0338 21cfr601 26 2007

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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§ 601.26

21 CFR Ch. I (4–1–05 Edition)

IIIA biological product is one for which
an advisory review panel has recommended under § 601.25(e)(3), the Commissioner of Food and Drugs (Commissioner) has proposed under § 601.25(f)(3),
or the Commissioner has finally decided under § 601.25(g) that available
data are insufficient to determine
whether the product license should be
revoked or affirmed and which may be
marketed pending the completion of
further testing. All of these Category
IIIA products will either be reclassified
into Category I (safe, effective, and not
misbranded) or Category II (unsafe, ineffective, or misbranded) in accordance
with the procedures set forth below.
(a) Advisory review panels. The Commissioner will appoint advisory review
panels and use existing advisory review
panels to (1) evaluate the safety and effectiveness of all Category IIIA biological products; (2) review the labeling of
such products; and (3) advise the Commissioner on which Category IIIA biological products are safe, effective, and
not misbranded. These advisory review
panels will be established in accordance with procedures set forth in
§ 601.25(a).
(b) Deliberations of advisory review
panels. The deliberations of advisory
review panels will be conducted in accordance with § 601.25(d).
(c) Advisory review panel report to the
Commissioner. An advisory review panel
shall submit to the Commissioner a report containing the panel’s conclusions
and recommendations with respect to
the biological products falling within
the category of products reviewed by
the panel. The panel report shall include:
(1) A statement designating the biological products in the category under
review in accordance with either
§ 601.25(e)(1) or § 601.25(e)(2).
(2) A statement identifying those biological products designated under
§ 601.25(e)(2) that the panel recommends
should be designated as safe and presumptively effective and should remain
on the market pending completion of
further testing because there is a compelling medical need and no suitable
alternative therapeutic, prophylactic,
or diagnostic agent that is available in
sufficient quantities to meet current
medical needs. For the products or cat-

egories of products so recommended,
the report shall include:
(i) A description and evaluation of
the available evidence concerning effectiveness and an explanation why the
evidence shows that the product has
any benefit; and
(ii) A description of the alternative
therapeutic, prophylactic, or diagnostic agents considered and a statement of why such alternatives are not
suitable. In making this recommendation the panel shall also take into account the seriousness of the condition
intended to be treated, prevented, or
diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based
upon existing data, the effectiveness of
the product can eventually be established by further testing and new test
development. The report shall also recommend with as much specificity as
possible the type of further testing required and the time period within
which it might reasonably be concluded.
(d) Proposed order. After reviewing
the conclusions and recommendations
of the advisory review panels, the Commissioner shall publish in the FEDERAL
REGISTER a proposed order containing:
(1) A statement designating the biological products in the category under
review in accordance with either
§ 601.25(e)(1) or 601.25(e)(2);
(2) A notice of availability of the full
panel report or reports. The full panel
report or reports shall be made publicly available at the time of publication of the proposed order.
(3) A proposal to accept or reject the
findings of the advisory review panel
required by § 601.26(c)(2)(i) and (ii).
(4) A statement identifying those biological products that the Commissioner
proposes should be designated as safe
and presumptively effective under
§ 601.26(c)(2) and should be permitted to
remain on the market pending completion of further testing because there is
a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for the product that is available in sufficient quantities to meet current medical needs.
In making this proposal, the Commissioner shall take into account the seriousness of the condition to be treated,

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Food and Drug Administration, HHS

§ 601.26

prevented, or diagnosed by the product,
the risks involved in the continued use
of the product, and the likelihood that,
based upon existing data, the effectiveness of the product can eventually be
established by further testing.
(e) Final order. After reviewing the
comments on the proposed order, the
Commissioner shall publish in the FEDERAL REGISTER a final order on the
matters covered in the proposed order.
Where the Commissioner determines
that there is a compelling medical need
and no suitable alternative therapeutic, prophylactic, or diagnostic
agent for any biological product that is
available in sufficient quantities to
meet current medical needs, the final
order shall provide that the biologics
license application for that biological
product 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 final order
shall describe the tests necessary to resolve whatever effectiveness questions
exist.
(f) Additional studies and labeling. (1)
Within 60 days following publication of
the final order, each licensed manufacturer for a biological product designated as requiring further study to
justify continued marketing on an interim basis, under paragraph (e) of this
section, shall submit to the Commissioner a written statement intended to
show that studies adequate and appropriate to resolve the questions raised
about the product have been undertaken. The Federal Government may
undertake the studies. Any study involving a clinical investigation that involves human subjects shall be conducted in compliance with the requirements for informed consent under part
50 of this chapter. Such a study is also
subject to the requirements for institutional review under part 56 of this
chapter unless exempt under § 56.104 or
§ 56.105. The Commissioner may extend
this 60-day period if necessary, either
to review and act on proposed protocols
or upon indication from the licensed
manufacturer that the studies will
commence at a specified reasonable
time. If no such commitment is made,
or adequate and appropriate studies are

not undertaken, the biologics license
or licenses shall be revoked.
(2) A progress report shall be filed on
the studies by January 1 and July 1
until completion. If the progress report
is inadequate or if the Commissioner
concludes that the studies are not
being pursued promptly and diligently,
or if interim results indicate the product is not a medical necessity, the biologics license or licenses shall be revoked.
(3) Promptly upon completion of the
studies undertaken on the product, the
Commissioner will review all available
data and will either retain or revoke
the biologics license or licenses involved. In making this review the Commissioner may again consult the advisory review panel which prepared the
report on the product, or other advisory committees, professional organizations, or experts. The Commissioner
shall take such action by notice published in the FEDERAL REGISTER.
(4) Labeling and promotional material for those biological products requiring additional studies shall bear a
box statement in the following format:
Based on a review by the (insert name
of appropriate advisory review panel) and
other information, the Food and Drug
Administration has directed that further investigation be conducted before
this product is conclusively determined
to be effective for labeled indication(s).
(5) A written informed consent shall
be obtained from participants in any
additional studies required under paragraph (f)(1) of this section, explaining
the nature of the product and the investigation. The explanation shall consist of such disclosure and be made so
that intelligent and informed consent
be given and that a clear opportunity
to refuse is presented.
(g) Court appeal. The final order(s)
published pursuant to paragraph (e) 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 the Commissioner’s discretion, stay the effective date for part
or all of the final order or notice, pending appeal and final court adjudication.
(h) [Reserved]

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§ 601.27

21 CFR Ch. I (4–1–05 Edition)

(i) Institutional review and informed
consent. Information and data submitted under this section after July 27,
1981, shall include statements regarding each clinical investigation involving human subjects, that it was conducted in compliance with the requirements for informed consent under part
50 of this chapter. Such a study is also
subject to the requirements for institutional review under part 56 of this
chapter, unless exempt under § 56.104 or
§ 56.105.

tients 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

[47 FR 44071, Oct. 5, 1982, as amended at 64 FR
56452, Oct. 20, 1999]

§ 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 pa-

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