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Auxiliary medication labelling

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  • Ferenc
    29/01/2019 10:09
    I am working intensively with clinical supplies and particularly arranging auxiliary medication for studies. It is a recurring problem all the time: what type of label to place to these non-IMPs and whether the SMPC/patient leaflet shall be provided (if yes: what language) or not. The products particularly in question now are provided to sites for diagnostic purposes to perform certain visit assessments. These drugs are not going to subjects, they are used by professional site staff, they are ready to use, and are marketed in EU but we are to send these to non-EU countries as well. We will supply these centrally. I could not find clear instruction in GMP Annex13 concerning the labelling of auxiliary medication. The 'Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use' however refers to 'Clinical trials - Regulation EU No 536/2014' Chapter X and the Annex VI. Are these this sections the right place to use as a reference to define the labelling needs? As the drugs are used at site by site staff, for EU I would use the English language only and translate for non-EU languages only. Is this ok? Now: the products we aim to send to sites are registered in EU, however might not be available in the particular country. I would count with the requirements stated under section "B Unauthorised Auxiliary Medicinal Product". Is this a right approach for auxiliary medication? The use of product is simple: instill to the eye 1 drop etc., it is detailed in the protocol as well. Shall SMPC provided to sites in local language or English (we use the original packaging so there will be in the package, but it might be German or other)? Who is charge for the recall process in this case? The party procuring the medication? Is the CoA needed for filing of these auxiliary medication (to confirm that these are of appropriate quality)? (For some countries CoA is needed for the import licence, but that is an other issue). Is it enough to keep an inventory record only at site that captures the use of the dosing units for subjects (i.e: amount of units used, for which patient, which visit, from which batch; so no any per patient accountability - as product is used for diagnostics)? The continuity of supplies are ensured through a supply plan centrally. Sorry for the length.
  • GMP Committee
    08/03/2019 17:22
    Your question illustrates well the many challenges of auxiliary/non-investigational medicinal products! Whilst you have referenced Regulation (EU) No 536/2014, be aware that this is not yet in effect and that the current legislation is Directive 2001/20/EC and the national legislation put in place under this. The approach may need to vary from Member State to Member State. Further, the scope of Directive 2001/20/EC and Annex 13 is investigational medicinal products; they do not directly deal with non-IMPs. Regulation (EU) No 536/2014 will address this gap when it comes into effect. The further guidance “Guidance on IMPs/NIMPs”, should also be noted, however this is silent with regards to labelling requirements https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/imp_03-2011.pdf Given that Directive 2001/20/EC and Annex 13 do not cover non-IMPs, Chapter X and Annex VI of Regulation (EU) No 536/2014 are probably the best sources of information on EU regulatory expectations for the labelling of auxiliary/non-investigational products. There is a general expectation that labelling particulars appear in the official language(s) of the Member State to which the product is supplied. This makes it difficult to centrally source non-IMPs intended to be supplied as commercial packs: Even if the product has a central EU authorisation, there will be different packs (with the appropriate language) intended for each Member State. It may be possible to use English labelling and SmPC (or PIL) if the non-IMP is dosed at the study site, but you would need to check national requirements. Under 2.1.6, Other issues, section 25 of CT-1 states that 25. “The Commission encourages national competent authorities to accept the English language in their communication with applicants and for documentation which is not destined for the public or the clinical trial participant, such as scientific documentation”. Which may be used to support use of English language documents Both Regulation (EU) No 536/2014 and Directive 2001/20/EC are EU legislation and all references within them to ‘authorised product’ relate to product authorised within the EU. If you provide product outside the EU, then the local requirements of the destination country need to be met, not those of the EU legislation. Sorry for the lengthy reply!
  • Ferenc
    18/03/2019 15:34
    Thank you very much for the feedback, it is a bit more clear now. I have few further questions though - sorry ;). These would concern the requirements for the NIMP label contents and the need for providing NIMP SPC. My approach is that when we supply an international study centrally with NIMP, the labeling requirements for the NIMPs are practically the same as for an IMP - unless it is coming from hospital stock, but then it is a not centrally supplied. Am I right with this approach? I am asking this because I often see that sponsors are less careful with NIMPs as those are only "NIMPs" and I also found with few auditors as well. However as I see: we provide medicinal supplies in a trial to subjects therefore traceability, chain of custody, recall, appropriate instructions for use shall be provided. The NIMP might or might not be marketed in the particular country, and even if marketed, it is almost sure that sponsor won't procure the drugs from all the country markets, but only from 1 country and then the language/instructions on the packaging/leaflet will be useless for the site staff in all the other countries. The "Guidance on IMPs/NIMPs" indeed silent in terms of labelling. However up to now I interpreted section 3.2 as it requires the same approach for NIMP like for an IMP: "To meet the requirements of Articles 3(2) and as referred to in Article 6(3) of Directive 2001/20/EC relating to protection of the trial subject, the same level of quality and safety should be ensured for the NIMPs as for the IMPs used in the trials". Did I interpret this correctly? I have the same understanding - so to say - when looking into GCP. The guidance says nothing about NIMP, but still: it is not an excuse for any of us for not recording storage temperatures for NIMP etc. because GCP only requires that for the IMP. GCP section 2.12 and 5.13.1 states only IMP but my view is that these apply to NIMPs as well. Is this a right? Thank you for the clarification in terms of the language of the labels! Let me just confirm: that the SPC of the product or if this does not exist in the particular language the local translation of it or an appropriate "instructions for use" document shall be provided with the NIMP supplies or maybe rather in the site file for the site staff, right (we still talk about NIMP for professional use, so not a NIMP that goes to subjects)? Do you think that there might be scenarios though where the label of the NIMP would be sufficient for this purpose and the SPC/instruction for use won't be needed?
  • GMP Committee response
    16/12/2019 17:58
    The guidance points to labelling unauthorised NIMPs (those without a marketing authorisation) in the same manner as IMPs. There is no specific guidance about SPC/instructions for use. However, the key principle of safeguarding the clinical trial subject should help you to make appropriate choices – the subject, through label or additional instructions for use, and investigator, through investigator brochure, site trial file or similar, should have all that they need to use the product as intended and to be aware of any other important information. You are correct that the sponsor should ensure that NIMPs are handled in the same manner as IMPs with regards to matters such as storage and traceability.
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