacturer and covering all locations of
manufacture shall authorize persons other than such manufacturer to conduct
at places other than such locations the initial, and partial manufacturing
of a product for shipment solely to such manufacturer only to the extent
that the names of such persons and places are registered with the
Commissioner of Food and Drugs and it is found upon application of such
manufacturer, that the product is in short supply due either to the peculiar
growth requirements of the organism involved or to the scarcity of the
animal required for manufacturing purposes, and such manufacturer has
established with respect to such persons and places such procedures,
inspections, tests or other arrangements as will ensure full compliance with
the applicable regulations of this subchapter related to continued safety,
purity, and potency. Such persons and places shall be subject to all
regulations of this subchapter except 601.2 to 601.6, 601.9, 601.10, 601.20,
601.21 to 601.33, and 610.60 to 610.65 of this chapter. For persons and
places authorized under this section to conduct the initial and partial
manufacturing of a product for shipment solely to a manufacturer of a
product subject to licensure under 601.2(c), the following additional
regulations shall not be applicable: 600.10(b) and (c), 600.11, 600.12,
600.13, and 610.53 of this chapter. Failure of such manufacturer to maintain
such procedures, inspections, tests, or other arrangements, or failure of
any person conducting such partial manufacturing to comply with applicable
regulations shall constitute a ground for suspension or revocation of the
authority conferred pursuant to this section on the same basis as provided
in 601.6 to 601.8 with respect to the suspension and the revocation of
licenses.
[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996; 64 FR
56452, Oct. 20, 1999; 80 FR 37974, July 2, 2015]

Sec. 601.27 Pediatric studies.

(a) Required assessment. Except as provided in paragraphs (b), (c), and (d)

of this section, each application for a new active ingredient, new
indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the safety and
effectiveness of the product for the claimed indications in all relevant
pediatric subpopulations, and to support dosing and administration for each
pediatric subpopulation for which the product is safe and effective. Where
the course of the disease and the effects of the product are similar in
adults and pediatric patients, FDA may conclude that pediatric effectiveness
can be extrapolated from adequate and well-controlled effectiveness studies
in adults, usually supplemented with other information in pediatric
patients, such as pharmacokinetic studies. In addition, studies may not be
needed in each pediatric age group, if data from one age group can be
extrapolated to another. Assessments required under this section for a
product that represents a meaningful therapeutic benefit over existing
treatments must be carried out using appropriate formulations for the age
group(s) for which the assessment is required.
(b) Deferred submission. (1) FDA may, on its own initiative or at the
request of an applicant, defer submission of some or all assessments of
safety and effectiveness described in paragraph (a) of this section until
after licensing of the product for use in adults. Deferral may be granted
if, among other reasons, the product is ready for approval in adults before
studies in pediatric patients are complete, pediatric studies should be
delayed until additional safety or effectiveness data have been collected.
If an applicant requests deferred submission, the request must provide an
adequate justification for delaying pediatric studies, a description of the
planned or ongoing studies, and evidence that the studies are being or will
be conducted with due diligence and at the earliest possible time.
(2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety and
effectiveness, the product may be licensed for use in adults subject to the
requirement that the applicant submit the required assessments within a
specified time.
(c) Waivers --(1) General. FDA may grant a full or partial waiver of the
requirements of paragraph (a) of this section on its own initiative or at
the request of an applicant. A request for a waiver must provide an adequate
justification.
(2) Full waiver. An applicant may request a waiver of the requirements of
paragraph (a) of this section if the applicant certifies that:
(i) The product does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients and is not likely to be used in a
substantial number of pediatric patients;
(ii) Necessary studies are impossible or highly impractical because, e.g.,
the number of such patients is so small or geographically dispersed; or
(iii) There is evidence strongly suggesting that the product would be
ineffective or unsafe in all pediatric age groups.
(3) Partial waiver. An applicant may request a waiver of the requirements of
paragraph (a) of this section with respect to a specified pediatric age
group, if the applicant certifies that:
(i) The product does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients in that age group, and is not
likely to be used in a substantial number of patients in that age group;
(ii) Necessary studies are impossible or highly impractical because, e.g.,
the number of patients in that age group is so small or geographically
dispersed;
(iii) There is evidence strongly suggesting that the product would be
ineffective or unsafe in that age group; or
(iv) The applicant can demonstrate that reasonable attempts to produce a
pediatric formulation necessary for that age group have failed.
(4) FDA action on waiver. FDA shall grant a full or partial waiver, as
appropriate, if the agency finds that there is a reasonable basis on which
to conclude that one or more of the grounds for waiver specified in
paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is
granted on the ground that it is not possible to develop a pediatric
formulation, the waiver will cover only those pediatric age groups requiring
that formulation. If a waiver is granted because there is evidence that the
product would be ineffective or unsafe in pediatric populations, this
information will be included in the product's labeling.
(5) Definition of "meaningful therapeutic benefit". For purposes of this
section, a product will be considered to offer a meaningful therapeutic
benefit over existing therapies if FDA estimates that:
(i) If approved, the product would represent a significant improvement in
the treatment, diagnosis, or prevention of a disease, compared to marketed
products adequately labeled for that use in the relevant pediatric
population. Examples of how improvement might be demonstrated include, e.g.,
evidence of increased effectiveness in treatment, prevention, or diagnosis
of disease; elimination or substantial reduction of a treatment-limiting
drug reaction; documented enhancement of compliance; or evidence of safety
and effectiveness in a new subpopulation; or
(ii) The product is in a class of products or for an indication for which
there is a need for additional therapeutic options.
(d) Exemption for orphan drugs. This section does not apply to any product
for an indication or indications for which orphan designation has been
granted under part 316, subpart C, of this chapter.
[63 FR 66671, Dec. 2, 1998]

