Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5432_Библиотеки_им_академика_М_И_Перельмана.pdf
CHAPTER
341
31
Product Labeling
L
abeling is a general term encom-
passing many things about a drug.
Human drug labeling contains a
summary of the essential scientific
information needed for the safe and
effective use of the drug. Labeling is
divided for pharmacovigilance pur-
poses into several different documents.
For drugs that are not yet on the mar-
ket (approved or authorized for sale),
the labeling used for adverse events
(AE) reporting and all other “official”
considerations is the “Investigator Bro-
chure” as prepared by the sponsor and
submitted to the health authorities,
Institutional Review Boards/Ethics
Committees, Data Safety Monitoring
Boards, and investigational sites. After
a drug is approved for marketing (e.g.,
New Drug Application or Marketing
Authorization granted), the labeling
that is used for regulatory reporting
of AEs changes to that document pre-
pared by the sponsor and submitted to,
negotiated with, and approved by the
health authority for that jurisdiction:
Prescribing Information, Medication
Guides, Patient Package Inserts, and/or
Instructions for Use, and/or carton and
container labeling, the “Package Insert”
(PI) in the United States, and the Sum-
mary of Product Characteristics (SmPC
or sometimes erroneously referred to as
the SPC (Supplementary Protection Cer-
tificate; sometimes Single Point of Con-
tact)) in the European Union. The other
342 Cobert’s Manual of Drug Safety and Pharmacovigilance
key labeling document is the Company
Core Safety Information (CCSI). All are
discussed in the following sections.
Introduction
Labeling, the creation, maintenance, and updates to,
is generally managed and overseen by the Regulatory
Affairs and Legal departments as the documents encom-
passed in these activities are regulatorily controlled
and submitted to the agencies, and often to IRBs/ECs
and DSMBs. Even though the Regulatory Affairs team
should own the process for the creation, maintenance,
and updates to these documents, companies with lim-
ited resources may outsource the responsibility to ven-
dors, consultants, or CROs, or other functional areas
such as Safety & Pharmacovigilance, or Medical Affairs.
Regardless of who at the company oversees these activ-
ities, there should be standardized procedures in place
that are cross-functional and involve the input and
involvement from regulatory affairs, safety and phar-
macovigilance, clinical development, biostatistics, data
management, medical affairs, legal, and ultimately
approved by the Chief Medical Officer or Scientific Offi-
cer responsible for the scientific data for that product.
Final company approver should be an individual (by
title in SOPs) rather than a department. The procedures
should be label specific, outlining who is responsible
for the maintenance and update of each, the timeta-
ble for updates (scheduled and variations due to new
safety data), as well as the submission and archival
responsibilities.
Note that the requirement for labeling and safety
reporting begins when the product is approved even if
marketing is delayed. Marketing might be delayed for
various reasons (e.g. manufacturing scale up, awaiting
the onset of the disease being treated such as influenza
in the autumn and winter etc.).
Investigator Brochure
The requirements for the Investigator Brochure (IB) are
listed in ICH E6 Guidance on Good Clinical Practices,
which has been adopted in most jurisdictions, includ-
ing the FDA which issued a guidance for Industry in
2018, E6(R2) Good Clinical Practice: integrated Adden-
dum to ICH E6(R1) is the IB is a compilation of clinical
and non-clinical data on the study product that is rel-
evant to the investigators performing the trial, allow-
ing them to understand the rationale and key features
of the drug. Its purpose is to provide the investigators
and others involved in the trial with the information to
facilitate their understanding of the rationale for, and
their compliance with, many key features of the proto-
col, such as the dose, dose frequency/interval, methods
of administration: and safety monitoring procedures.
1
It is the sponsor’s responsibility to prepare the IB and
keep it up to date. It summarizes the chemical, physical,
and pharmacologic properties of the drug; non-clinical
studies; effects in humans; including absorption, dis-
tribution, metabolism, and excretion (ADME) data, as
well as clinical studies in volunteers and patients cov-
ering both efficacy and safety. Marketing experience, if
available, is also included. There should be a single IB,
in English, for global use.
