Chapter 5: Pharmaceutical Labeling in the US
44 Regulatory Affairs Professionals Society (RAPS)
Examples of PAS changes are addition
of an indication, information to strengthen a
claim, additional clinical or pharmacokinetic
information, or revisions to the Highlights
section.
The labeling components submitted
with a PAS are the same as those included
with NDA or BLA submissions (i.e., SPL)55
along with a manuscript in an editable
format, such as MS Word, showing the
sponsor’s proposed revisions to the currently
approved labeling and a PDF file with
annotations to supporting material. Labeling
components, such as carton or container
labels, not affected by the proposed change
may be omitted from the submission. FDA
review can take 6 to 10 months depend-
ing on the nature of the change and data
submitted and can involve iterative negotia-
tions to reach agreed wording for the revised
labeling. Implementation for revised labeling
submitted as a PAS must await FDA
approval.
• Changes Being Effected (CBE) supplement
is used for moderate changes. FDA approval
is not required prior to implementation of
the revised labeling. However, the FDA will
issue an approval letter for a CBE supple-
ment. Timeframe can vary.
º CBE-30 submissions are used to make
changes to CMC-related labeling con-
tent, such as those relating to the drug
substance or drug product. The revised
labeling may be implemented 30 days
after submission.60,65 Approval from
the FDA may be received at any time
following submission, often four to six
months after filing.
º CBE-0 submissions are intended for
certain safety-related updates, such
as the addition or strengthening of a
contraindication, warning, precaution,
or adverse reactions statements about
abuse and dependence instruction
about dosage and administration that
is intended to increase the safe use
or deletion of false or misleading or
unsupported claims of effectiveness. The
revised labeling may be implemented
immediately upon submission. This sub-
mission mechanism allows sponsors to
comply with the requirement to revise
labeling “…to include a warning about
a clinically significant hazard as soon as
there is reasonable evidence of a causal
association with a drug a causal rela-
tionship need not have been definitely
established.”60,65,66 Depending upon the
nature of the change, the sponsor may
wish to discuss the proposed change
with the FDA’s project manager prior to
implementing the revised labeling for a
CBE-0 submission to avoid the risk of
the agency requiring significant changes
following its review of the support-
ing data. The timing of formal FDA
approval for such supplements will vary.
The labeling components submitted
with a CBE supplement are the same as
those for other submissions, including
SPL,55 a manuscript marked with revi-
sions to the currently approved labeling
and an annotated PDF file, but will
include copies of final printed labeling.
Note that implementation without
FDA approval may involve printing
components at risk, since the FDA may
require changes to the submitted and
implemented labeling update. For this
reason, such decisions will benefit from
consultation with personnel responsible
for managing packaging inventory so
they may limit quantities until approval
is granted.
• Safety change notification letters67,68 –
Section 505(o)(4) of the FD&C Act (added
as the result of FDAAA Section 901) autho-
rizes the FDA to require – and, if necessary,
order – labeling changes for prescription
products if it learns of new information
about serious risks it determines should be
included in the labeling. Previously, in the
absence of such authority, negotiations with
sponsors over agency-requested changes
could be protracted. New safety information
reflects a serious risk or unexpected serious
risk associated with the drug that has been
identified since approval. Revisions to boxed
44 Regulatory Affairs Professionals Society (RAPS)
Examples of PAS changes are addition
of an indication, information to strengthen a
claim, additional clinical or pharmacokinetic
information, or revisions to the Highlights
section.
The labeling components submitted
with a PAS are the same as those included
with NDA or BLA submissions (i.e., SPL)55
along with a manuscript in an editable
format, such as MS Word, showing the
sponsor’s proposed revisions to the currently
approved labeling and a PDF file with
annotations to supporting material. Labeling
components, such as carton or container
labels, not affected by the proposed change
may be omitted from the submission. FDA
review can take 6 to 10 months depend-
ing on the nature of the change and data
submitted and can involve iterative negotia-
tions to reach agreed wording for the revised
labeling. Implementation for revised labeling
submitted as a PAS must await FDA
approval.
• Changes Being Effected (CBE) supplement
is used for moderate changes. FDA approval
is not required prior to implementation of
the revised labeling. However, the FDA will
issue an approval letter for a CBE supple-
ment. Timeframe can vary.
º CBE-30 submissions are used to make
changes to CMC-related labeling con-
tent, such as those relating to the drug
substance or drug product. The revised
labeling may be implemented 30 days
after submission.60,65 Approval from
the FDA may be received at any time
following submission, often four to six
months after filing.
º CBE-0 submissions are intended for
certain safety-related updates, such
as the addition or strengthening of a
contraindication, warning, precaution,
or adverse reactions statements about
abuse and dependence instruction
about dosage and administration that
is intended to increase the safe use
or deletion of false or misleading or
unsupported claims of effectiveness. The
revised labeling may be implemented
immediately upon submission. This sub-
mission mechanism allows sponsors to
comply with the requirement to revise
labeling “…to include a warning about
a clinically significant hazard as soon as
there is reasonable evidence of a causal
association with a drug a causal rela-
tionship need not have been definitely
established.”60,65,66 Depending upon the
nature of the change, the sponsor may
wish to discuss the proposed change
with the FDA’s project manager prior to
implementing the revised labeling for a
CBE-0 submission to avoid the risk of
the agency requiring significant changes
following its review of the support-
ing data. The timing of formal FDA
approval for such supplements will vary.
The labeling components submitted
with a CBE supplement are the same as
those for other submissions, including
SPL,55 a manuscript marked with revi-
sions to the currently approved labeling
and an annotated PDF file, but will
include copies of final printed labeling.
Note that implementation without
FDA approval may involve printing
components at risk, since the FDA may
require changes to the submitted and
implemented labeling update. For this
reason, such decisions will benefit from
consultation with personnel responsible
for managing packaging inventory so
they may limit quantities until approval
is granted.
• Safety change notification letters67,68 –
Section 505(o)(4) of the FD&C Act (added
as the result of FDAAA Section 901) autho-
rizes the FDA to require – and, if necessary,
order – labeling changes for prescription
products if it learns of new information
about serious risks it determines should be
included in the labeling. Previously, in the
absence of such authority, negotiations with
sponsors over agency-requested changes
could be protracted. New safety information
reflects a serious risk or unexpected serious
risk associated with the drug that has been
identified since approval. Revisions to boxed