FDA Guidance for Food and Drug Labelling #peivandpirouzi #training #canada #pirouzi #international #funding #immigrants #refugees #canada #immigration #education

1. This lecture is regarding compliance for post-marketing activities for updating the product label
(U.S.) or the Summary of Product Characteristics (SmPC - EMEA) based on product related post-
market updates on new indications, target populations, post marketing Safety data, product
Efficacy and pharmacology data.

2.  A new FDA final rule, "Requirements on Content and
Format of Labelling for Human Prescription Drug and
Biological Products," became effective in June 2006.
 The rule is part of FDA's initiative to manage the risks
of medical product use and minimize adverse events.
 The new labelling reorders and reorganizes sections
found in the previous labelling format.
 FDA has designed new labelling to help health care
practitioners easily find, read, and convey information
important for the safe and effective use of
prescription drugs.

3.  A label is now divided into highlights of
prescribing information, contents of the full
prescribing information (FPI), and the FPI. The
highlights section is a half-page summary of
the information that health care practitioners
most commonly refer to and view as most
important.

4.  FDA has instituted a flexible implementation
schedule that phases in the new labelling
requirements; more time to achieve
compliance is provided for older products.
The revision of labelling for products
approved or submitted for approval under an
abbreviated new drug application (ANDA)
depends on the labelling of the listed drug
referenced in the ANDA. The new
requirements do not apply to nonprescription
drug products.

5.  A prescription drug product label (also known as a
professional label, package insert, direction circular, and
package circular) is a compilation of information about a
product written by the manufacturer and approved by FDA.
 Labelling is based on the agency's thorough analysis of the
new drug application (NDA) or biological license
application. The labelling, or prescribing information, is
thus subject to FDA regulations and is a requirement for
all approved drug and biological drug products.
 A label contains information necessary for safe and
effective use and is written primarily for the health care
practitioner.

6.  Confusing medical information maybe
contributing to the approximately 300,000
preventable adverse events occurring each year
in U. S. Hospitals.
 Research has shown that these adverse events
may be reduced by prioritizing the warning
information on the label.
 Based on multiple public meetings and surveys,
FDA identified the most common ways
practitioners use prescription drug labelling and
the prescribing information they consider most
important and applied its findings to the
revisions.

7.  The new labelling reorders and reorganizes
sections found in the previous labelling
format (next slide).
 Under the new system, a label is divided into
highlights of prescribing information,
contents of the full prescribing information
(FPI), and the FPI.

8. Comparison of previous labelling format with revised format. (Subheadings may vary for

9.  A label begins with highlights, a succinct, half-page summary of
the information that health care practitioners most commonly
refer to and view as most important (next slide).
 This section provides immediate access to the information most
crucial for a drug's safe and effective use and contains numerical
cross-references to more details in the FPI.
 In designing the highlights section, FDA used established
techniques to enhance the communication of large amounts of
complex information.
 Highlights summarizes the information from the FPI that is most
important for prescribing a drug safely and effectively and
logically organizes it to enhance accessibility and retention. The
design combines multiple textual and graphic elements (e.g.,
tables, bulleted lists, boldface, italics).

10. Example of highlights section (for a fictitious drug).

11.  Highlights does not include all the
information necessary to use a drug safely
and effectively. For this reason, it is prefaced
with a limitations statement that reads,
"These highlights do not include all the
information needed to use drug X safely and
effectively. See full prescribing information
for drug X. "

12.  Product Names and Date of Initial FDA Approval. The listing of other names for the
product can be important to avoid confusion. The date of approval provides
context on the relative newness of a product, since there may be limited clinical
information about a new product compared with one that has been on the market
for some time.
 Boxed Warning. Many drug product labels contain a boxed warning, often referred
to by health care practitioners as a black-box warning, to emphasize certain risks.
The boxed warning that appears in the highlights section may be a condensed
version of the complete boxed warning in the FPI and is limited to 20 lines.[1]
Cross-references maybe made to additional safety information in the FPI.
 Recent Major Changes. Changes that have been made to certain sections of the FPI
are listed. Marginal notations appear in the corresponding sections of the FPI to
indicate where the changes occurred.
 Indications and Usage. Listed are the indications for use of a drug, the major
limitations to use, the pharmacologic class, and the mechanism of action.