The IB should include a brief summary highlight-
ing the significant physical, chemical, pharmaceuti-
cal, pharmacological, toxicological, pharmacokinetic,
metabolic, and clinical information available that is
relevant to the stage of clinical development of the
investigational product. The Summary should be fol-
lowed by, at a minimum, the following sections: Intro-
duction, Physical, Chemical, and Pharmaceutical
Properties and Formulation, Nonclinical Studies, Non-
clinical Pharmacology, Pharmacokinetics and Product
Metabolism in Animals, Effects in Humans (Pharma-
cokinetics and Product Metabolism in Humans, Safety
and Efficacy, Marketing Experience), Summary of Data
and Guidance for the Investigator.
The IB should contain summaries of safety across
multiple trials with indications in sub-groups using
tabular summaries of Adverse Drug Reactions (ADRs).
Important differences in ADR patterns/incidences across
indications or sub-groups should be noted if present.
The IB should provide a description of the possible risks
and ADRs to be anticipated based on prior experiences
1
FDA E6(R2) Good Clinical Practice: Integrated Addendum to ICH
E6(R1) Guidance for Industry March 2018.
Product Labeling 343
with the product and with related products. Any pre-
cautions or special monitoring to be done should also
be noted. The overall aim of this section is to provide
the investigator with a clear understanding of the possi-
ble risks and adverse reactions, and of the specific tests,
observations, and precautions that may be needed for
a clinical trial. This understanding should be based on
the available physical, chemical, pharmaceutical, phar-
macological, toxicological, and clinical information on
the investigational product(s). Guidance should also be
provided to the clinical investigator on the recognition
and treatment of possible overdose and adverse drug
reactions that are based on previous human experience
and on the pharmacology of the investigational product.
Note: While Overdose is not necessarily an AE, it can
lead to AEs or be considered as a product quality defect
and should be monitored for safety and outcome of the
patient. The IB can be dozens of pages long and should
be more inclusive rather than less inclusive. It is not a
marketing document and will be reviewed by investiga-
tors, Investigational Review Boards/Ethics Committees,
and Data Safety Management Committees/Independent
Data Monitoring Committees.
The IB should be updated yearly or more often if
new, clinically relevant information, particularly about
safety, becomes available. This document is used in the
preparation of 7- and 15-day expedited (alert) reports to
the health authorities, partners, and for investigational
new drug annual reports (e.g., Development Safety
Update Reports, or DSURs); the criteria “expected” or
“unexpected” is assessed according to the IB content.
After a drug is approved for marketing and if
it is also in clinical trials, it will have both an IB and
post-marketing labeling (e.g., EU SmPC, US PI). Note
that a product is not ordinarily approved/launched
simultaneously in all markets, so multiple documents
(not necessarily fully complementary) may exist.
Company Core Safety
Information
The “Core Safety Information” (CSI), or “Company
Core Safety Information” (CCSI), which is part of the
larger “Company Core Data Sheet” (CCDS), contains
the key safety data for the marketed product. This doc-
ument was defined originally by the CIOMS III and
CIOMS V working group reports. The CCSI contains
(only) basic safety information that should appear in
the safety labeling for the product in all countries where
the product is registered/licensed. It should not contain
speculation or safety information that might appear
in only one country’s labeling for some local reason.
Thus, the information in the CCSI represents the min-
imal safety data that should appear globally in all local
or national labeling. Additions may be made in local
labeling beyond what is in the CCSI if the local health
authority or company so chooses (insists?). Marketing
considerations should not play a role in preparing the
CCSI. AEs due to excipients should be included, but
those that have no well-established relationship to the
drug should not be included. The CCSI is used to deter-
mine which AEs are considered “listed” when prepar-
ing Periodic Safety Update Reports (PSURs/PBRERs). It
is not used for expedited reporting expectedness (the
approved, post-marketing label is used instead).
Other safety documents used in various countries
include the Development Core Safety Information
(DCSI), the Development Core Data Sheet. They are all
like the CCSI and contain key safety information used
for clinical trials, periodic reporting, and so forth.