Sec. 601.28 Annual reports of postmarketing pediatric studies.

Sponsors of licensed biological products shall submit the following

information each year within 60 days of the anniversary date of approval of
each product under the license to the Director, Center for Biologics
Evaluation and Research or the Director, Center for Drug Evaluation and
Research (see mailing addresses in 600.2(a) or (b) of this chapter):
(a) Summary. A brief summary stating whether labeling supplements for
pediatric use have been submitted and whether new studies in the pediatric
population to support appropriate labeling for the pediatric population have
been initiated. Where possible, an estimate of patient exposure to the drug
product, with special reference to the pediatric population (neonates,
infants, children, and adolescents) shall be provided, including dosage
form.
(b) Clinical data. Analysis of available safety and efficacy data in the
pediatric population and changes proposed in the labeling based on this
information. An assessment of data needed to ensure appropriate labeling for
the pediatric population shall be included.
(c) Status reports. A statement on the current status of any postmarketing
studies in the pediatric population performed by, or on behalf of, the
applicant. The statement shall include whether postmarketing clinical
studies in pediatric populations were required or agreed to, and, if so, the
status of these studies shall be reported to FDA in annual progress reports
of postmarketing studies under 601.70 rather than under this section.
[65 FR 59718, Oct. 6, 2000, as amended at 65 FR 64618, Oct. 30, 2000; 70 FR
14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, 2015]

Sec. 601.29 Guidance documents.

(a) FDA has made available guidance documents under 10.115 of this chapter
to help you comply with certain requirements of this part.
(b) The Center for Biologics Evaluation and Research (CBER) maintains a list
of guidance documents that apply to the center's regulations. The lists are
maintained on the Internet and are published annually in the Federal
Register. You may request a copy of the CBER list from the Food and Drug
Administration, Center for Biologics Evaluation and Research, Office of
Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg. 71,
Rm. 3103, Silver Spring, MD 20993-0002.
[65 FR 56480, Sept. 19, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80
FR 18092, Apr. 3, 2015]

Subpart D--Diagnostic Radiopharmaceuticals

Sec. 601.30 Scope.

This subpart applies to radiopharmaceuticals intended for in vivo

administration for diagnostic and monitoring use. It does not apply to
radiopharmaceuticals intended for therapeutic purposes. In situations where
a particular radiopharmaceutical is proposed for both diagnostic and
therapeutic uses, the radiopharmaceutical must be evaluated taking into
account each intended use.