13.  Dosage and administration. The recommended dosage regimen for the
given indications is provided, along with the starting dosage, dosage
range, whether the drug should be taken with or without food, critical
differences among population subsets, monitoring recommendations,
and significant clinical pharmacologic information.
 Dosage Forms and Strengths. The available dosage forms and strengths
are detailed.
 Contraindications. No relative contraindications are listed, only
circumstances when the drug should absolutely not be used. The
contraindications statement must be included even if there are no
contraindications.
 Warnings and Precautions. An abbreviated summary of the most
clinically significant adverse drug reactions (ADRs), how to monitor
them, and how to treat them is provided.

14.  Adverse Reactions. Listed are the most common ADRs, their
frequencies, and how they should be reported to the
manufacturer and to FDA.
 Drug Interactions. The drug interactions are briefly described.
 Use in Specific Populations. This section, which was previously
integrated into the precautions section, summarizes important
information about use in specific populations.
 Patient Counseling Information. The practitioner is reminded of
information important to convey to the patient.
 Contents. The contents section serves as a navigational tool that
references all the sections and subsections in the FPI, some of
which may not be referenced in highlights (Figure 3). The
contents sectional so allows for hyperlinks in electronic formats.

16.  Changes in Content. The clinical pharmacology section describes
drug-drug interaction study results and alerts practitioners to
the extent of particular interactions.
 The contraindications section now describes only known hazards
and no longer includes the statement "allergic to any component
of the drug." A contraindication exists only when the risk from
use clearly outweighs any possible therapeutic benefit. “None” is
stated when no contraindications are known, and no relative or
hypothetical contraindications are listed. The order in which
contraindications are listed is based on their likelihood and the
size of the population affected.
 The warnings and precautions sections are consolidated into one
section containing the most critical safety information. This new
section also includes clinically significant ADRs that require
discontinuation of the drug, dosage adjustment, or addition of
another drug; that could be prevented or managed with
appropriate patient selection or avoidance of concomitant
therapy; and that significantly affect patient compliance.

17.  ADRs observed in post marketing clinical trials are included with the
clinical trial experience.
 Post marketing spontaneous-ADR reports are listed separately. This
section no longer contains a "laundry list" of ADRs. It provides additional
detail on the nature, severity, and frequency of ADRs and their
relationship to dosage and patient demographics.
 Contact information for reporting ADRs is provided.
 Some product identification information (color, scoring) is located in
both the how-supplied section and the dosage forms and strengths
section to preserve the integrity and enhance the understanding of both
sections.
 The clinical and nonclinical toxicology sections, which were previously
optional, are now required.

18.  A separate section on patient-counseling
information has been added in response to
the requirement that all FDA-approved
patient information be reprinted in or
accompany drug product labelling.
 The requirement regarding the inclusion of all
FDA-approved patient information also
applies to older products not otherwise
subject to the new content and format
requirements.

19.  Patient information (including patient package
inserts and medication guides) is designed to
communicate to patients in understandable
language the most important information they
need to use a product appropriately.
 Patient counseling information is specifically
written for health care practitioners to inform
them about what information is important to
convey to the patient at the time of prescribing
for the drug to be used safely and effectively.

20.  The information practitioners refer to most
frequently and consider most important (e.g.,
boxed warning, indications and usage,
dosage and administration, dosage forms and
strengths, and storage and handling) is
located at the front of the prescribing
information. As a result of feedback from two
national physician surveys,[1,2] the indications
and usage section and the dosage and
administration section are now at the
beginning of the FPI.

21.  FDA has instituted a flexible implementation
schedule that phases in the new labelling
requirements ( Table 1 ).
 The schedule bases compliance on the date the
application was submitted to the agency.
 More time to achieve compliance is provided for
older products; labelling for newer products
(typically those with more complex labelling and
those with labelling that practitioners refer to
more often) must be updated first.

22. Applications Required To Conform to New Time by Which Conforming Labelling Must Be
Requirements* Submitted to FDA for Approval
Applications submitted on or after June 30, 2006 Time of submission
Applications pending on June 30, 2006, and June 30, 2009
applications approved 0-1 yr before June 30,
2006
Applications approved 1-2 yr before June 30, June 30, 2010
2006
Applications approved 2-3 yr before June 30, June 30, 2011
2006
Applications approved 3-4 yr before June 30, June 30, 2012
2006
Applications approved 4-5 yr before June 30, June 30, 2013
2006
Applications approved more than 5 yr before Voluntarily at any time
June 30, 2006
* Includes new drug applications, biological license applications, and efficacy supplements.

23.  The labelling of a drug product submitted for approval
under an ANDA will have to have the same format as the
labelling of the listed drug referenced in the NDA
 Except for changes required because of differences
approved or because the drug product and the referenced
listed drug are produced/distributed by different
manufacturers.
 Such differences in labelling may include differences in
expiration date, formulation, bio availability, or
pharmacokinetics; labelling revisions done to comply with
current FDA labelling guidelines or other guidance; or
omission of an indication or other aspect of labelling
protected by patent or accorded exclusivity.