United States Labeling
for Marketed Products
The US requirements for labeling are summarized in
21CFR1. The official definition of labeling for a mar-
keted product is 21CFR1.3(a) as follows:
(a) Labeling includes all written, printed, or graphic
matter accompanying an article at any time
while such article is in interstate commerce or
held for sale after shipment or delivery in inter-
state commerce.
(b) Label means any display of written, printed, or
graphic matter on the immediate container of
any article, or any such matter affixed to any
consumer commodity or affixed to or appear-
ing upon a package containing any consumer
commodity.
344 Cobert’s Manual of Drug Safety and Pharmacovigilance
Thus, in the US, “Labeling” includes the FDA-ap-
proved written material describing a drug, such as the
Package Insert and the packaging and box that a drug is
shipped or sold in. Commonly used terms for the subset
of labeling designated “Package Insert” include “profes-
sional labeling”, “direction circular”, “approved label-
ing”, and “package circular” or just plain “labeling.” It
also includes the FDA-approved patient labeling (called
“Medication Guides”) where this exists.
In 2003, the FDA introduced the new requirements
for the electronic specifications for exchange of Pack-
age Inserts, called “Structured Product Labeling” (SPL),
using a document markup standard approved by FDA
and Health Level 7. All Package Inserts must be submit-
ted in SPL format. See FDA’s website for further infor-
mation on this labeling initiative.
The specific requirements for drug labeling are
found in 21CFR201.57. These labeling requirements,
include the following:
Highlights section, drug names, dosage form,
route of administration and controlled sub-
stance symbol (if such a drug), initial US
approval, boxed warning (if any), recent major
changes, indications and usage, dosage and
admin istration, dosage forms and strengths,
contraindications, warnings and precautions,
adverse reactions, interactions, use in specific
populations (including pregnancy, teratogenic-
ity, geriatric and pediatric use), patient coun-
seling information, revision date, drug abuse/
dependence, overdosage, clinical pharmacol-
ogy, non-clinical toxicology, clinical studies,
references, how supplied, and patient counsel-
ing information.
Note that the highlights section is a short summary
(1/2 to 2 pages) of the rest of the Package Insert. Labels
before 2006 largely have the same sections, though
there is no highlights section, and the safety sections
are much shorter in many cases.
FDA issued a guidance covering the new require-
ments in more detail, entitled Labeling for Human Pre-
scription Drug and Biological Products — Implementing
the New Content and Format Requirements. Several
other guidances covering the various sections of the
labeling were also issued.
The guidance covering the adverse reaction section
will be discussed briefly here as follows:
1. The goal is to include only information useful
to practitioners making treatment decisions and
monitoring patients. Exhaustive lists of AEs
should be avoided.
2. The Adverse Reactions (ARs) section should
contain those that occur with the drug itself and
ARs from the class, if appropriate, and even if
not yet observed with the new product. Clini-
cal trial and spontaneous reports must be listed
separately.
3. All serious and otherwise important ARs should
be listed and cross-referenced (e.g., Boxed
Warning, Warnings and Precautions).
4. ARs that resulted in a significant rate of discon-
tinuation or other clinical intervention, such as
dose change in clinical trials.
5. ARs from clinical trials is the major component
of the AR section and should include the most
commonly occurring ARs (e.g., all ARs >10%
and 2 × placebo rate). This section should
describe the clinical trial database in terms of
exposure, number of patients, demograph-
ics, types of studies, doses, and so forth. Data
should be presented in a table to allow side-
by-side comparisons. The best available data
should be used — placebo-controlled and dose
response studies.
6. Less common ARs should be presented if clini-
cally important and here is a basis to feel that a
causal relationship to the drug exists.
7. Additional information should be given for the
most clinically significant ARs (i.e., most com-
mon, cause discontinuation, or dose change or
require monitoring).
8. Dose response, demographic, and sub-group
information should be included if important.
9. If there are multiple indications and/or multiple
formulations, a discussion about these issues
regarding safety should be included.
Product Labeling 345
10. A separate listing of spontaneous ARs should
be included, particularly those that are serious,
frequent, or seem to be causally related ARs.
11. When reporting rates are included, all cases of
that AE should be used rather than just those
the reporter feels are related.
12. Comparative safety claims (frequency, severity,
or character of the AR) must be based on data
from adequate and well-controlled studies.
