Summary of Product Characteristics (SPC/SmPC): Introduction, Overview and relevance in aggregate reports


In this article, I mean to introduce summary of product characteristics (SmPC or SPC), what it is, contents (the sections it has), high-level overview of various key SPC sections (with focus on sections 4.4 and 4.8) and its contents, what makes SmPC so special, such a key document that provides essential information on a medicine, principles of presenting information in SmPC, what not to include/write in SmPC, difference between SmPC and RSI and various documents and its relevance in aggregate reports and other drug safety verticals.

However, more importantly I intend to introduce many PowerPoints and materials relevant to SmPC that I suggest for reading at the end of this introductory article. For ease of access, I have embedded them in the article itself.

For whom is this article relevant and intended?

A lot of material is available for individual safety sections of SmPC (such as sections 4.3 to 4.8) and it would be massively beneficial for any ambitious and curious aggregate reports person (and regulatory people) who wants to take his/her career further. This is the difference on this subject matter. In my opinion, this information and documents are must for any aspirational ‘aggregate reports plus’ professional who looks beyond and ahead of aggregate reports career, advance or in regulatory affairs! If one wants to switch from CRO to a core company (as we all do!) this information can be vital so please do read these all documents yourself while my article is merely a tip of the iceberg in this context! In fact, I’ve seen questions regarding this in written tests for some advance companies myself!

I have kept the format of this article short, crisp to-the point and concise. A lot more to come based on the materials I have embedded in this article :-)

What is SmPC and why it is so critical?

The SmPC is a living document that requires update when new relevant information emerges E.g.: New adverse reactions observed after marketing of the product reported to the national competent authorities or the company — Following safety communication updates

The SmPC is a legal document approved as part of the marketing authorization of each medicine

  • It’s a continuously updated document pertaining to molecules.
  • The SmPC is the result of the agreed position on the medicinal product, as distilled during the course of the assessment process, before and after marketing authorization.
  • It’s a legally binding document of consequence.
  • Article 11 of Directive 2001/83/EC defines the content and the order of the SmPC

How is the information included in the SmPC prepared by the MAH?

Why is the SmPC an essential source of information on a medicine?

  • It is an integral part of the marketing authorization
  • The information provided in the SmPC is validated by competent authorities
  • Information is kept up to date based on continuous life cycle PVG
  • Basis for the preparation of the package leaflet and advertisement
  • Evidence-based scientific information
  • Legal document

Key highlights of guidelines on SPC preparation (29 pages document)

Read the guideline here:

The SmPC sets out the agreed position of the medicinal product as distilled during the course of the assessment process.

SmPC remains the cornerstone between assessment and information

Need for relevance:

  • Applicants should maintain the integrity of each section of the document by only including information in each section, which is relevant to the section heading.
  • Separate SmPCs are required for each pharmaceutical form and strength by the European Commission and certain Member States.
  • For the purposes of giving information to prescribers, the SmPCs of different pharmaceutical forms and strengths may be combined for appropriate products within the same range.

Principles of presenting information in SmPC:

  • The SmPC should be worded in clear and concise language
  • SmPC should be written in English language
  • Each section of the SmPC should first deal with those issues that apply to the core population for whom the medicine is indicated followed — when necessary — by specific information for any relevant special population (e.g. children or elderly).
  • Public Assessment Reports provide detailed information on medicinal products and are available on the website of the European Medicines Agency, of Heads of medicines Agencies or other National Competent Authorities. A link to the relevant website should be included in SmPCs when a public assessment report is available.
  • Consistent medical terminology should be used throughout the SmPC. For example, the use of MedDRA as described in the annex for section 4.8 should be applied though the SmPC, in particular for sections 4.3 and 4.4 and 4.8.
  • The SmPC provides information on a particular medicinal product; therefore it should not include reference to other medicinal products (e.g. through statement such as “Like other medicines of the same class …”) except when it is a class warning recommended by a competent authority.
  • The principles set-out in this guideline are applicable to all medicinal products. The application of those principles for a particular medicinal product will depend on the scientific knowledge on the medicinal product, the legal basis of a marketing authorization and public health needs. Deviation from this guideline should therefore be justified in the relevant Overview or Summary in the marketing authorization application.
  • Practical advice on how to draw up the SmPC is provided to the applicant in the form of templates developed by the Quality Review of Documents (QRD) group, for centralized, decentralized and mutual recognition procedures.

What is not included in the SmPC?