24.  Brand name drug labelling must accompany
drug product samples.
 The new requirements do not apply to non
prescription drug products (including those
approved under an NDA).

25.  Submitting labelling in electronic and structured
product labelling (SPL) format will support
initiatives to improve patient care through
electronic prescribing and improve the drug
labelling review process so that FDA can provide
immediate access to the most recent drug
information.
 SPL-formatted labelling will be available on the
Facts@fda website
(www.fda.gov/cder/news/FactsatFDA.htm), a
comprehensive resource designed to give one-
stop access to information about all FDA-
regulated products

26.  The new electronic labelling will be a key element
of and primary source of medication information
for Daily Med, a new interagency online health
information clearinghouse created cooperatively
by FDA and the National Library of Medicine.
 Daily Med will make current information about
FDA-regulated products available free of charge
to health care professionals and patients. This is
an important step toward providing practitioners
with electronic access to up-to-date information
on drug safety and effectiveness at the point of
care.
 http://dailymed.nlm.nih.gov

27.  Update of the revised European Labelling
Guideline – the European Summary of Product
Characteristics (SEP 2009)

28. • Overview of the new recommendations
• Data based on requested clinical studies in
paediatric population
• How to calculate frequencies of unwanted
drug reactions based on clinical studies, post
authorisation safety studies and spontaneous
reports
• Similarities and differences between
European Guideline and FDA labelling
practice

29. . Explain the importance of the European SmPC Guideline
• Discuss the changes due to the revision of the SmPC
Guideline
• Outline the use of the medicinal product in the
paediatric population
• Explain the similarities and differences in comparison to
FDA labelling practice from the perspective of global
labelling and company core safety data documentation

30.  Guidelines on Product Characteristics
 http://www.ema.europa.eu/htms/human/raguidelines/productinformation.h
tm

31.  Directive 2001/83/EG as amended serves as legal base
changed 2004 with effect on product information
 Guideline on the Summary of Product Characteristics Most
relevant documents revised in September 2009 due to
above changes
 Template on SmPC (as by revised QRD template) as a
consequence of both revisions
 MedDRA-SOCs for grouping adverse drug reactions
 Excipients-Guideline
 Standard Terms of EDQM
 Guideline on risk Assessment on Human Reproduction
 and Lactation: From Data to Labelling revised guideline
and new recommendations for labelling

33. Implementation of new requirements for information on
paediatric use
Art. 11 Dir. 2001/83/EC
Paediatric Regulation 1901/2006, especially. Art. 2 (3), Art. 28
Extensive revision of Undesirable Effects section
after extensive discussions improved description of the safety
profile
Additional information on pharmacogenomic aspects
Additional changes due to current guidance documents
Declaration of active substance of biotech products
Considering advanced therapies
Composition
Storage conditions

35.  The summary of product characteristics contains a description of a
certain medicinal product’s properties and the conditions attached to its
use.
 Example:
◦ Name
◦ Composition (declaration)
◦ Pharmaceutical form and strength
◦ Authorised applications (indications)
◦ Adverse reactions
◦ Cautions and safety regulations
◦ Shelf-life
◦ Storage conditions
◦ Holder of marketing authorisation (firm)
 The summary of product characteristics is prepared for the use of
"professional people" and contains a certain amount of professional
language.
 Patients are therefore advised to seek information either in the package
leaflets, from general practitioner or at the pharmacy.

36.  Definitive statement between the competent
authority and the marketing authorisation holder
 Basis of information for health professionals
 It is not the remit of the SmPC to give general advice
of the treatment of a particular disease

37.  The SmPC Guideline…
Gives advice on the principles of presenting
Requires to maintain the integrity of each section
Allows cross-references to other sections when these
contain relevant additional information.
 A SmPC is to be presented for each
pharmaceutical form and strength.

38.  Each section of the SmPC should first deal
with those issues that apply to the core
population followed by specific information
for any relevant special population (e.g.
children or elderly).
 Consistent medical terminology should be
used throughout the SmPC.
 Public Assessment Reports provide detailed
information.