13. Negative findings, if convincingly demonstrated
in an adequate trial, may be included.
14. Data may be pooled from studies when the
studies are appropriate to pool (similar design,
populations, etc.).
15. Data should be coded meaningfully and grouped
as appropriate (e.g., sedation, somnolence, and
drowsiness should be grouped as a single AR).
Syndromes should be used where appropriate
(e.g., hypersensitivity).
16. ARs should be categorized by body system, by
severity (in decreasing frequency), or by a com-
bination of both. An appropriate frequency cut-
off may be specified.
17. Quantitative data (e.g., labs, vital signs, ECGs)
should be presented as rates of abnormal val-
ues, with a cutoff for inclusion (e.g., five times
the upper limit of normal) rather than a grading
system.
18. If the AR rate is less than it is for the placebo,
this information should not be included unless
there is a compelling reason to do so.
19. Statistical significance should not be included
unless based on an adequately designed and
powered study.
20. The label should be reviewed at least annually
to be sure all appropriate data are included.
For an example of this labeling, see the Zyprexa
(olanzapine) label. The label has historically been 35
pages long, and the Warnings and Precaution section
runs about 8 pages and includes 7 tables. The AR sec-
tion runs 9 pages and contains 14 tables, and the Inter-
actions section runs 2 pages. From a practical point
of view, if a practitioner has a question, such as “Does
this drug cause headache?” and if it is not listed in the
summary, the most expedient way to find this is to load
the document onto a computer or handheld device or
pull the label from an online database as a PDF file and
search for that term. Multiple hits may occur, leading to
listings in several tables from which the practitioner can
draw his or her conclusions. One might observe that
this is not necessarily a quick or practical way to find
out whether a specific AE or problem has occurred with
the product in question.
In the United States, many, but not all, prescription
drug labels are printed in the reference book known
as the Physicians’ Desk Reference (PDR), published
yearly by Thomson. It is about 3000 pages long and has
photos of many of the products as well as the product
information.
Daily Med (https://dailymed.nlm.nih.gov/dailymed/
index.cfm) from the US National Library of Medi-
cine also has the labeling, however the official cop-
ies of the drug label remains the responsibility of the
company. There are also many other companies (e.g.,
rxlist.com and drugs.com) and organizations that have
drug information available on line that is taken from
the approved US labeling. They are often more user-
friendly than the labeling itself and are often broken
down by sections that are easily navigated. Other
countries have the equivalent publications with drug
labeling.
Many drug labels and patient information for spe-
cific drugs can be found at the FDA website (https://
labels.fda.gov/). In addition, most pharmaceutical
companies have posted their product labeling on
their websites. If the drug is sold in multiple coun-
tries, each local company website usually posts the
local labeling.
Regardless of where a drug label is posted (see
above), the official copy of the drug label remains the
responsibility of the company and company employ-
ees, safety personnel, etc. should only be referencing
approved company drug labels for assessing expected-
ness; it is considered poor practice for a company to
instruct employees to reference a non-company spon-
sored website (such as Daily Med, Drugs@FDA, RxList,
Drugs.com, etc.) as the company does not own or oper-
ate those websites and cannot guarantee the accuracy of
the data on them.
346 Cobert’s Manual of Drug Safety and Pharmacovigilance
European Union Safety
Labeling for Marketed
Products
The requirements for labeling in the European Union
(which is called the Summary of Product Characteris-
tics [SmPC or SPC]) is found in EudraLex Volume 2C,
which includes the requirements for submitting the
dossier for a new product (https://ec.europa.eu/health/
documents/eudralex/vol-2_en). The SmPC “sets out
the agreed position of the medicinal product as distilled
during the course of the assessment process”. It cannot
be changed without agreement by the health authorities.
If a drug is approved centrally in the European Union,
or if the labeling is harmonized, then there should only
be one SmPC per product (in English), though there
may be additional SmPCs for the same chemical entity
if there are different forms or strengths. Drugs that are
not approved or harmonized may have a different SmPC
in each member state. The SmPC will usually be in the
local language of the country.