Sec. 601.31 Definition.

For purposes of this part,diagnostic radiopharmaceutical means:

(a) An article that is intended for use in the diagnosis or monitoring of a
disease or a manifestation of a disease in humans and that exhibits
spontaneous disintegration of unstable nuclei with the emission of nuclear
particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is intended to
be used in the preparation of such article as defined in paragraph (a) of
this section.

Sec. 601.32 General factors relevant to safety and effectiveness.

FDA's determination of the safety and effectiveness of a diagnostic

radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the practice
of medicine;
(b) The pharmacological and toxicological activity of the diagnostic
radiopharmaceutical (including any carrier or ligand component of the
diagnostic radiopharmaceutical); and
(c) The estimated absorbed radiation dose of the diagnostic
radiopharmaceutical.

Sec. 601.33 Indications.

(a) For diagnostic radiopharmaceuticals, the categories of proposed

indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to provide
disease-specific information, the proposed indications for use may refer to
a biochemical, physiological, anatomical, or pathological process or to more
than one disease or condition.

Sec. 601.34 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by

evaluating its ability to provide useful clinical information related to its
proposed indications for use. The method of this evaluation varies depending
upon the proposed indication(s) and may use one or more of the following
criteria:
(1) The claim of structure delineation is established by demonstrating in a
defined clinical setting the ability to locate anatomical structures and to
characterize their anatomy.
(2) The claim of functional, physiological, or biochemical assessment is
established by demonstrating in a defined clinical setting reliable
measurement of function(s) or physiological, biochemical, or molecular
process(es).
(3) The claim of disease or pathology detection or assessment is established
by demonstrating in a defined clinical setting that the diagnostic
radiopharmaceutical has sufficient accuracy in identifying or characterizing
the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is established
by demonstrating in a defined clinical setting that the test is useful in
diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories
identified in 601.33, the applicant or sponsor should consult FDA on how to
establish the effectiveness of the diagnostic radiopharmaceutical for the
claim.
(b) The accuracy and usefulness of the diagnostic information is determined
by comparison with a reliable assessment of actual clinical status. A
reliable assessment of actual clinical status may be provided by a
diagnostic standard or standards of demonstrated accuracy. In the absence of
such diagnostic standard(s), the actual clinical status must be established
in another manner, e.g., patient followup.

Sec. 601.35 Evaluation of safety.

(a) Factors considered in the safety assessment of a diagnostic

radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical, including
any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for other uses;
and
(6) Results of any previous human experience with the carrier or ligand of
the radiopharmaceutical when the same chemical entity as the carrier or
ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is not
limited to, an evaluation of the potential of the diagnostic
radiopharmaceutical, including the carrier or ligand, to elicit the
following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target and
nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA may
require, among other information, the following types of data:
(A) Pharmacology data,
(B) Toxicology data,
(C) Clinical adverse event data, and
(D) Radiation safety assessment.
(2) The amount of new safety data required will depend on the
characteristics of the product and available information regarding the
safety of the diagnostic radiopharmaceutical, and its carrier or ligand,
obtained from other studies and uses. Such information may include, but is
not limited to, the dose, route of administration, frequency of use, half-
life of the ligand or carrier, half-life of the radionuclide, and results of
clinical and preclinical studies. FDA will establish categories of
diagnostic radiopharmaceuticals based on defined characteristics relevant to
risk and will specify the amount and type of safety data that are
appropriate for each category (e.g., required safety data may be limited for
diagnostic radiopharmaceuticals with a well established, low-risk profile).
Upon reviewing the relevant product characteristics and safety information,
FDA will place each diagnostic radiopharmaceutical into the appropriate
safety risk category.
(d) Radiation safety assessment. The radiation safety assessment must
establish the radiation dose of a diagnostic radiopharmaceutical by
radiation dosimetry evaluations in humans and appropriate animal models. The
maximum tolerated dose need not be established.

Subpart E--Accelerated Approval of Biological Products for Serious or Life-

Threatening Illnesses

Sec. 601.40 Scope.