41.  Data of relevance for administration in
paediatric population must be addressed
under a dedicated sub-heading in all sections
except contra-indications
 Knowledge should be presented as precisely
as possible
 Decision of the Paediatric Committee (PDCO)
must be included

42.  The wording should be clearly and concisely
 Indicate: treatment, primary or secondary
prevention or diagnostic indication
 When appropriate, define the target population
especially when restrictions to the patient
populations apply
 Age group should be stated
 Study endpoints are normally not included

44.  Product indicated for use in children
specific age groups as appropriate
 Product not indicated for use in children
New: Indication should state, that the product is for use
in adults only
 Product currently not indicated for use in
children
New: “Lack of information” does not mean
contraindication, but information may be provided
in section 4.2 or 5.1 according to assessment
and decision taken by PDCO

46. New: Subsection “paediatric patients”: always to be included
Paediatric indication not yet authorised
“The <safety> <and> <efficacy> of X in children from the age of x to y <has><have> not
<yet> been established;
<no data are available><currently available data are described in section <4.8><5.1><5.2>>.“
no longer: “The experience in children is limited.” or “There is no experience in children.”
Contraindicated for children in general or in specific age groups
Refer to 4.3 Contraindications
Not recommended for children in general or in specific age groups
Indication not relevant – dedicating the product to e.g. adults
“safety or efficacy concerns to be explained” – Refer to 4.8 Undesirable effects or 5.1
Pharmcodynamic properties as appropriate
New: Recommendations as specific as possible
Description of application specifics
Adjustment to daily life: school, out-school activities etc..

48. New subsection: “Paediatric population”
 Warnings specific to the paediatric population
or any subset of the paediatric population
 Any necessary warning or precaution in
relation to long-term safety (consideration of
development phase in childhood, gender,
daytime activity, sleeping behaviour and
rhythms)

50.  Sections 5.1 – 5.3 should normally mention
information relevant to the prescriber and to other
health-care professionals taking into account the
approved therapeutic indication(s) and the
potential ADRs
 Statements should be brief and precise
 Sections should be updated regularly

51.  Pharmacotherapeutic group (ATC Code)
 Mechanism of action (if known)
 Pharmacodynamic effects
 Clinical efficacy and safety
(statistically compelling and clinically relevant, using
absolute figures, pharmacogenetic data)
 Paediatric population
 Additional information on “conditional
approval” and under “exceptional
circumstances“

52. New Section : “Paediatric population”
 Results of all clinically relevant data (pharmacodynamic and
efficacy) according
to age groups
1. Exploratory studies: results according to the main criteria within
the population studied
2. Confirmatory studies: precise and comprehensive summary of
study results.
3. Additional clinical data as appropriate
 Reasons for deferring a paediatric investigation plan
– <it is considered appropriate to conduct studies in adults prior to
initiating studies in the paediatric population>
– <studies in the paediatric population will take longer to conduct than
studies in adults> <additional non-clinical data are considered
necessary>
– <major quality problems prevent development of the relevant
formulation(s)>.
 Reasons to notify a waiver for paediatric development

55.  Any findings of non-clinical testing
of relevance for the prescribers
recognising the safety profile in the authorised
indication(s)
not already mentioned in in other SmPC sections
described in brief with qualitative statements
 Regarding use in the paediatric population
(subheading):
Results of all relevant non-clinical data in juvenile
animals
Discussion of clinical relevance
 Environmental risk assessment as appropriate

57. 4.8 Undesirable effects → Completely rewritten
NEW: Summary of safety profile as an introduction
• “Most serious or most frequently occurring adverse reactions, together with
common risk factors” factors
• “Consistent with the important identified risks mentioned in the Safety
Specification of the Risk Management Plan“
• Refer to 4.4 Special warnings and precautions as appropriate
New: Information on source data behind table of adverse reactions
• Clinical studies, PASS and/or post marketing reports etc.
New: A paediatric sub-section should always be included (unless irrelevant)
New: Guidance on estimation of frequency of adverse reactions, but no
change of definition of frequency definitions
New: Combination products: attribution of adverse reactions to components

59.  The content of this section should be justified in
the Clinical overview of the marketing
authorisation application based upon a best-
evidence assessment of all observed adverse
events and all facts relevant to the assessment of
causality, severity and frequency.