Similar to other country labeling, the SmPC includes
the name, strength, pharmaceutical form, composi-
tion, indications, dosing (called “posology”), method
of administration, special populations (renal, hepatic
impairment, elderly, genotype-particular patients, pedi-
atrics), contraindications, special warnings, precau-
tions (including ARs to which healthcare professionals
need to be alerted), interactions, fertility, pregnancy and
lactation, effects on driving and machine use, undesir-
able effects (adverse reactions), overdose, pharmacolog-
ical properties, pre-clinical safety data, pharmaceutical
details, including excipients, incompatibilities, shelf
life, storage, appropriate container, disposal instruc-
tions, and registration and update information.
The adverse reaction section should include all ARs
from clinical trials, post-authorization safety studies,
and spontaneous reports “for which a causal relation-
ship between the medicinal product and the adverse
event is at least a reasonable possibility”. ARs should
not be listed if there is no suspicion of a causal relation-
ship. The section should contain the following:
A summary of the safety profile containing informa-
tion on the most serious and/or most frequent ARs.
A tabulated list of ARs with frequency. It should be a
single table in general though separate tables may be
used in exceptional circumstances (e.g., using a
product in different indications or dosages). Med-
DRA
®
Preferred Terms (PTs) should be used. If
appropriate, data from several trials may be pooled.
A description of selected ARs that “may be useful
to prevent, assess or manage the occurrence of an
adverse reaction in clinical practice.” For further
detail, see Volume 2C.
The full information to be included in each section,
is specified in the “Guideline on Summary of Product
Characteristics”. Quality Review of Documents (QRD)
templates were developed by the EMA; they give strict
recommendations on the format to be used. Package
Leaflet guidelines have been updated several times over
the past years; the last update is dated June 2023. They
can be retrieved on the European Community Website.
Due to the numerous languages used in the EU,
the translation part in the process of labeling updates
remains tricky. Except for decentralized procedures
(where the SmPC is approved in the local language),
the SmPC is proposed, discussed and validated in
English. Then a translation process is done taking the
new English language label and translating it into each
local language. Previously, the pharma companies had
to provide the EMA with all translated SmPCs within
a very short timeframe. Due to significant translation
mistakes, the EMA is now, (prospectively and for label-
ing updates only), preparing the approved updated sec-
tion in each of the 24 official EU languages.
Other Countries
Most countries of the world have fairly similar reg-
istration and approval systems, involving a multi-
disciplinary review of all the submitted data and
labeling based on the submitted data. The approvals
may vary significantly from country to country; how-
ever, they are based on different data submitted or
emphasized, different indications requested, different
formulations, different patient populations treated,
and local customs. Thus, the labeling may be some-
what different from country to country. In addition,
Product Labeling 347
in non-English-speaking countries, the labeling is, of
course, in the local language.
Comments about Labeling
Content
In the European Union, the approved labeling is known
as the Summary of Product Characteristics (SmPC).
There is a curious use of terminology by some people.
In the United States, the generic term labeling (some-
times called the “Package Insert”, or “PI”) is used to
refer to the official FDA-approved US product infor-
mation. The word “labeling” is also used in the United
States for the SmPC when referring to European label-
ing. Some in the European Union, conversely, use the
term “SmPC” when they are referring to their own offi-
cial labeling or to the US labeling. Thus, one might hear
a reference to the US SmPC — a concept that does not
really exist in the United States. This refers, in practice,
to the US official Package Insert and not the European
Union SmPC.
In terms of pharmacovigilance, sections of labeling
of most interest include the AEs, warnings, drug inter-
actions, precautions, and pregnancy information. In
particular, the labeling is used to determine whether a
particular AE that is reported for that product is expected
in many but not all countries, if an AE is expected, it
does not have to be reported to the health authority as
an expedited report. Class labeling of a particular AE/
AR is not considered expected or labeled for the pur-
poses of expedited reporting in most jurisdictions.
Changes, additions, removals, “variations”, and
alterations to product labeling must usually be approved
by the health authority concerned. In many jurisdic-
tions, the sponsor (NDA holder, MAH) may change the
labeling to add an urgent safety warning without prior
approval by the health agency. In the United States, this
is known as “Changes Being Effected”. Of course, the
FDA must be told rapidly. This is permitted.
