0338 21cfr601 25 2007

Food and Drug Administration, HHS

§ 601.25

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.

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, 610.11, 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.

[64 FR 56451, Oct. 20, 1999, as amended at 70
FR 14983, Mar. 24, 2005]

§ 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).

[42 FR 4718, Jan. 25, 1977, as amended at 61
FR 24233, May 14, 1996; 64 FR 56452, Oct. 20,
1999]

§ 601.25 Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions
of use.

[64 FR 56451, Oct. 20, 1999]

§ 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

For purposes of reviewing biological
products that have been licensed prior
to July 1, 1972, to determine that they
are safe and effective and not misbranded, the following regulations
shall apply. Prior administrative action exempting biological products
from the provisions of the Federal
Food, Drug, and Cosmetic Act is superseded to the extent that these regulations result in imposing requirements
pursuant to provisions therein for a
designated biological product or category of products.
(a) Advisory review panels. The Commissioner of Food and Drugs shall appoint advisory review panels (1) to
evaluate the safety and effectiveness of
biological products for which a license
has been issued pursuant to section 351
of the Public Health Service Act, (2) to

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§ 601.25

21 CFR Ch. I (4–1–05 Edition)

review the labeling of such biological
products, and (3) to advise him on
which of the biological products under
review are safe, effective, and not misbranded. An advisory review panel
shall be established for each designated
category of biological product. The
members of a panel shall be qualified
experts, appointed by the Commissioner, and shall include persons from
lists submitted by organizations representing professional, consumer, and
industry interests. Such persons shall
represent a wide divergence of responsible medical and scientific opinion.
The Commissioner shall designate the
chairman of each panel, and summary
minutes of all meetings shall be made.
(b) Request for data and views. (1) The
Commissioner of Food and Drugs will
publish a notice in the FEDERAL REGISTER requesting interested persons to
submit, for review and evaluation by
an advisory review panel, published
and unpublished data and information
pertinent to a designated category of
biological products.
(2) Data and information submitted
pursuant to a published notice, and
falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b),
or 21 U.S.C. 331(j), shall be handled by
the advisory review panel and the Food
and Drug Administration as confidential until publication of a proposed
evaluation of the biologics under review and the full report or reports of
the panel. Thirty days thereafter such
data and information shall be made
publicly available and may be viewed
at the Division of Dockets Management of the Food and Drug Administration, except to the extent that the
person submitting it demonstrates that
it still falls within the confidentiality
provisions of one or more of those statutes.
(3) To be considered, 12 copies of the
submission on any marketed biological
product within the class shall be submitted, preferably bound, indexed, and
on standard sized paper, approximately
81⁄2 × 11 inches. The time allotted for
submissions will be 60 days, unless otherwise indicated in the specific notice
requesting data and views for a particular category of biological products.
When requested, abbreviated submissions should be sent. All submissions

shall be in the following format, indicating ‘‘none’’ or ‘‘not applicable’’
where appropriate, unless changed in
the FEDERAL REGISTER notice:
BIOLOGICAL PRODUCTS REVIEW INFORMATION
I. Label or labels and all other labeling
(preferably mounted. Facsimile labeling is
acceptable in lieu of actual container labeling), including labeling for export.
II. Representative advertising used during
the past 5 years.
III. The complete quantitative composition
of the biological product.
IV. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
B. Combinations of the individual active
components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
V. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination as to the
safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active
components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination as to the
safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination as to the
safety of the finished biological product.
5. Pertinent medical and scientific literature.
VI. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.

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Food and Drug Administration, HHS

§ 601.25

3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active
components.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination as to the effectiveness of combinations of the individual
active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled
studies.
3. Documented case reports.
4. Pertinent marketing experiences that
may influence a determination as to the effectiveness of the finished biological product.
5. Pertinent medical and scientific literature.
VII. A summary of the data and views setting forth the medical rational and purpose
(or lack thereof) for the biological product
and its components and the scientific basis
(or lack thereof) for the conclusion that the
biological product, including its components,
has been proven safe and effective and is
properly labeled for the intended use or uses.
If there is an absence of controlled studies in
the materials submitted, an explanation as
to why such studies are not considered necessary or feasible shall be included.
VIII. If the submission is by a licensed
manufacturer, a statement signed by the authorized official of the licensed manufacturer shall be included, stating that to the
best of his or her knowledge and belief, it includes all information, favorable and unfavorable, pertinent to an evaluation of the
safety, effectiveness, and labeling of the
product, including information derived from
investigation, commercial marketing, or
published literature. If the submission is by
an interested person other than a licensed
manufacturer, a statement signed by the
person responsible for such submission shall
be included, stating that to the best of his
knowledge and belief, it fairly reflects a balance of all the available information, favorable and unfavorable available to him, pertinent to an evaluation of the safety, effectiveness, and labeling of the product.

