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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.

Fda guidance for food and drug labelling professor pirouzi

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FDA Guidance for Food and Drug Labelling

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Page 1: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 2: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 3: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 4: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 5: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 6: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 7: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 8: Fda guidance for food and drug labelling   professor pirouzi

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

Page 9: Fda guidance for food and drug labelling   professor pirouzi

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).

Page 10: Fda guidance for food and drug labelling   professor pirouzi

Example of highlights section (for a fictitious drug).

Page 11: Fda guidance for food and drug labelling   professor pirouzi

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. "

Page 12: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 13: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 14: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 15: Fda guidance for food and drug labelling   professor pirouzi
Page 16: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 17: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 18: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 19: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 20: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 21: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 22: Fda guidance for food and drug labelling   professor pirouzi

Applications Required To Conform to New Requirements*

Time by Which Conforming Labelling Must Be Submitted to FDA for Approval

Applications submitted on or after June 30, 2006 Time of submission

Applications pending on June 30, 2006, and applications approved 0-1 yr before June 30, 2006

June 30, 2009

Applications approved 1-2 yr before June 30, 2006

June 30, 2010

Applications approved 2-3 yr before June 30, 2006

June 30, 2011

Applications approved 3-4 yr before June 30, 2006

June 30, 2012

Applications approved 4-5 yr before June 30, 2006

June 30, 2013

Applications approved more than 5 yr before June 30, 2006

Voluntarily at any time

* Includes new drug applications, biological license applications, and efficacy supplements.

Page 23: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 24: Fda guidance for food and drug labelling   professor pirouzi

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).

Page 25: Fda guidance for food and drug labelling   professor pirouzi

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

Page 26: Fda guidance for food and drug labelling   professor pirouzi

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

Page 27: Fda guidance for food and drug labelling   professor pirouzi

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

Page 28: Fda guidance for food and drug labelling   professor pirouzi

• 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

Page 29: Fda guidance for food and drug labelling   professor pirouzi

. 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

Page 31: Fda guidance for food and drug labelling   professor pirouzi

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

Page 32: Fda guidance for food and drug labelling   professor pirouzi
Page 33: Fda guidance for food and drug labelling   professor pirouzi

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

Page 34: Fda guidance for food and drug labelling   professor pirouzi
Page 35: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 36: Fda guidance for food and drug labelling   professor pirouzi

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

Page 37: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 38: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 40: Fda guidance for food and drug labelling   professor pirouzi
Page 41: Fda guidance for food and drug labelling   professor pirouzi

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

Page 42: Fda guidance for food and drug labelling   professor pirouzi

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

Page 44: Fda guidance for food and drug labelling   professor pirouzi

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

Page 45: Fda guidance for food and drug labelling   professor pirouzi
Page 46: Fda guidance for food and drug labelling   professor pirouzi

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..

Page 48: Fda guidance for food and drug labelling   professor pirouzi

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)

Page 49: Fda guidance for food and drug labelling   professor pirouzi
Page 50: Fda guidance for food and drug labelling   professor pirouzi

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

Page 51: Fda guidance for food and drug labelling   professor pirouzi

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“

Page 52: Fda guidance for food and drug labelling   professor pirouzi

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

Page 54: Fda guidance for food and drug labelling   professor pirouzi
Page 55: Fda guidance for food and drug labelling   professor pirouzi

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

Page 57: Fda guidance for food and drug labelling   professor pirouzi

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

Page 59: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 60: Fda guidance for food and drug labelling   professor pirouzi

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)>

Page 61: Fda guidance for food and drug labelling   professor pirouzi

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)’

Page 62: Fda guidance for food and drug labelling   professor pirouzi
Page 63: Fda guidance for food and drug labelling   professor pirouzi

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)

Page 64: Fda guidance for food and drug labelling   professor pirouzi

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

Page 65: Fda guidance for food and drug labelling   professor pirouzi

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.

Page 66: Fda guidance for food and drug labelling   professor pirouzi

• 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

Page 67: Fda guidance for food and drug labelling   professor pirouzi

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

Page 68: Fda guidance for food and drug labelling   professor pirouzi

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?

Page 69: Fda guidance for food and drug labelling   professor pirouzi

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

Page 70: Fda guidance for food and drug labelling   professor pirouzi

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)?

Page 71: Fda guidance for food and drug labelling   professor pirouzi

…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.