This subpart applies to certain biological products that have been studied
for their safety and effectiveness in treating serious or life-threatening
illnesses and that provide meaningful therapeutic benefit to patients over
existing treatments (e.g., ability to treat patients unresponsive to, or
intolerant of, available therapy, or improved patient response over
available therapy).

Sec. 601.41 Approval based on a surrogate endpoint or on an effect on a

clinical endpoint other than survival or irreversible morbidity.

FDA may grant marketing approval for a biological product on the basis of
adequate and well-controlled clinical trials establishing that the
biological product has an effect on a surrogate endpoint that is reasonably
likely, based on epidemiologic, therapeutic, pathophysiologic, or other
evidence, to predict clinical benefit or on the basis of an effect on a
clinical endpoint other than survival or irreversible morbidity. Approval
under this section will be subject to the requirement that the applicant
study the biological product further, to verify and describe its clinical
benefit, where there is uncertainty as to the relation of the surrogate
endpoint to clinical benefit, or of the observed clinical benefit to
ultimate outcome. Postmarketing studies would usually be studies already
underway. When required to be conducted, such studies must also be adequate
and well-controlled. The applicant shall carry out any such studies with due
diligence.

Sec. 601.42 Approval with restrictions to assure safe use.

(a) If FDA concludes that a biological product shown to be effective can be

safely used only if distribution or use is restricted, FDA will require such
postmarketing restrictions as are needed to assure safe use of the
biological product, such as:
(1) Distribution restricted to certain facilities or physicians with special
training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific safety
concerns presented by the biological product.

Sec. 601.43 Withdrawal procedures.

(a) For biological products approved under 601.41 or 601.42, FDA may
withdraw approval, following a hearing as provided in part 15 of this
chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study with due
diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are
inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions agreed
upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not shown to
be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center for
Biologics Evaluation and Research or the Director of the Center for Drug
Evaluation and Research will give the applicant notice of an opportunity for
a hearing on the Center's proposal to withdraw the approval of an
application approved under 601.41 or 601.42. The notice, which will
ordinarily be a letter, will state generally the reasons for the action and
the proposed grounds for the order.
(c) Submission of data and information. (1) If the applicant fails to file a
written request for a hearing within 15 days of receipt of the notice, the
applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the agency will
publish a notice of hearing in the Federal Register in accordance with
12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must, within 30
days of receipt of the notice of opportunity for a hearing, submit the data
and information upon which the applicant intends to rely at the hearing.
(d) Separation of functions. Separation of functions (as specified in 10.55
of this chapter) will not apply at any point in withdrawal proceedings under
this section.
(e) Procedures for hearings. Hearings held under this section will be
conducted in accordance with the provisions of part 15 of this chapter, with
the following modifications:
(1) An advisory committee duly constituted under part 14 of this chapter
will be present at the hearing. The committee will be asked to review the
issues involved and to provide advice and recommendations to the
Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to three
representatives of the applicant, and up to three representatives of the
Center may question any person during or at the conclusion of the person's
presentation. No other person attending the hearing may question a person
making a presentation. The presiding officer may, as a matter of discretion,
permit questions to be submitted to the presiding officer for response by a
person making a presentation.
(f) Judicial review. The Commissioner's decision constitutes final agency
action from which the applicant may petition for judicial review. Before
requesting an order from a court for a stay of action pending review, an
applicant must first submit a petition for a stay of action under 10.35 of
this chapter.
[57 FR 58959, Dec. 11, 1992, as amended at 68 FR 34797, June 11, 2003; 70 FR
14984, Mar. 24, 2005]

Sec. 601.44 Postmarketing safety reporting.

Biological products approved under this program are subject to the

postmarketing recordkeeping and safety reporting applicable to all approved
biological products.

Sec. 601.45 Promotional materials.

For biological products being considered for approval under this subpart,
unless otherwise informed by the agency, applicants must submit to the
agency for consideration during the preapproval review period copies of all
promotional materials, including promotional labeling as well as
advertisements, intended for dissemination or publication within 120 days
following marketing approval. After 120 days following marketing approval,
unless otherwise informed by the agency, the applicant must submit
promotional materials at least 30 days prior to the intended time of initial
dissemination of the labeling or initial publication of the advertisement.