  • Detailed information on the scientific development which is available in the public assessment report
  • Information in non-approved indication — Because the MAH has not claimed the indication — An indication has been claimed but data did not demonstrate a positive benefit risk of the medicine; withdrawal or refusal AR provide available data — Exception in the paediatric group; the Paediatric Regulation aims to improve the information regarding this subgroup by providing all information on clinically relevant trials
  • Specific issue for which data is lacking
  • General advice on the treatment of particular medical conditions

SmPC and it’s sections/ contents:

High-level overview of various key SPC sections and its contents

  • Section 4.1 should define unambiguously for whom the medicine is indicated specifying any limitation, e.g. age
  • Section 4.2 should clearly specify the posology for each indication and relevant patient category for which the medicine is indicated, including any special population in which dose adjustment may be required
  • Section 4.3 “Contraindications” should only include situations where the medicine must not be given
  • Section 4.4 should present information on a specific risk only when the risk leads to a precaution for use or when healthcare professionals have to be warned of this risk
  • Section 4.5 should highlight the clinically relevant interactions, which result in a recommendation for use
  • Section 4.6 Effects on pregnancy, fertility and breast-feeding
  • Section 4.7 should provide information regarding the influence of the medicinal product on the ability to drive and use machine
  • Section 4.8 should summarise the safety profile of the medicine and list all adverse reactions (but not the adverse events)
  • Section 4.9 Overdose- symptoms and management
  • Section 5.1 may provide limited information on clinical results if it is relevant to the prescriber, statistically compelling and supports the authorised indication(s)
  • Section 5.3 Provides preclinical safety data

Safety sections of SPC and most important points you should know

· Sections 4.3 (contraindications), Section 4.4 (Warnings and precautions), Section 4.5 (Drug interactions), Sections 4.6 (Pregnancy, fertility and breast-feeding), Section 4.7 (Effects on ability to drive and handle machines) and Section 4.8 (Safety profile of the medicine and list all adverse reactions) are considered the safety sections of SPC.

  • These are the clinically most relevant and most important sections of SPC.
  • Most relevant for aggregate reports in various aspects.
  • Sections 4.4, 4.5, 4.6 and 4.8 are medically most relevant as they are used to derive safety concerns for aggregate reports and RMP if no previous reports/RMP and CMDH safety concerns are not available (more on this later)
  • All topics/events discussed in section 4.4 are by default important risks (but not necessarily identified)
  • All events tabulated in section 4.8 are by default-identified risks (but not necessarily important)
  • The objective of section 4.4 is to provide information on a specific risk when healthcare professionals have to be warned of this risk or the risk leads to a precaution for use to avoid harm

Safety warnings in section 4.4 of SmPC should be:

  • Clear
  • Compelling
  • Effective

Situations leading to a warning or precaution (section 4.4 of SmPC) :

  • Conditions to fulfil before use, e.g. measure required by Risk Management Plan, should be described
  • Conditions in which use of product could be acceptable provided special conditions are fulfilled.
  • To ensure safe and effective use describe specific risk minimisation measures as part of a risk minimisation plan
  • Special population at increased risk
  • Serious adverse reactions for alerting healthcare professionals : Serious adverse reactions to which health care professionals need to be alerted and the situations in which these may occur and the action that may be required
  • Measures to identify patients at risk or to prevent noxious conditions
  • Specific clinical or laboratory monitoring
  • Risks associated with starting or stopping the product
  • Warnings and precautions for use that are specific to the paediatric population or any subset of the paediatric population (to be identified under a subheading)
  • Warnings necessary for excipients or residues
  • Ethanol content in herbal medicinal products
  • Warnings necessary with respect to transmissible agents
  • Risks associated with incorrect route of administration
  • Specific interference with laboratory tests

All events in section 4.8 of the RSI are by default ‘identified’ (since we have cases known- a prerequisite for inclusion in 4.8 to begin with) but not all of them are important! All events discussed in section 4.4 of the RSI are by default ‘important’ but not all of them are identified (as cases may or may not be reported)!

Some important points regarding section 4.8 Undesirable effects in SmPC

  • Section 4.8 of the SmPC is the most important section which should include ALL ADRs (not AEs) from trials, PASS and spontaneous reporting.
  • A single table (or structured listing) should list all adverse reactions with their respective frequency category.
  • The purpose of a single table of adverse reactions with their respective frequency is to integrate comprehensive data from different sources (trials, PASS and spontaneous reporting) to provide clear and informative data to healthcare professionals
  • Section 4.8 should integrate comprehensive safety data from different sources (clinical trials, post-authorisation safety studies, spontaneous reporting) and should be regularly reviewed and updated to ensure that appropriate information is continuously provided.
  • Any ADR listed in 4.8 means causal relationship between ADR and medicine is at least a reasonable possibility
  • Whole section should be worded in CONCISE AND SPECIFIC LANGUAGE
  • Provide information on the most serious and/or most frequently occurring adverse reactions. Frequencies to be stated as accurately as possible

Which information should be included in the summary of safety profile?

  • The summary of safety profile should provide information on the most serious and/or most frequent occurring adverse reactions.
  • It should not be a summary of the safety database.
  • Brief information on the source of the safety database can be provided to introduce the tabulated list of adverse reactions

What not to write in section 4.8

  • Adverse events, without at least a suspected causal relationship
  • Comparative frequency statements other than those described in the subsection entitled ‘Further guidance on the estimation of frequency of adverse reactions’
  • Statements of general good tolerability such as “well tolerated”
  • Claims regarding absence of specific adverse reactions

Proposing/deriving safety concerns based on RSI/SmPC:

We can simplify the formula:

· Section 4.4 + Section 4.8= Important identified risk

· Just section 4.4/ 4.5/ 4.6 or if mentioned as a drug class effect and not in 4.8= Important potential risk

· Impact on individual patient is one parameter we need to consider when proposing risk characterization as well.

