Chapter 5: Pharmaceutical Labeling in the US
46 Regulatory Affairs Professionals Society (RAPS)
product labeling (RPL) consistent with the indi-
cations to be registered for the biosimilar product
but will not necessarily use identical language
as the reference biologic. This accounts for the
natural variation in biologically sourced prod-
ucts, whereby the biosimilar labeling will include
details relevant to the safe and effective use of that
specific product, which may differ from that of the
reference biologic. So, unlike generic drug labeling,
which must be essentially identical to the RLD
labeling, biosimilar labeling will be similar but is
not expected to be identical. (Any Instructions
for Use [IFU] of the biosimilar will incorporate
relevant information from the reference product’s
IFU but will be modified to represent the biosim-
ilar product’s appropriate use.)
Information about the clinical research that
provided evidence of the reference product’s
safety and effectiveness should be included in
the biosimilar labeling. In contrast, the clinical
studies conducted to demonstrate biosimilarity
with the reference product generally should not
be described in the labeling, as it is not helpful
for prescribers.
Biosimilar product submissions will include
the RPL, an annotated “tracked changes” man-
uscript for the biosimilar labeling highlighting
and explaining differences from the RPL, and a
clean proposed version of the biosimilar labeling
manuscript.
Revisions to Generic Drug and
Biosimilar Labeling
Due to the requirement to mirror the RLD label-
ing, when revisions are made to innovator product
labeling, the generic product labeling needs to
be updated as quickly as possible. While the
FDA’s Office of Generic Drugs had been alerting
ANDA sponsors to changes, the onus for moni-
toring updates to RLD labeling has now shifted
to the ANDA holder, who is then responsible for
timely revision of the generic product’s labeling
consistent with that of the RLD.75 (The link in
the guidance is no longer maintained, so ANDA
holders are expected to monitor Drugs@FDA78
for updates to RLD labeling.)
Some safety issues that arise with the use
of a generic version of a drug product may be
related to the specific product marketed under
the ANDA, such as excipients used in the final
product formulation. However, evidence may
point to risks associated with the therapeutic
agent. In these cases, information should be
shared with the RLD sponsor to determine
whether a labeling change is warranted. The
FDA, under the authority and mechanism
discussed above, may require labeling revisions to
the RLD (and thereby the labeling of all relevant
generic products) for safety reasons.67,68
Even after the NDA for an RLD has
been withdrawn for reasons other than safety
or effectiveness, the ANDA holder retains the
obligation to prevent the labeling of its generic
version from becoming false or misleading as
knowledge about the product advances. ANDA
sponsors perform regular pharmacovigilance
reviews of postmarketing data and have access to
other, nonproprietary sources of relevant infor-
mation, such as updates to the labeling of drugs
in the same pharmacologic class and published
literature, and may submit a PAS to revise their
products’ labeling.79 Alternatively, under the
authority and mechanism discussed above, the
FDA may require labeling revisions to the label-
ing of all generic versions of a product without
an active RLD.67,68
In 2013, the FDA proposed a rule80 that
would permit an ANDA holder to unilaterally
implement a labeling revision for a generic drug
for safety reasons, using a CBE-0 submission to
the FDA and then sharing the revised labeling
and justification sources with the RLD spon-
sor. The RLD sponsor would submit its own
CBE-0 supplement with different changes if it
disagreed with the ANDA holder’s revisions.
The FDA would review the submissions and
approve a version of the labeling to be carried
by all products, including those of other ANDA
holders. The proposal met with vociferous indus-
try opposition, particularly the generic industry.
In December 2018, the FDA withdrew the
proposal, citing challenges and unexpected con-
sequences likely with its implementation, such as
confusion among healthcare professionals owing
to prolonged differences in labeling for brand
and generic drugs. Notice of the withdrawal
offered the FDA a chance to underscore generic
46 Regulatory Affairs Professionals Society (RAPS)
product labeling (RPL) consistent with the indi-
cations to be registered for the biosimilar product
but will not necessarily use identical language
as the reference biologic. This accounts for the
natural variation in biologically sourced prod-
ucts, whereby the biosimilar labeling will include
details relevant to the safe and effective use of that
specific product, which may differ from that of the
reference biologic. So, unlike generic drug labeling,
which must be essentially identical to the RLD
labeling, biosimilar labeling will be similar but is
not expected to be identical. (Any Instructions
for Use [IFU] of the biosimilar will incorporate
relevant information from the reference product’s
IFU but will be modified to represent the biosim-
ilar product’s appropriate use.)
Information about the clinical research that
provided evidence of the reference product’s
safety and effectiveness should be included in
the biosimilar labeling. In contrast, the clinical
studies conducted to demonstrate biosimilarity
with the reference product generally should not
be described in the labeling, as it is not helpful
for prescribers.
Biosimilar product submissions will include
the RPL, an annotated “tracked changes” man-
uscript for the biosimilar labeling highlighting
and explaining differences from the RPL, and a
clean proposed version of the biosimilar labeling
manuscript.
Revisions to Generic Drug and
Biosimilar Labeling
Due to the requirement to mirror the RLD label-
ing, when revisions are made to innovator product
labeling, the generic product labeling needs to
be updated as quickly as possible. While the
FDA’s Office of Generic Drugs had been alerting
ANDA sponsors to changes, the onus for moni-
toring updates to RLD labeling has now shifted
to the ANDA holder, who is then responsible for
timely revision of the generic product’s labeling
consistent with that of the RLD.75 (The link in
the guidance is no longer maintained, so ANDA
holders are expected to monitor Drugs@FDA78
for updates to RLD labeling.)
Some safety issues that arise with the use
of a generic version of a drug product may be
related to the specific product marketed under
the ANDA, such as excipients used in the final
product formulation. However, evidence may
point to risks associated with the therapeutic
agent. In these cases, information should be
shared with the RLD sponsor to determine
whether a labeling change is warranted. The
FDA, under the authority and mechanism
discussed above, may require labeling revisions to
the RLD (and thereby the labeling of all relevant
generic products) for safety reasons.67,68
Even after the NDA for an RLD has
been withdrawn for reasons other than safety
or effectiveness, the ANDA holder retains the
obligation to prevent the labeling of its generic
version from becoming false or misleading as
knowledge about the product advances. ANDA
sponsors perform regular pharmacovigilance
reviews of postmarketing data and have access to
other, nonproprietary sources of relevant infor-
mation, such as updates to the labeling of drugs
in the same pharmacologic class and published
literature, and may submit a PAS to revise their
products’ labeling.79 Alternatively, under the
authority and mechanism discussed above, the
FDA may require labeling revisions to the label-
ing of all generic versions of a product without
an active RLD.67,68
In 2013, the FDA proposed a rule80 that
would permit an ANDA holder to unilaterally
implement a labeling revision for a generic drug
for safety reasons, using a CBE-0 submission to
the FDA and then sharing the revised labeling
and justification sources with the RLD spon-
sor. The RLD sponsor would submit its own
CBE-0 supplement with different changes if it
disagreed with the ANDA holder’s revisions.
The FDA would review the submissions and
approve a version of the labeling to be carried
by all products, including those of other ANDA
holders. The proposal met with vociferous indus-
try opposition, particularly the generic industry.
In December 2018, the FDA withdrew the
proposal, citing challenges and unexpected con-
sequences likely with its implementation, such as
confusion among healthcare professionals owing
to prolonged differences in labeling for brand
and generic drugs. Notice of the withdrawal
offered the FDA a chance to underscore generic