Q&A for labelling

The requirements for labelling of Investigational medicinal products are given in European Commission guideline: The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Annex 13,  Investigational Medicinal Products. This guideline is translated to the Czech and listed as VYR-32 Appendix 13.  

English version of the document is available on website of European Commission:
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf

Czech version of the document is available on SÚKL website (VYR-32 Appendix 13):
https://www.sukl.cz/leciva/doplnek-13-verze-1

1. Changes on labels which should be submitted to the Institute

Question:

Does any change of the study medication label which has already been approved during the initial assessment have to be submitted to the regulatory authority? Does the regulatory authority always send a statement to the Sponsor?

Answer:

Only substantial changes to the labels should be submitted to SÚKL, i.e. changes related to the omission of any mandatory information given by the Annex 13, compared to the originally approved version of the labels, or changes related to another substantial change in the given clinical trial (e.g. change of the Sponsor). Substantial changes to the labels are approved by the Institute and letter of approval is sent to the Sponsor. Other changes are considered non-substantial and therefore they do not need to be submitted separately. Non-substantial changes may be submitted together with another substantial change.

2. Change of Sponsor – how to proceed

Question:

The Sponsor has been changed during the ongoing clinical trial. New labels with the name and address of the new Sponsor will be submitted to the regulatory authority. Is it possible to use the existing supply of drug products, i.e. drug products with the name and address of the previous Sponsor on the label? Is it possible to continue to supply clinical centres with drug products in their previous packaging? Is it possible to have drug products with the name and address of the previous Sponsor on the label and at the same time drug products with the name and address of the new Sponsor on the label at the healthcare facility? What is the transitional period for the implementation of new labels in a clinical trial?

Answer:

According to Section 59 of Act No. 378/2007 Coll., on Pharmaceuticals, as amended, a change of the Sponsor is a change that must be approved by SÚKL in advance (it is considered to be a Substantial amendment/modification). Therefore, in this case, new labels of IMPs must be submitted to the regulatory authority for approval.

The drug product supply with labels containing the original name of the Sponsor may be used until depletion. The IMP packaging that is in the healthcare facility will remain unchanged, but subjects should receive supplement to the “Information for volunteer and informed consent form” where they will be informed of this change.

Manufactured IMPs in the packaging with the original Sponsor on the label can be delivered to the healthcare facilities until stocks are depleted. Newly manufactured batches should be labelled with labels approved as a substantial amendment which contain the new Sponsor identification. In case of IMPs that have been already manufactured and labelled with the previous information but not yet distributed, the Sponsor chooses how to proceed - either as mentioned above, i.e. the packaging will remain unchanged, but the subjects will be informed of the change as described in the paragraph above, or the Sponsor may re-label the IMPs at suitable facility.

Consequently, there may be drug products with both old and new labels at the healthcare facility. It is important to inform the trial subjects about this possibility.

There is no specified transitional period for the implementation of new labelling in a clinical trial. Each situation is assessed on a case-by-case basis. One situation is if all IMPs have been manufactured and no other clinical batches will be manufactured. Another situation is if there is a plan for a future batch production.

3. An assessment of whether the change of the label is substantial

Question:

Is a change in the designation of the active substance (e.g. from ABC-123 to NAME) listed on the label considered to be a substantial change that needs to be submitted to the regulatory authority for approval?

Answer:

The change in the designation of the active substance is considered to be a non-substantial change. Therefore, it is not necessary to submit this change separately to the authority for approval.

4. Is it possible to use one label for multiple clinical trials?

Question:

Is it possible to have one label for multiple clinical trials?

Answer:

Yes, it is possible to use one label for multiple clinical trials. However, it must be clear from the label for which clinical trial it is intended. Information on how this is ensured should be stated in the cover letter (e.g. by crossing out other clinical trial numbers).

5. Who may perform labelling, may it be done by the clinical trial monitor?

Question:

Re-labelling of investigational medicinal products will be performed due to the shelf-life extension. Does the re-labelling always need to be carried out or supervised by a pharmacist or can it be carried out by someone else, e.g. a monitor under the supervision of another member of the study team, etc.?