60. a. Summary of the safety profile
b. Tabulated summary of adverse reactions
c. Description of selected adverse reactions
d. <Paediatric population>
e. <Other special population(s)>

61. 1. • Information about the most serious and/or most frequently occurring
adverse reactions
2. • Non-serious adverse reactions that are frequent in the beginning of
the treatment but may disappear with its continuation
3. • Adverse reaction associated with long-term use
4. • Consistent with the important identified risks mentioned in the Safety
Specification of the Risk Management Plan
5. • Consistent with the table of adverse reactions
Example:
‘At the beginning of the treatment, nausea, diarrhoea, headache or vertigo may
occur; these reactions usually disappear within a few days even if treatment
is continued. The most commonly reported adverse reactions during
treatment are dizziness and headache, both occurring in approximately 6%
of patients. Serious acute liver injury and agranulocytosis may occur rarely
(less than 1 case per 1,000 patients)’

63.  Single table or structured listing of adverse reactions
(from clinical studies and post marketing)
 State the source of data
 Structured presentation according to MedDRA SOCs
(system organ class)
 Frequency groupings should follow standard terms
established in each official language using the
following convention:
• very common (≥ 1/10)
• common (≥1/100, <1/10)
• uncommon (≥ 1/1,000, <1/100)
• rare (≥ 1/10,000, <1/1,000)
• very rare (<1/10,000)
• not known (cannot be estimated from the available data)

64. Principles:
a. Highest frequency should be chosen
b. Different terms representing the same phenomenon
should ordinarily be grouped together as a single adverse
reaction
Adverse reactions from clinical trials
Frequency category based on pooled data and crude
incidence rates
Adverse reactions from safety studies
Frequency category based on the point estimate of the
crude incidence rate

65. Number of patients studied in controlled trials:
21000
• If an adverse reaction has a risk to occur in ≤ 1 in 7000
patients, the frequency category class should be “rare”.
Number of patients studied in controlled trials:
33000
• If an adverse reaction has a risk to occur in ≤ 1 in 11000
patients, the frequency category class should be “very
rare”.
• Only, if more than 30000 patients are included in the
clinical development program it will be allowed to assign
frequency class “very rare” to a so far not reported
adverse reaction.

66. • Information characterising
◦ specific adverse reaction which may be useful to prevent, assess or manage the
occurrence of an adverse reaction in clinical practice
◦ individual serious and/or frequently occurring adverse reactionsfor particular severe
cases
◦ may describe for example reversibility, time of onset, severity, duration, mechanism
of the reaction (if of clinical relevance), dose relationship, relationship with duration
of exposure or risk factors
• Measures to be taken to avoid specific adverse reactions should be
mentioned under 4.4 and cross-referenced here.
• Any adverse reactions resulting directly from an interaction should be
mentioned here and cross-referenced to section 4.5.
• In the case of combination products, information should be included in
this sub-section pointing out particular adverse reactions

67. A paediatric sub-section should always be included (unless
irrelevant)
 Any clinically relevant differences (i.e., in nature,
frequency, seriousness or reversibility of adverse
reactions) between the safety profiles in adult and
paediatric populations, or in any relevant age groups,
should be described and stratified by age group.
Other special populations:
 Information on any clinically relevant differences (i.e., in
nature, frequency, seriousness or reversibility of adverse
reactions, or need for monitoring specifically observed in
other special populations such as elderly, patients with
renal impairment, patients with hepatic impairment,
patients with other diseases or a specific genotype

68.  A man, 54 years of age, swallowed two tablets
Lapidar 100 mg with a glas of juice
 1 hour later he experienced extreme tiredness
and fall in sleep for 2 hours
 Circumstances of use: Correct indication,
 dose, administration etc.?
 Causal relationship: Alternative explanations
 for sleepiness?
 Severity: Life threatening?
 Expectedness: What does the SmPC say?

69.  Dose was twice as high as recommended.
 Grapefruit juice instead of water
 The man had worked at night and was therefore extremely tired
 Circumstances of use: Not the right dose, grapefruit may
enhance the plasma concentration etc.
 Causal relationship: At least a reasonable possibility
 Exists
 Severity: Not life threatening
 Expectedness: Tiredness is labelled, sleepiness isn`t

70. Assessment must also consider:
• Existence of similar cases (post marketing, from clinical
studies)
• Pharmacologic plausibility
• Pharmacokinetic aspects
• Bibliographical data, epidemiological studies
The ultimate questions:
• Is it necessary to include this phenomenon (sleepiness)
in product information?
• If so, where to include it and how to “frame’’ it (as a
“stand alone” adverse reaction and/or result of an
interaction and/or result of overdose)?

71. …all adverse reactions from:
1. clinical trials
2. post-authorisation safety studies
3. spontaneous reporting for which a causal
relationship between the medicinal product and the
adverse event is at least a reasonable possibility,
based for example:
a. • on their comparative incidence in clinical trials
b. • on findings from epidemiological studies
c. • on an evaluation of causality from individual case reports.
Adverse events, without at least a suspected causal
relationship, should not be listed in the SmPC.