Sec. 601.46 Termination of requirements.

If FDA determines after approval that the requirements established in
601.42, 601.43, or 601.45 are no longer necessary for the safe and effective
use of a biological product, it will so notify the applicant. Ordinarily,
for biological products approved under 601.41, these requirements will no
longer apply when FDA determines that the required postmarketing study
verifies and describes the biological product's clinical benefit and the
biological product would be appropriate for approval under traditional
procedures. For biological products approved under 601.42, the restrictions
would no longer apply when FDA determines that safe use of the biological
product can be assured through appropriate labeling. FDA also retains the
discretion to remove specific postapproval requirements upon review of a
petition submitted by the sponsor in accordance with 10.30.

Subpart F--Confidentiality of Information

Sec. 601.50 Confidentiality of data and information in an investigational

new drug notice for a biological product.

(a) The existence of an IND notice for a biological product will not be
disclosed by the Food and Drug Administration unless it has previously been
publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and information in an
IND file for a biological product shall be handled in accordance with the
provisions established in 601.51.
(c) Notwithstanding the provisions of 601.51, the Food and Drug
Administration shall disclose upon request to an individual on whom an
investigational biological product has been used a copy of any adverse
reaction report relating to such use.
[39 FR 44656, Dec. 24, 1974]

Sec. 601.51 Confidentiality of data and information in applications for

biologics licenses.

(a) For purposes of this section the biological product file includes all
data and information submitted with or incorporated by reference in any
application for a biologics license, IND's incorporated into any such
application, master files, and other related submissions. The availability
for public disclosure of any record in the biological product file shall be
handled in accordance with the provisions of this section.
(b) The existence of a biological product file will not be disclosed by the
Food and Drug Administration before a biologics license application has been
approved unless it has previously been publicly disclosed or acknowledged.
The Food and Drug Administration will maintain a list available for public
disclosure of biological products for which a license application has been
approved.
(c) If the existence of a biological product file has not been publicly
disclosed or acknowledged, no data or information in the biological product
file is available for public disclosure.
(d)(1) If the existence of a biological product file has been publicly
disclosed or acknowledged before a license has been issued, no data or
information contained in the file is available for public disclosure before
such license is issued, but the Commissioner may, in his discretion,
disclose a summary of such selected portions of the safety and effectiveness
data as are appropriate for public consideration of a specific pending
issue, e.g., at an open session of a Food and Drug Administration advisory
committee or pursuant to an exchange of important regulatory information
with a foreign government.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IND that was
required to be filed in Docket Number 95S-0158 in the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852, for investigations involving an exception from
informed consent under 50.24 of this chapter. Persons wishing to request
this information shall submit a request under the Freedom of Information
Act.
(e) After a license has been issued, the following data and information in
the biological product file are immediately available for public disclosure
unless extraordinary circumstances are shown:
(1) All safety and effectiveness data and information.
(2) A protocol for a test or study, unless it is shown to fall within the
exemption established for trade secrets and confidential commercial or
financial information in 20.61 of this chapter.
(3) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using the
product.
(ii) Names and any information that would identify any third party involved
with the report, such as a physician or hospital or other institution.
(4) A list of all active ingredients and any inactive ingredients previously
disclosed to the public, as defined in 20.81 of this chapter.
(5) An assay method or other analytical method, unless it serves no
regulatory or compliance purpose and it is shown to fall within the
exemption established in 20.61 of this chapter.
(6) All correspondence and written summaries of oral discussions relating to
the biological product file, in accordance with the provisions of part 20 of
this chapter.
(7) All records showing the manufacturer's testing of a particular lot,
after deletion of data or information that would show the volume of the drug
produced, manufacturing procedures and controls, yield from raw materials,
costs, or other material falling within 20.61 of this chapter.
(8) All records showing the testing of and action on a particular lot by the
Food and Drug Administration.
(f) The following data and information in a biological product file are not
available for public disclosure unless they have been previously disclosed
to the public as defined in 20.81 of this chapter or they relate to a
product or ingredient that has been abandoned and they no longer represent a
trade secret or confidential commercial or financial information as defined
in 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control
procedures.
(2) Production, sales, distribution, and similar data and information,
except that any compilation of such data and information aggregated and
prepared in a way that does not reveal data or information which is not
available for public disclosure under this provision is available for public
disclosure.
(3) Quantitative or semiquantitative formulas.
(g) For purposes of this regulation, safety and effectiveness data include
all studies and tests of a biological product on animals and humans and all
studies and tests on the drug for identity, stability, purity, potency, and
bioavailability.
[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 49 FR
23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 2, 1996;
64 FR 56452, Oct. 20, 1999; 68 FR 24879, May 9, 2003; 69 FR 13717, Mar. 24,
2004; 70 FR 14984, Mar. 24, 2005]