Answer:

The Annex 13 (point 33) states: “If it becomes necessary to change the use-by date, an additional label should be affixed to the investigational medicinal product. … This operation should be performed at an appropriately authorised manufacturing site. However, when justified, it may be performed at the investigational site by or under the supervision of the clinical trial site pharmacist, or other health care professional in accordance with national regulations. Where this is not possible, it may be performed by the clinical trial monitor(s) who should be appropriately trained. The operation should be performed in accordance with GMP principles, specific and standard operating procedures and under contract, if applicable, and should be checked by a second person. This additional labelling should be properly documented in both the trial documentation and in the batch records.”

Considering the above, the re-labelling of investigational medicinal products due to the shelf-life extension may be performed by an appropriately trained monitor, following the procedures stated above.

6. May the Pharmacy carry out additional labelling of the secondary packaging of the IMP?

Question:

Is it possible for a pharmacy to label an authorised drug product for the purpose of a clinical trial in the Czech Republic? May the Pharmacy change the secondary packaging of the IMP?

Answer:

Yes, the Pharmacy may perform labelling of the investigational medicinal product. The conditions for clinical trials of medicinal products in Pharmacies are further regulated by the SÚKL guideline LEK-12 version 2. Unfortunately, no English version of this document is available. However, this guideline contains, among other things, information concerning labelling in Pharmacies given by Good Pharmacy Practice, in accordance with the requirements of Section 19 of Decree No. 226/2008 Coll. If a Pharmacy provides an additional label for an investigational medicinal product, it must first remove the unique identifier (UI) from the National repositories system containing information on the safety features for the specific product / package. It is further dealt with as an investigational medicinal product.

At the same time, we must draw attention to the fact that the Pharmacy of the healthcare facility may re-label the investigational medicinal product if this is done at the healthcare service provider by persons authorized to prepare or modify drug products and the investigational medicinal product is intended for use exclusively at the healthcare service provider (according to Section 57 par. 1 of Act No. 378/2007 Coll.).

A Pharmacy authorized to prepare medicinal products may re-label the investigational medicinal product for another healthcare service provider. However, this Pharmacy must deliver the re-labelled investigational medicinal products directly to the healthcare facility, not to another Pharmacy (according to the SÚKL guideline LEK-9, which specifies the requirements of Decree No. 84/2008 Coll.).

7. Labelling of authorised medicinal products to be used in non-commercial clinical trials

Question:

What are the requirements on the labelling of authorised medicinal products sourced from local market intended for the non-commercial clinical trials?

Answer:

The requirements for labelling of investigational medicinal products are given by the EU GMP Guideline EudraLex Volume 4, Annex 13 (https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf). Czech version of this document is VYR-32 Appendix 13 (https://www.sukl.cz/leciva/doplnek-13-verze-1). The information on the labels should be stated in the official language(s) of the country in which the investigational medicinal product is to be used.

The characteristics for these clinical trials are identified in Article 14 of Directive 2001/20/EC (non-commercial clinical trials with authorized medicinal products performed on trial subjects with the same characteristics covered by the indications stated in the marketing authorization). In addition to the statement “For clinical trial use only” or similar wording the following particulars should be added to the original packaging but should not obscure the original labelling:

  • name of Sponsor, contract research organisation or investigator;
  • trial reference code allowing identification of the trial site, investigator and trial subject.

If these products are not used in the same indication as given in the marketing authorization (off-label use), the label should contain the particulars according to point 26 of Annex 13. However, it is not necessary to provide information already stated on the original packaging (e.g. name of the product, strength, pharmaceutical dosage form, batch number, shelf-life). This label should be placed on the original container but should not obscure the original labelling.

8. May the label on the primary packaging be in English only?

Question:

The investigational medicinal product is a solution for injection that will be administered to a patient in a hospital. May such a product be labelled in English only?

Answer:

According to Annex 13 (point 28), the information on the labels should be given in the official language(s) of the country in which the investigational medicinal product is to be used. In exceptional and justified cases, the labels on the primary packaging provided in English may be accepted. In any case, the labels on the secondary packaging must be in the Czech language.

Please note that a situation where the product is administered in a healthcare facility and thus will not be handled by a patient is not a sufficient justification for the absence of a Czech label.

