Patient leaflet and SmPC: keeping them consistent at every update

A patient leaflet that does not say exactly what the SmPC says is noticed quickly: during an inspection, when a variation is submitted, or when a healthcare professional compares the two texts. Patient leaflet and SmPC consistency follows from Directive 2001/83/EC, which makes the summary of product characteristics the source of the leaflet. The risk rarely lies in the initial version, which is reviewed carefully. It lies in successive updates: a posology corrected on one side only, a contraindication reworded in Annex I and forgotten in Annex III, a language version left behind. This article sets out the cross-review method we apply.

The leaflet is drawn up in accordance with the SmPC

Article 11 of Directive 2001/83/EC sets the content of the summary of product characteristics: composition, pharmaceutical form, therapeutic indications, posology and method of administration, contraindications, special warnings and precautions for use, interactions, pregnancy and lactation, undesirable effects, overdose, pharmacological properties, marketing authorisation holder and date of revision of the text.

Article 59 sets the content of the package leaflet and states the principle: it is drawn up in accordance with the summary of product characteristics. Two practical consequences follow. First, the leaflet cannot introduce clinical information that is absent from the SmPC. Second, it cannot leave out information the patient needs. The same article requires the leaflet to reflect the results of consultations with target patient groups, what practitioners call readability testing. Article 62 allows explanatory material useful to the patient, provided nothing in it is promotional in nature.

The hierarchy is visible in the structure of the dossier: the SmPC is Annex I of the authorisation, while labelling and the leaflet form Annex III. The leaflet is a derived document, never a standalone one.

The QRD template fixes the form, not the substance

The QRD (Quality Review of Documents) templates standardise the structure, the numbering and part of the standard wording of the SmPC, the labelling and the leaflet. The EMA publishes the templates that apply to the centralised procedure. The CMDh publishes the annotated version used for mutual recognition, decentralised and national procedures. The European guideline on readability completes those templates on presentation.

A text that complies with the QRD template is not automatically consistent. The template guarantees that the "Do not take" section appears in the leaflet. It does not guarantee that this section lists exactly the contraindications of SmPC section 4.3. That is precisely where the gaps sit.

Checking patient leaflet and SmPC consistency in both directions

A one-way review lets half the gaps through. We work in two passes.

Downward pass, from the SmPC to the leaflet

Section by section, we check that every piece of information intended for the patient has been carried across:

• section 4.1 to "What it is used for"
• section 4.2 to "How to take this medicine", including special population regimens
• section 4.3 to "Do not take"
• sections 4.4 and 4.5 to "Warnings and precautions" and "Other medicines"
• sections 4.6 and 4.7 to "Pregnancy, breast-feeding and fertility" and "Driving and using machines"
• section 4.8 to "Possible side effects", frequency categories included
• sections 2, 6.3, 6.4 and 7 to excipients with known effect, storage conditions and holder details

Upward pass, from the leaflet to the SmPC

We then read the leaflet as a patient would, asking one question of every statement: where does it come from? Any sentence with no anchor in the SmPC is either explanatory material permitted by Article 62, or a gap to be handled. This is the pass most often skipped, and the one that surfaces historical additions that were never re-examined.

The gaps we see most often

• Posology for special populations: renal or hepatic impairment, elderly patients, the paediatric population. Section 4.2 moves on, the leaflet keeps the old regimen.
• A contraindication that has become a warning, or the reverse: the leaflet keeps the information under "Do not take" when it now belongs under warnings.
• Undesirable effects added in section 4.8 with no counterpart on the patient side, or a frequency amended without changing the matching category in the leaflet.
• Excipients with known effect: a composition change in section 2 that does not trigger an update of the dedicated statements.
• Storage: in-use shelf life after first opening or reconstitution, present in section 6.3 and missing from the leaflet.
• Administrative particulars: holder, local representative, manufacturer responsible for batch release, names of the medicine in other Member States.
• Date of revision of the text: SmPC section 10 moves forward while the last line of the leaflet keeps the previous date, and one language version sometimes stays on the earlier state.

The variation, where the gap is created

Regulation (EC) No 1234/2008 governs the examination of variations to the terms of a marketing authorisation and classifies them as minor variations of type IA and IB, major variations of type II, and extensions. Where a variation leads to a revision of the SmPC, the labelling or the leaflet, that revision is an integral part of the variation.

For variation applications under the French national procedure, the ANSM describes the applicable regime, with an implicit decision to accept type IA and IB variations and an implicit decision to reject type II variations. Changes to the labelling or the leaflet that are not connected with the SmPC follow the separate procedure set out in Article 61 of the Directive.

The point to watch is organisational. Several variations may run in parallel on the same product, with different effective dates, and each one produces its own version of the annexes. Without a single dated reference version, the leaflet that finally goes to print mixes successive states.

Record the review, do not only correct it

A consistency check is only worth something if it leaves a usable trace. Three items deserve to be kept: the exact version of each annex compared, the list of gaps found with the passage quoted on both sides, and the decision taken for each one, either a correction or a justification for keeping the wording. Past decisions then become a reference framework: they prevent the same discussion about a phrase from reopening every year.

This is also the moment to bring in your own reference documents, such as a writing charter, a patient glossary or a list of approved wordings. They make the review reproducible from one reviewer to the next. You can see the list of frameworks we cover and how to submit your internal requirements.

In practice

• Treat the leaflet as a document derived from the SmPC, and repeat the upward pass at every variation, however minor.
• Freeze a reference version of the annexes before the review, and compare dated versions rather than working files.
• Finish with the particulars that sit outside the clinical content: date of revision of the text, administrative particulars, language versions.

Across a portfolio of several dozen products, this comparison consumes a great deal of expert time. It is the kind of check we have tooled in EryonOne, which brings the two documents together and quotes the exact passage on each side. The report remains working material: the decision belongs to the regulatory affairs lead. Our page on patient leaflet and SmPC review sets out this use case.