Subpart G--Postmarketing Studies

Sec. 601.70 Annual progress reports of postmarketing studies.

(a) General requirements. This section applies to all required postmarketing

studies (e.g., accelerated approval clinical benefit studies, pediatric
studies) and postmarketing studies that an applicant has committed, in
writing, to conduct either at the time of approval of an application or a
supplement to an application, or after approval of an application or a
supplement. Postmarketing studies within the meaning of this section are
those that concern:
(1) Clinical safety;
(2) Clinical efficacy;
(3) Clinical pharmacology; and
(4) Nonclinical toxicology.
(b) What to report. Each applicant of a licensed biological product shall
submit a report to FDA on the status of postmarketing studies for each
approved product application. The status of these postmarketing studies
shall be reported annually until FDA notifies the applicant, in writing,
that the agency concurs with the applicant's determination that the study
commitment has been fulfilled, or that the study is either no longer
feasible or would no longer provide useful information. Each annual progress
report shall be accompanied by a completed transmittal Form FDA-2252, and
shall include all the information required under this section that the
applicant received or otherwise obtained during the annual reporting
interval which ends on the U.S. anniversary date. The report must provide
the following information for each postmarketing study:
(1) Applicant's name.
(2) Product name. Include the approved product's proper name and the
proprietary name, if any.
(3) Biologics license application (BLA) and supplement number.
(4) Date of U.S. approval of BLA.
(5) Date of postmarketing study commitment.
(6) Description of postmarketing study commitment. The description must
include sufficient information to uniquely describe the study. This
information may include the purpose of the study, the type of study, the
patient population addressed by the study and the indication(s) and
dosage(s) that are to be studied.
(7) Schedule for completion and reporting of the postmarketing study
commitment. The schedule should include the actual or projected dates for
submission of the study protocol to FDA, completion of patient accrual or
initiation of an animal study, completion of the study, submission of the
final study report to FDA, and any additional milestones or submissions for
which projected dates were specified as part of the commitment. In addition,
it should include a revised schedule, as appropriate. If the schedule has
been previously revised, provide both the original schedule and the most
recent, previously submitted revision.
(8) Current status of the postmarketing study commitment. The status of each
postmarketing study should be categorized using one of the following terms
that describes the study's status on the anniversary date of U.S. approval
of the application or other agreed upon date:
(i) Pending. The study has not been initiated, but does not meet the
criterion for delayed.
(ii) Ongoing. The study is proceeding according to or ahead of the original
schedule described under paragraph (b)(7) of this section.
(iii) Delayed. The study is behind the original schedule described under
paragraph (b)(7) of this section.
(iv) Terminated. The study was ended before completion but a final study
report has not been submitted to FDA.
(v) Submitted. The study has been completed or terminated and a final study
report has been submitted to FDA.
(9) Explanation of the study's status. Provide a brief description of the
status of the study, including the patient accrual rate (expressed by
providing the number of patients or subjects enrolled to date, and the total
planned enrollment), and an explanation of the study's status identified
under paragraph (b)(8) of this section. If the study has been completed,
include the date the study was completed and the date the final study report
was submitted to FDA, as applicable. Provide a revised schedule, as well as
the reason(s) for the revision, if the schedule under paragraph (b)(7) of
this section has changed since the previous report.
(c) When to report. Annual progress reports for postmarketing study
commitments entered into by applicants shall be reported to FDA within 60
days of the anniversary date of the U.S. approval of the application for the
product.
(d) Where to report. Submit two copies of the annual progress report of
postmarketing studies to the Center for Biologics Evaluation and Research or
Center for Drug Evaluation and Research (see mailing addresses in 600.2(a)
or (b) of this chapter).
(e) Public disclosure of information. Except for the information described
in this paragraph, FDA may publicly disclose any information concerning a
postmarketing study, within the meaning of this section, if the agency
determines that the information is necessary to identify an applicant or to
establish the status of the study including the reasons, if any, for failure
to conduct, complete, and report the study. Under this section, FDA will not
publicly disclose trade secrets, as defined in 20.61 of this chapter, or
information, described in 20.63 of this chapter, the disclosure of which
would constitute an unwarranted invasion of personal privacy.
[65 FR 64618, Oct. 30, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR
18092, Apr. 3, 2015]