9. May the label on the primary packaging be in English only?

Question:

Both the investigational medicinal product and the placebo are sterile solutions for intravenous infusion (5 ml solution in a 10 ml vial). The solution will be diluted and administered as an intravenous infusion in a healthcare facility. The infusion will be prepared by a trained pharmacist.

Since the IMP and placebo are stored at -60 °C to -90 °C and only a limited amount of study drug is available at an early stage of development, the vials will be labelled after filling, during the manufacture of the investigational medicinal product, just before freezing the product to the temperature recommended for storage. The primary packaging of placebo will be labelled in the same way as it corresponds to the primary packaging of IMP.

For these reasons, it is not possible to state the data in the Czech language on the label of the primary packaging. The medicinal product will be supplied as a vial in a box. The packaging should remain undivided until the preparation of the product by the pharmacist. The secondary packaging will be provided with a label in the Czech language, which will contain all the particulars required by the Annex 13.

The primary packaging label will contain the batch number, unique packaging number, Protocol number, drug product name (IMP / Placebo), strength, pharmaceutical dosage form (Solution for infusion), and the Sponsor's logo.

Answer:

With regard to the specifics described above (limited amount of product frozen at -90 °C immediately after filling), the use of English on the label of the primary packaging can be considered justified. We recommend to the Sponsor to point this out in the appropriate Pharmacist's manual to avoid any doubts regarding the correctness of the packaging and also provide this information and justification in the Cover Letter within the clinical trial submission.

10. May the label on the primary packaging (MDI canister) be in English only?

Question:

Is it possible to label an MDI canister, which is inserted into the metered dose inhaler, with a label in English only? Attachment of a larger label on the MDI canister is not feasible, as it would interfere during insertion of the canister into the inhaler chamber, and it would not work properly. The information on the MDI canister label is also stated in the inhaler booklet, which contains the label in the Czech language. The patient card, which explains the use of the inhaler, contains all the basic information in the Czech language as well.

Answer:

According to the Annex 13 (point 28), the data on the labels should be written in the Czech language. In exceptional and justified cases, labels on the primary packaging in English only may be accepted.  Taking into consideration the circumstances mentioned above, the use of English on the label of the primary packaging can be considered justified.

11. May the details about the Sponsor be in English only?

Question:

Is it acceptable to provide contact details in English? E.g.  not to translate the terms "Sponsor", "Address", "Department", "Vienna", "Austria" into Czech? Of course, other information on the label will be provided in the Czech language.

Answer:

According to the Annex 13 (point 28), the information on the labels should be given in the Czech language. However, the sponsor address itself does not need to be translated and may remain in its original form.

12. May the label with statement "For clinical trial purposes only" be written in English?

Question:

An additional label containing statement “For clinical trial purposes only” and a label to identify the Protocol and EudraCT will be affixed to the authorised drug product. Is it possible for this information to be in English, or must it be in Czech?

Answer:

The text "For clinical trial use only" must be written in the Czech language. The "EudraCT number" does not need to be translated, so it can be left in this form, followed by the study number.

13. Information about the Sponsor listed on the labels

Question:

Does the full address of the Sponsor of the clinical trial, including the telephone number, have to be on the labels, or is the name of the sponsor enough?

Answer:

According to Annex 13 (point 26), the name, address and telephone number of the Sponsor, contract research organisation or investigator (the main contact for information about the product, clinical trial and emergency unblinding) should be provided on the label. At the same time (point 27), the address and telephone number of the main contact for information about the product, clinical trials and for emergency unblinding cases do not need to appear on the label if the subject has received a leaflet or card providing this information and has been instructed to keep it in their possession at all times.

14. Absence of any information on label

Question:

Is it possible to approve label with missing investigator’s name and clinical trial site? Clinical trial site and also name of the investigator could be identified with the trial subject identification number.

Answer:

The above mentioned justification for absence of this information is sufficient and should be submitted along with the proposed labels (e.g. in the Cover Letter). Additionally, we would like to point out that it is not necessary to state investigator name on the label when this information is listed, for example, on the Patient Card.

15. Rules for labelling of authorised non-investigational medicinal products used in the CT (AxMP, formerly NIMP)

Question:

What are the rules for labelling of authorised medicinal products which are used in the clinical trial as non-investigational and are supplied for this clinical trial by the Sponsor (not sourced from the current stock of pharmacies)?