“to add or strengthen a contraindication, warn-
ing, precaution, or adverse reaction for which
the evidence of a causal association satisfies the
standard for inclusion in the labeling...to add
or strengthen a statement about abuse, depen-
dence, psychological effect, or overdosage...to
add or strengthen an instruction about dosage
and administration that is intended to increase
the safety of the use of the product” (See CFR
Title 1).
See, for example, 21CFR601.12 Changes to an
approved application for biologics. Similarly, in the
European Union, “urgent safety restrictions” are per-
mitted. In such circumstances, the MAH is required to
submit a variation within 15 cal. Day and speed up the
implementation for both SmPC and PI.
Note that drug labels do not always use MedDRA
terms for AEs. Many drugs are quite old and date back
many years to pre-MedDRA days. Thus, terms used are
from other dictionaries, such as COSTART or WHO-
ART, or the terms may be non-standardized. In addi-
tion, CIOMS has developed the concept of MedDRA
Labeling Groupings that may appear in labels. This can
clearly produce issues when one attempts to determine
whether a term (e.g., a MedDRA term) is considered
labeled or listed if a similar but not quite exactly match-
ing term is found. Semantic interoperability remains
aspirational, so other terminologies may continue to
be represented in labeling, e.g., Common Terminology
Criteria for Adverse Events (CTCAE), with or without
severity grades, for some oncology products.
In Canada, the equivalent of the PDR is called the
Compendium of Pharmaceuticals and Specialties, avail-
able in English and French. In France, it is called the
“Vidal” (this website is in French) and in Germany, the
“Rote Liste” (this website is in German). In the United
Kingdom, SmPCs and Patient Information Leaflets
(PILs) are available on the MHRA website.
OTC Labeling in the United
States
The labeling for OTC products in the United States is
usually different from the labeling of prescription prod-
ucts. With most OTC drugs, labeling is derived from
“monographs” (the CFR sections dealing with these
products and specifying which products may be sold
348 Cobert’s Manual of Drug Safety and Pharmacovigilance
without an NDA or Abbreviated New Drug Application,
ANDA). OTC drugs are used by patients and consumers
without a healthcare intermediary (physician, pharma-
cist, nurse) to explain the product, its use, its adverse
events, and so forth. The labeling is what is written on
the package (box) in the section marked “Drug Facts”.
This is a lay version of a Package Insert but is often very
skimpy regarding AEs. Sometimes none are listed at
all. This is often most surprising because certain prod-
ucts that had extensive lists of AEs (e.g., loratadine,
non-steroidal anti-inflammatory drugs, and others) in
the Package Insert when they were prescription drugs
now have minimal safety information in the OTC Drug
Facts. Note that an OTC product in the US may be a
prescription product elsewhere.
Some OTC products may be sold under an NDA or
ANDA, and these products may have a classic Package
Insert. These drugs do not fall under the monographs
and were previously prescription drugs with an NDA or
ANDA that remains in effect.
Similarly, for food supplements, there is a label
marked “Supplement Facts.” Many companies that sell
OTC products sell supplements, drugs, devices, and
sometimes even cosmetics, making for very compli-
cated AE collection and reporting.
This labeling situation complicates AE reporting to
the FDA. A product may be an OTC through (usually)
one of two mechanisms: (1) an approved NDA or ANDA
that was originally for a prescription product that has
been switched to OTC status or (2) through the OTC
drug monograph process. Safety reporting obligations
depend on which route was used. For products with an
NDA or ANDA the requirements are the same as for pre-
scription products (e.g., expedited reporting, approved
labeling, Periodic Reports/PSURs). Until 2007, there
was no obligatory safety reporting for monograph prod-
ucts, though some companies voluntarily submitted
safety reports, usually for SAEs. The Dietary Supple-
ment and Non-prescription Drug Consumer Protection
Act of 2006 and a subsequent guidance in 2009 clarified
the situation. On this matter, an FDA Q&A should also
be checked (see FDA Website)
The reporting requirements are as follows:
1. Manufacturer, packer, or distributor whose name
is on the label (called the “responsible person”)
must submit to FDA all SAEs with a copy of the
label within 15 business days.