Subpart H--Approval of Biological Products When Human Efficacy Studies Are

Not Ethical or Feasible

Sec. 601.90 Scope.

This subpart applies to certain biological products that have been studied
for their safety and efficacy in ameliorating or preventing serious or life-
threatening conditions caused by exposure to lethal or permanently disabling
toxic biological, chemical, radiological, or nuclear substances. This
subpart applies only to those biological products for which: Definitive
human efficacy studies cannot be conducted because it would be unethical to
deliberately expose healthy human volunteers to a lethal or permanently
disabling toxic biological, chemical, radiological, or nuclear substance;
and field trials to study the product's efficacy after an accidental or
hostile exposure have not been feasible. This subpart does not apply to
products that can be approved based on efficacy standards described
elsewhere in FDA's regulations (e.g., accelerated approval based on
surrogate markers or clinical endpoints other than survival or irreversible
morbidity), nor does it address the safety evaluation for the products to
which it does apply.

Sec. 601.91 Approval based on evidence of effectiveness from studies in

animals.

(a) FDA may grant marketing approval for a biological product for which
safety has been established and for which the requirements of 601.90 are met
based on adequate and well-controlled animal studies when the results of
those animal studies establish that the biological product is reasonably
likely to produce clinical benefit in humans. In assessing the sufficiency
of animal data, the agency may take into account other data, including human
data, available to the agency. FDA will rely on the evidence from studies in
animals to provide substantial evidence of the effectiveness of these
products only when:
(1) There is a reasonably well-understood pathophysiological mechanism of
the toxicity of the substance and its prevention or substantial reduction by
the product;
(2) The effect is demonstrated in more than one animal species expected to
react with a response predictive for humans, unless the effect is
demonstrated in a single animal species that represents a sufficiently well-
characterized animal model for predicting the response in humans;
(3) The animal study endpoint is clearly related to the desired benefit in
humans, generally the enhancement of survival or prevention of major
morbidity; and
(4) The data or information on the kinetics and pharmacodynamics of the
product or other relevant data or information, in animals and humans, allows
selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three requirements:
(1) Postmarketing studies. The applicant must conduct postmarketing studies,
such as field studies, to verify and describe the biological product's
clinical benefit and to assess its safety when used as indicated when such
studies are feasible and ethical. Such postmarketing studies would not be
feasible until an exigency arises. When such studies are feasible, the
applicant must conduct such studies with due diligence. Applicants must
include as part of their application a plan or approach to postmarketing
study commitments in the event such studies become ethical and feasible.
(2) Approval with restrictions to ensure safe use. If FDA concludes that a
biological product shown to be effective under this subpart can be safely
used only if distribution or use is restricted, FDA will require such
postmarketing restrictions as are needed to ensure safe use of the
biological product, commensurate with the specific safety concerns presented
by the biological product, such as:
(i) Distribution restricted to certain facilities or health care
practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified medical
procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping requirements.
(3) Information to be provided to patient recipients. For biological
products or specific indications approved under this subpart, applicants
must prepare, as part of their proposed labeling, labeling to be provided to
patient recipients. The patient labeling must explain that, for ethical or
feasibility reasons, the biological product's approval was based on efficacy
studies conducted in animals alone and must give the biological product's
indication(s), directions for use (dosage and administration),
contraindications, a description of any reasonably foreseeable risks,
adverse reactions, anticipated benefits, drug interactions, and any other
relevant information required by FDA at the time of approval. The patient
labeling must be available with the product to be provided to patients prior
to administration or dispensing of the biological product for the use
approved under this subpart, if possible.