Answer:

Act No. 378/2007 Coll., on Pharmaceuticals, as amended, and Decree No. 226/2008 Coll. do not mention any obligation to label  non-investigational medicinal products (AxMP = Auxiliary Medicinal Product, formerly NIMP = Non-Investigational Medicinal Product). The requirements for the label of AxMP are also not defined in the guideline Annex 13. Generally, it is recommended to follow applicable principles for labelling of investigational medicinal products defined in the guideline Annex 13.

If the AxMP for clinical trial is supplied by the Sponsor than it is recommended to add at least a label with the statement "For clinical trial use only" (or similar wording) and with a trial reference code allowing identification of the trial (e.g. EudraCT number, Protocol code number). The reason is that all study medication has to be kept separate from other medications in both the pharmacy and the clinical trial site so the unlabelled AxMPs cannot be confused with the pharmacy’s regular supplies.

If the AxMP is in the packaging labelled in foreign language than addition of label with at least the above-mentioned information is strongly recommended. Unlabelled AxMP could be considered as unauthorised medicinal product as referred to under Section 8(3) of the Act on Pharmaceuticals which is subject to the reporting obligation to the Authority. The correct handling of such AxMP and the training of the trial subject on storage, use, dosage and possible adverse reactions should be ensured by the investigator based on the drug product information received from the Sponsor.

Distribution of AxMP is subjected to the same rules as for investigational medicinal products.

16. Labelling of non-investigational medicinal products (AxMP, formerly NIMP) authorised in the Czech Republic

Question:

Is it required to label AxMP authorised in the Czech Republic or only medicinal products with labels in foreign language should be re-labelled?  

Answer:

If the authorised AxMP is supplied by the Sponsor than it is recommended to add at least label with the statement "For clinical trial use only" (or similar wording) and with a trial reference code allowing identification of the trial (e.g. EudraCT number, Protocol code number). The reason is that all study medication has to be kept separately from other medications in both the pharmacy and the clinical trial site in order not to confuse the unlabelled AxMPs with the pharmacy’s regular supplies. AxMPs used should be introduced in the Cover Letter, where it should be also described how they will be labelled. In this case it is not necessary to submit proposed labels.

It is not necessary to label AxMPs sourced from the local market. 

17. Labelling of non-investigational medicinal products (AxMP, formerly NIMP) supplied from the foreign countries

Question:

Is it required to submit labels for AxMPs supplied from the EU market or it is not necessary as for AxMPs sourced from the local market?

Answer:

According to the current legislation, it is not required to submit labels for authorised AxMPs.

In case that the Sponsor submits proposed labels for AxMPs, which is allowed, the authority will assess these labels. In that case it is recommended to identify where the labelling is performed. Labelling should be carried out by the manufacturer in the same way as for investigational medicinal products in accordance with the GMP requirements or by pharmacy in accordance with the guideline LEK-12. The exact requirements for labelling of AxMPs are not defined; however, labels should not include illegible, incomplete, incorrect, or misleading information which could affect the course of the clinical trial and the safety of the subjects. Generally, it is recommended to follow applicable principles for labelling of investigational medicinal products defined in the guideline Annex 13.

18. Labelling of non-investigational medicinal products (AxMP, formerly NIMP) – is it acceptable to label the whole package?

Question:

If the whole package is supplied to the pharmacy, is it acceptable to label the whole package (to distinguish it from the pharmacy’s regular supplies) or is it necessary to label secondary packaging of each medicinal product separately (each individual box)?

Answer:

The current legislation does not define the exact requirements for labelling of non-investigational medicinal products. However, to distinguish the study medication from the pharmacy’s regular supplies, it is recommended to label each individual box.

19. Use of coloured labels

Question:

Is it possible to use a different colour of label for each strength of the investigational medicinal product to minimize the risk of confusing the patients? Is the use of coloured labels restricted by legislation?

Answer:

Current legislation for labelling of investigational medicinal products does not restrict use of coloured labels on packaging. However, it should be noted that in the case of blinded clinical trial, any differences should be carefully considered in order to maintain the blinding of the study.