Section

[Code of Federal Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR601.25]

[Page 27-31]

TITLE 21--FOOD AND DRUGS

DEPARTMENT OF HEALTH AND HUMAN SERVICES--(Continued)

PART 601--LICENSING--Table of Contents

Subpart C--Biologics Licensing

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

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provisions of the Federal Food, Drug, and Cosmetic Act is superseded to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 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

[[Page 28]]

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review panel, published and unpublished data and information pertinent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 Dockets Management Branch 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 8\1/2\ x 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.
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.

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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.

(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 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 of effectiveness shall
consist of controlled clinical investigations as defined in Sec. 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

[[Page 30]]

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 Secs. 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\
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\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
Sec. 601.26 of this chapter. The superseded text is included for the
convenience of the user only.
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(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:

[[Page 31]]

(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\
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(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 Dockets Management Branch 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]