Sec. 601.92 Withdrawal procedures.

(a) Reasons to withdraw approval. For biological products approved under

this subpart, FDA may withdraw approval, following a hearing as provided in
part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due
diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are
inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions applied
at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not shown to
be safe or effective under its conditions of use.
(b) Notice of opportunity for a hearing. The Director of the Center for
Biologics Evaluation and Research or the Director of the Center for Drug
Evaluation and Research will give the applicant notice of an opportunity for
a hearing on the proposal to withdraw the approval of an application
approved under this subpart. The notice, which will ordinarily be a letter,
will state generally the reasons for the action and the proposed grounds for
the order.
(c) Submission of data and information. (1) If the applicant fails to file a
written request for a hearing within 15 days of receipt of the notice, the
applicant waives the opportunity for a hearing.
(2) If the applicant files a timely request for a hearing, the agency will
publish a notice of hearing in the Federal Register in accordance with
12.32(e) and 15.20 of this chapter.
(3) An applicant who requests a hearing under this section must, within 30
days of receipt of the notice of opportunity for a hearing, submit the data
and information upon which the applicant intends to rely at the hearing.
(d) Separation of functions. Separation of functions (as specified in 10.55
of this chapter) will not apply at any point in withdrawal proceedings under
this section.
(e) Procedures for hearings. Hearings held under this section will be
conducted in accordance with the provisions of part 15 of this chapter, with
the following modifications:
(1) An advisory committee duly constituted under part 14 of this chapter
will be present at the hearing. The committee will be asked to review the
issues involved and to provide advice and recommendations to the
Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to three
representatives of the applicant, and up to three representatives of CBER
may question any person during or at the conclusion of the person's
presentation. No other person attending the hearing may question a person
making a presentation. The presiding officer may, as a matter of discretion,
permit questions to be submitted to the presiding officer for response by a
person making a presentation.
(f) Judicial review. The Commissioner of Food and Drugs' decision
constitutes final agency action from which the applicant may petition for
judicial review. Before requesting an order from a court for a stay of
action pending review, an applicant must first submit a petition for a stay
of action under 10.35 of this chapter.
[67 FR 37996, May 31, 2002, as amended at 70 FR 14984, Mar. 24, 2005]

Sec. 601.93 Postmarketing safety reporting.

Biological products approved under this subpart are subject to the

postmarketing recordkeeping and safety reporting applicable to all approved
biological products.

Sec. 601.94 Promotional materials.

For biological products being considered for approval under this subpart,
unless otherwise informed by the agency, applicants must submit to the
agency for consideration during the preapproval review period copies of all
promotional materials, including promotional labeling as well as
advertisements, intended for dissemination or publication within 120 days
following marketing approval. After 120 days following marketing approval,
unless otherwise informed by the agency, the applicant must submit
promotional materials at least 30 days prior to the intended time of initial
dissemination of the labeling or initial publication of the advertisement.

Sec. 601.95 Termination of requirements.

If FDA determines after approval under this subpart that the requirements
established in 601.91(b)(2), 601.92, and 601.93 are no longer necessary for
the safe and effective use of a biological product, FDA will so notify the
applicant. Ordinarily, for biological products approved under 601.91, these
requirements will no longer apply when FDA determines that the postmarketing
study verifies and describes the biological product's clinical benefit. For
biological products approved under 601.91, the restrictions would no longer
apply when FDA determines that safe use of the biological product can be
ensured through appropriate labeling. FDA also retains the discretion to
remove specific postapproval requirements upon review of a petition
submitted by the sponsor in accordance with 10.30 of this chapter.

Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355, 356b,
360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262,
263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).
Source: 38 FR 32052, Nov. 20, 1973, unless otherwise noted.