its conclusions and recommendations
to the Commissioner of Food and Drugs
with respect to the safety, effectiveness, and labeling of the biological
products in the designated category
under review.
(1) A panel may also consult any individual or group.
(2) Any interested person may request in writing an opportunity to
present oral views to the panel. Such
written requests for oral presentations
should include a summarization of the
data to be presented to the panel. Such
request may be granted or denied by
the panel.
(3) Any interested person may
present written data and views which
shall be considered by the panel. This
information shall be presented to the
panel in the format set forth in paragraph (b)(3) of this section and within
the time period established for the biological product category in the notice
for review by a panel.
(d) Standards for safety, effectiveness,
and labeling. The advisory review panel,
in reviewing the submitted data and
preparing the panel’s conclusions and
recommendations, and the Commissioner of Food and Drugs, in reviewing
and implementing the conclusions and
recommendations of the panel, shall
apply the following standards to determine that a biological product is safe
and effective and not misbranded.
(1) Safety means the relative freedom
from harmful effect to persons affected, directly or indirectly, by a
product when prudently administered,
taking into consideration the character of the product in relation to the
condition of the recipient at the time.
Proof of safety shall consist of adequate tests by methods reasonably applicable to show the biological product
is safe under the prescribed conditions
of use, including results of significant
human experience during use.
(2) Effectiveness means a reasonable
expectation that, in a significant proportion of the target population, the
pharmacological or other effect of the
biological product, when used under
adequate directions, for use and warnings against unsafe use, will serve a
clinically significant function in the
diagnosis, cure, mitigation, treatment,
or prevention of disease in man. Proof

(c) Deliberations of an advisory review
panel. An advisory review panel will
meet as often and for as long as is appropriate to review the data submitted
to it and to prepare a report containing

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§ 601.25

21 CFR Ch. I (4–1–05 Edition)

of effectiveness shall consist of controlled clinical investigations as defined in § 314.126 of this chapter, unless
this requirement is waived on the basis
of a showing that it is not reasonably
applicable to the biological product or
essential to the validity of the investigation, and that an alternative method of investigation is adequate to substantiate
effectiveness.
Alternate
methods, such as serological response
evaluation in clinical studies and appropriate animal and other laboratory
assay evaluations may be adequate to
substantiate effectiveness where a previously accepted correlation between
data generated in this way and clinical
effectiveness already exists. Investigations may be corroborated by partially
controlled or uncontrolled studies, documented clinical studies by qualified
experts, and reports of significant
human experience during marketing.
Isolated case reports, random experience, and reports lacking the details
which permit scientific evaluation will
not be considered.
(3) The benefit-to-risk ratio of a biological product shall be considered in
determining safety and effectiveness.
(4) A biological product may combine
two or more safe and effective active
components: (i) When each active component makes a contribution to the
claimed effect or effects; (ii) when combining of the active ingredients does
not decrease the purity, potency, safety, or effectiveness of any of the individual active components; and (iii) if
the combination, when used under adequate directions for use and warnings
against unsafe use, provides rational
concurrent preventive therapy or
treatment for a significant proportion
of the target population.
(5) Labeling shall be clear and truthful in all respects and may not be false
or misleading in any particular. It
shall comply with section 351 of the
Public Health Service Act and sections
502 and 503 of the Federal Food, Drug,
and Cosmetic Act, and in particular
with the applicable requirements of
§§ 610.60 through 610.65 and subpart D of
part 201 of this chapter.
(e) Advisory review panel report to the
Commissioner. An advisory review panel
shall submit to the Commissioner of
Food and Drugs a report containing the