2. All follow-up information received within 1 year
of the initial report must be submitted within 15
business days. Note that the law states only 1
year of follow-up, but FDA has indicated that it
wants no time limit. That is, report all follow-ups
forever.
3. MedWatch (3500A) form or E2B to be used for
reporting. Mandatory reporting by applicants
must be via E2B.
4. The NDA definitions for minimum criteria,
reportability, and so forth, are in effect here:
For brand families, it is necessary to know the
active ingredient to have a reportable drug;
If multiple suspect drugs, submit Individual
Case Safety Report (ICSR) to FDA and to
other manufacturers.
5. No aggregate reporting requirements.
6. Signaling is required for the NDA/ANDA prod-
ucts but is not specifically stated to be required
for monograph products, though it would be
wise to do so.
Note: In the European Union, there are no OTC
products without MAs, so all prescription drug report-
ing requirements apply to OTC products. In practice,
many companies treat all OTC products the same and
do expedited reporting, periodic reporting, and sig-
naling. Some countries have multiple and more com-
plex rules, including “OTC” and “behind-the-counter”
products, which do not require prescriptions but which
may (in the latter category) require the customer’s
talking to the pharmacist before being able to purchase
the product.
Labeling Update Process
When an authorization dossier (e.g., in the US an NDA
and in the EU a MAA) is submitted, the company team
working on its preparation must, among other things,
submit proposed labeling (US PI, EU SmPC & EU PL,
etc). Starting from scratch, the team must combine
and summarize the often large amounts of data col-
lected during the non-clinical and clinical develop-
ment. This is submitted in most cases as “annotated”
Product Labeling 349
labeling — that is, each statement, claim or fact must be
backed up by data referenced in a footnote. The final,
approved labeling usually does not have all the annota-
tions and footnotes.
After approval with the product on the market,
new information (efficacy, safety, regulatory, etc.) will
become known which needs to be included in the Prod-
uct Information. Such new information generates a
labeling update. The scheme below highlights the main
steps, milestones and stakeholders involved in this pro-
cess in the EU. It is similar for US labeling updates.
In large pharma companies, a specific team is
devoted to labeling activities, most often within the Reg-
ulatory Affairs department. After initial drug approval
and marketing, between 80% and 90% of the labeling
updates are due to new safety concerns. This means
both the PV and Labeling teams must work
closely together.
The Labeling Committee decision-makers must be
senior managers from PV, Reg. Affairs, Med. Affairs and
Legal. They usually meet as a committee and approve
the content and wording of the labeling updates. This is
an iterative process, as regulators and
In many cases, the key document that is updated
is the CCDS/CCSI which then serves as the source for
updating all other local labeling documents (US PI, EU
SmPC, EU PIL, etc). Considering the importance of
FDA and EMA at a worldwide level, some companies
prefer to update CCDS/CCSI, US PI and EU SmPC at
the same time and therefore request the Labeling Com-
mittee to approve these three documents.
For labeling updates, in order to ensure consistency
across countries, the best approach is to provide the
affiliates with a rationale or “package” for any labeling
update. Such documents are then submitted to local
agencies, supporting the update proposal.
When receiving the CCDS/CCSI update with the
scientific rationale, the affiliates prepare the local label
update which is then submitted to the local agency.
After assessment and potential wording changes, the
new label is implemented and therefore made available
to patients and healthcare professionals in that country.
Most companies maintain a computerized archive
of all labels used in all languages in all affiliates. This
would include both the current labeling in use in each
country as well as previous versions of the labels which
are now out of date. These archived labels may be needed
for research, scientific publications, lawsuits, etc.
From beginning to end, this complex process can
take months or even years. However, if a label change
is urgent or critical, it may need to be done in a mat-
ter of days. Companies and health agencies must have
a mechanism to do this. In many countries, all label
changes must be approved by the health agency. How-
ever, for emergencies, some countries allow labels to be
changed immediately (“changes being effected” in the
US) with approval by the health agency in the next day
or two.
Figure 1. Schematic Relationships in Labeling Updates.