Formulas for safety concerns:

Section 4.4/4.5/4.6 + Section 4.8= Important identified risk

Just section 4.4/ 4.5/ 4.6 or if mentioned as a drug class effect and NOT in 4.8= Important potential risk

SmPC and RSI (reference safety information)

RSI is very relevant for aggregate reports. It is the basis of scientifically known current information based on life cycle PVG activities cumulatively before the reporting period.

In PBRERs, we are supposed to focus on new and significant safety information for the molecule.

RSI is the basis on which ‘new’ is decided for the report.

RSI is the single most important key routine risk minimization tool!

RSI selection:

  • The PBRER should address aspects common to all products containing the active substance, with subsections that address specific formulations and indications.
  • If MAH has diff formulations of the same molecule, the MAH should specify a single reference product information document, which in practice is often the Company Core Data Sheet (CCDS).

If the MAH does not have a CCDS, then the MAH should use the most comprehensive local prescribing text.

An objective of a PBRER is to evaluate whether information obtained during the reporting interval is in accord with previous knowledge on the product’s benefit and risk profile, and to indicate whether changes should be made to the reference product information.

Having one reference source of information that can be applied across the three ICH regions would facilitate a practical, efficient, and consistent approach to the benefit-risk evaluation and make the PBRER a unique report accepted in all countries and regions.

Practical concerns for MAHs:

It is generally impractical for MAHs to have one reference information source that:

  • Encompasses all parameters that contribute towards the benefit-risk evaluation, (i.e., benefit, efficacy/effectiveness, indication(s) and safety information)
  • Common to all ICH regions
  • Addresses all circumstances, (e.g., generics, products licensed in one country only).
  • Therefore, guidelines propose more practical options that MAHs can consider in selecting the most appropriate reference product information for the PBRER.
  • The reference product information for the PBRER would include “core safety” and “approved indications” components.
  • The basis for the benefit evaluation should be the baseline important efficacy/effectiveness information summarized in Section 17.1 of the PBRER.

Options for RSI selection:

Company core data sheet (CCDS):

In accordance with ICH E2C (R1) recommendations, it is a common practice for MAHs to prepare their own CCDS, which includes sections relating to safety, indications, dosing, pharmacology, and other information concerning the medicinal product.

The CCDS includes:

  • Safety sections
  • Indications
  • Dosing
  • Pharmacology
  • Other information

The core safety information contained within the CCDS is referred to as the CCSI.

  • A practical option is for MAHs to use the latest CCDS in effect at the end of the reporting interval as the reference product information for both the risk sections of the PBRER as well as the main approved indications for which benefit is evaluated.
  • When the CCDS for a medicinal product does not contain information on approved indications, the MAH should clearly specify which document is used as the reference information for the approved indications in the PBRER.

Other options for the reference product information:

  • When there is no CCDS or CCSI for a product, e.g., where the product is approved in only one country or region or for established/generic products on the market for many years, the MAH should clearly specify the reference information being used. This may comprise national or regional product information such as the US Package Insert (USPI) or European Summary of Product Characteristics (SmPC), or the Japanese package insert, as appropriate.
  • The MAH should continuously evaluate whether any revision of the reference product information/RSI is needed whenever new safety information is obtained throughout the reporting interval.

Remember: Inclusion in section 4.8 is the highest level of PVG accomplishment!

Interesting: Lifecycle of an event in PVG:

· This is a very interesting topic to understand.

· What is the ultimate goal of whole DSRM activity: appropriate inclusion of an event in the RSI/SmPC/PI

· When regulators or MAH become aware of potential association of an event with a drug → Event under monitoring in section 15 of PBRER → Signal → Risk (safety concern) → Variation → Inclusion in the PI/SmPC in an appropriate section.

· Inclusion of any event in section 4.8 Undesirable events of the RSI/SmPC is the highest degree of PVG by all means!

Let us end this to-the point overview article with some key highlights and take home points:

Important points to remember for SPC (revision)

  • Is a legal reference document
  • Is the basis for safe and effective use of a medicinal product
  • Should be clear, concise, evidence-based, relevant to healthcare professionals
  • Should be updated regularly when new information becomes available
  • All parts of advertising must comply with the SmPC
  • The SmPC is a living document that requires update when new relevant information emerges
  • Section 4.8- A summary of safety profile of the medicine informing on the most serious and/or most frequently occurring adverse reactions

I intend to write extensively on all of above! SmPC sure as hell makes a critical aspect of PVG and individual section presentations provided above are very insightful. Please keep watching this space for more articles on SPC specific safety sections in particular!

I hope you liked the article. Please leave your feedback in the comments section :-)



🏳️‍🌈 Aditi Sheth 🏳️‍🌈

🏳️‍🌈📚 Bookworm fueled by curiosity | 750+ Certificates | PBRER | Aggregate reports | Artificial Intelligence | Trained Psychologist | Introvert | ISFJ |MBBS

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