panel’s conclusions and recommendations with respect to the biological
products falling within the category
covered by the panel. Included within
this report shall be:
(1) A statement which designates
those biological products determined
by the panel to be safe and effective
and not misbranded. This statement
may include any condition relating to
active components, labeling, tests required prior to release of lots, product
standards, or other conditions necessary or appropriate for their safety
and effectiveness.
(2) A statement which designates
those biological products determined
by the panel to be unsafe or ineffective,
or to be misbranded. The statement
shall include the panel’s reasons for
each such determination.
(3) A statement which designates
those biological products determined
by the panel not to fall within either
paragraph (e) (1) or (2) of this section
on the basis of the panel’s conclusion
that the available data are insufficient
to classify such biological products,
and for which further testing is therefore required. The report shall recommend with as must specificity as
possible the type of further testing required and the time period within
which it might reasonably be concluded. The report shall also recommend whether the product license
should or should not be revoked, thus
permitting or denying continued manufacturing and marketing of the biological product pending completion of the
testing. This recommendation will be
based on an assessment of the present
evidence of the safety and effectiveness
of the product and the potential benefits and risks likely to result from the
continued use of the product for a limited period of time while the questions
raised concerning the product are being
resolved by further study.2
2 As of November 4, 1982, the provisions
under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the
review and reclassification procedures under
§ 601.26 of this chapter. The superseded text is
included for the convenience of the user
only.

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Food and Drug Administration, HHS

§ 601.26

(f) Proposed order. After reviewing the
conclusions and recommendations of
the advisory review panel, the Commissioner of Food and Drugs shall publish
in the FEDERAL REGISTER a proposed
order containing:
(1) A statement designating the biological products in the category under
review that are determined by the
Commissioner of Food and Drugs to be
safe and effective and not misbranded.
This statement may include any condition relating to active components, labeling, tests required prior to release of
lots, product standards, or other conditions necessary or appropriate for their
safety and effectiveness, and may propose corresponding amendments in
other regulations under this subchapter F.
(2) A statement designating the biological products in the category under
review that are determined by the
Commissioner of Food and Drugs to be
unsafe or ineffective, or to be misbranded, together with the reasons
therefor. All licenses for such products
shall be proposed to be revoked.
(3) A statement designating the biological products not included in either
of the above two statements on the
basis of the Commissioner of Food and
Drugs determination that the available
data are insufficient to classify such
biological products under either paragraph (f) (1) or (2) of this section. Licenses for such products may be proposed to be revoked or to remain in effect on an interim basis. Where the
Commissioner determines that the potential benefits outweigh the potential
risks, the proposed order shall provide
that the biologics license for any biological product, falling within this
paragraph, will not be revoked but will
remain in effect on an interim basis
while the data necessary to support its
continued marketing are being obtained for evaluation by the Food and
Drug Administration. The tests necessary to resolve whatever safety or effectiveness questions exist shall be described.2

(4) The full report or reports of the
panel to the Commissioner of Food and
Drugs.
The summary minutes of the panel meeting or meetings shall be made available to
interested persons upon request. Any interested person may within 90 days after publication of the proposed order in the FEDERAL
REGISTER, file with the Hearing Clerk of the
Food and Drug Administration written comments in quintuplicate. Comments may be
accompanied by a memorandum or brief in
support thereof. All comments may be reviewed at the office of the Division of Dockets Management during regular working
hours, Monday through Friday.

(g) Final order. After reviewing the
comments, the Commissioner of Food
and Drugs shall publish in the FEDERAL
REGISTER a final order on the matters
covered in the proposed order. The
final order shall become effective as
specified in the order.
(h) [Reserved]
(i) Court Appeal. The final order(s)
published pursuant to paragraph (g) of
this section, and any notice published
pursuant to paragraph (h) of this section, constitute final agency action
from which appeal lies to the courts.
The Food and Drug Administration
will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and
Drugs may, at his discretion, stay the
effective date for part or all of the final
order or notice, pending appeal and
final court adjudication.
[38 FR 32052, Nov. 20, 1973, as amended at 39
FR 11535, Mar. 29, 1974; 40 FR 13498, Mar. 27,
1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071,
Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR
15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990;
62 FR 53538, Oct. 15, 1997; 64 FR 56452, Oct. 20,
1999]

§ 601.26 Reclassification procedures to
determine that licensed biological
products are safe, effective, and not
misbranded under prescribed, recommended, or suggested conditions
of use.
This regulation establishes procedures for the reclassification of all biological products that have been classified into Category IIIA. A Category

2 As of November 4, 1982, the provisions
under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the
review and reclassification procedures under

§ 601.26 of this chapter. The superseded text is
included for the convenience of the user
only.

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