Chapter 5: Pharmaceutical Labeling in the US
42 Regulatory Affairs Professionals Society (RAPS)
CFR 201.57(c)(10)), the section will identify
types of abuse that can occur and the adverse
reactions associated with abuse, as well as “par-
ticularly susceptible patient populations.” It also
must describe characteristics of psychological and
physical dependence, tolerance, and the effects of
chronic abuse and abrupt withdrawal. The draft
guidance highlights general labeling principles
and recommends content (including terminology
and definitions), organization of information,
and how to avoid redundancy in other prescrib-
ing information sections.
Submissions and Review
New prescription product labeling is included
in a new drug application (NDA)51 or biolog-
ics license application (BLA)52 in Module 1,
Administrative Information – 1.14 Labeling.
(With respect to the International Council for
Harmonisation’s [ICH] Common Technical
Document [CTD], this is considered region-
specific information.53) It can be argued that the
entire dossier exists principally to support the
manufacturing particulars and the product profile
described in the labeling. As noted previously,
all labeling content must be justified by evidence
and annotated to the appropriate dossier com-
ponents, whether in the summaries or overviews
or within individual reports. To facilitate review,
annotations should direct the reviewer to the
specific table or section rather than simply to the
relevant page in the supporting document.52,54
The labeling components are submitted in
Extensible Markup Language (XML) format
to meet Structured Product Labeling (SPL)
requirements.55 A sponsor also provides the
FDA reviewing division with the manuscript of
the prescribing information (and any required
patient labeling) as an annotated PDF file, along
with another copy in an editable format, such as
MS Word. The PDF file will include live links
from the labeling annotations directly to the
source documents within the dossier to facili-
tate reviewer navigation. The Word manuscript,
expunged of annotations, will be used as a work-
ing document for labeling negotiations between
the FDA and the sponsor to track iterative
proposals and counterproposals until all content
is agreed.
Comments are usually received from
the reviewing division approximately four to
six weeks before the action date set by the
Prescription Drug User Fee Act (PDUFA) for
the submission, but comments or information
requests can be requested at any time during
the review process. Typically, the FDA regula-
tory project manager coordinates the provision
of reviewer labeling comments to the sponsor.
Depending on the regulatory project manager,
comments and proposed changes may be collated
and sent in a single document or staggered and
sent as each reviewing discipline (e.g., clinical
pharmacology, clinical, nonclinical toxicology,
CMC) completes its review. For example, clinical
pharmacology reviewers will send comments
and proposed edits to text describing the active
ingredient’s mechanism of action, pharmaco-
dynamics, and pharmacokinetics (Section 12),
while feedback from the CMC reviewers will
address chemical characterization, pharmaceu-
tical particulars, and storage for the product and
its constituents (Sections 11 and 16). Nonclinical
reviewers will consider proposed text in the
nonclinical toxicology section (13), as well as
any discussion of animal data elsewhere in the
labeling, such as text describing what is known
about exposure during pregnancy and lactation
(Sections 8.1 and 8.2). Clinical reviewers will
share feedback on labeling content dealing with
safety and efficacy, including the description of
data from clinical trials and related directions
and warnings for prescribers. They also will
review the patient counseling section (17) and
any patient labeling prepared by the sponsor,
such as a Medication Guide.
While comments from the reviewing
division will focus on translating the data for a
benefit-risk assessment and provide guidance for
use, the FDA’s Labeling Policy Team will assess
the labeling as a communication tool. They also
review compliance with relevant guidances and
policies, as well as consistency across therapeutic
areas (reviewing divisions).56
42 Regulatory Affairs Professionals Society (RAPS)
CFR 201.57(c)(10)), the section will identify
types of abuse that can occur and the adverse
reactions associated with abuse, as well as “par-
ticularly susceptible patient populations.” It also
must describe characteristics of psychological and
physical dependence, tolerance, and the effects of
chronic abuse and abrupt withdrawal. The draft
guidance highlights general labeling principles
and recommends content (including terminology
and definitions), organization of information,
and how to avoid redundancy in other prescrib-
ing information sections.
Submissions and Review
New prescription product labeling is included
in a new drug application (NDA)51 or biolog-
ics license application (BLA)52 in Module 1,
Administrative Information – 1.14 Labeling.
(With respect to the International Council for
Harmonisation’s [ICH] Common Technical
Document [CTD], this is considered region-
specific information.53) It can be argued that the
entire dossier exists principally to support the
manufacturing particulars and the product profile
described in the labeling. As noted previously,
all labeling content must be justified by evidence
and annotated to the appropriate dossier com-
ponents, whether in the summaries or overviews
or within individual reports. To facilitate review,
annotations should direct the reviewer to the
specific table or section rather than simply to the
relevant page in the supporting document.52,54
The labeling components are submitted in
Extensible Markup Language (XML) format
to meet Structured Product Labeling (SPL)
requirements.55 A sponsor also provides the
FDA reviewing division with the manuscript of
the prescribing information (and any required
patient labeling) as an annotated PDF file, along
with another copy in an editable format, such as
MS Word. The PDF file will include live links
from the labeling annotations directly to the
source documents within the dossier to facili-
tate reviewer navigation. The Word manuscript,
expunged of annotations, will be used as a work-
ing document for labeling negotiations between
the FDA and the sponsor to track iterative
proposals and counterproposals until all content
is agreed.
Comments are usually received from
the reviewing division approximately four to
six weeks before the action date set by the
Prescription Drug User Fee Act (PDUFA) for
the submission, but comments or information
requests can be requested at any time during
the review process. Typically, the FDA regula-
tory project manager coordinates the provision
of reviewer labeling comments to the sponsor.
Depending on the regulatory project manager,
comments and proposed changes may be collated
and sent in a single document or staggered and
sent as each reviewing discipline (e.g., clinical
pharmacology, clinical, nonclinical toxicology,
CMC) completes its review. For example, clinical
pharmacology reviewers will send comments
and proposed edits to text describing the active
ingredient’s mechanism of action, pharmaco-
dynamics, and pharmacokinetics (Section 12),
while feedback from the CMC reviewers will
address chemical characterization, pharmaceu-
tical particulars, and storage for the product and
its constituents (Sections 11 and 16). Nonclinical
reviewers will consider proposed text in the
nonclinical toxicology section (13), as well as
any discussion of animal data elsewhere in the
labeling, such as text describing what is known
about exposure during pregnancy and lactation
(Sections 8.1 and 8.2). Clinical reviewers will
share feedback on labeling content dealing with
safety and efficacy, including the description of
data from clinical trials and related directions
and warnings for prescribers. They also will
review the patient counseling section (17) and
any patient labeling prepared by the sponsor,
such as a Medication Guide.
While comments from the reviewing
division will focus on translating the data for a
benefit-risk assessment and provide guidance for
use, the FDA’s Labeling Policy Team will assess
the labeling as a communication tool. They also
review compliance with relevant guidances and
policies, as well as consistency across therapeutic
areas (reviewing divisions).56