ITALY 2014-2017

UNITED KINGDOM 2014-2017

UNITED KINGDOM 2018

10.4 What in your opinion should be done or is done already to address these challenges?

10.3 What challenges, if any, did you as a CA encounter in implementing the Directive in relation to the administration of investigational medicinal products for human use that contain or consist of GMOs (e.g. notification, risk assessment, authorisation, control, etc.)? 10.4 What in your opinion should be done or is done already to address these challenges?

AT not applicable, due to specific regulations in Austria not applicable

AT 2018 none not applicable

BE In Belgium, depending on the characteristics and mode of administration of the medicinal product, it is possible that the GMO aspects of clinical trials with medicinal products for human use containing or consisting of GMOs do not require an authorisation under the deliberate release frameworks (Directive 2001/18/EC – Part B).



When there is no possible release of the GMO in the environment that may confer a risk to human health or the environment (e.g. in case of GM medication taken at home, no risk of shedding, spreading,…), or if proper management procedures and/or working practices are taken to prevent any possible release conferring a risk, then a ‘contained use’ procedure will generally be sufficient.

However, if there is a probability of possible release that may confer a risk to human health or the environment which cannot be avoided by proper management procedures or working practices, a notification under ‘deliberate release’ is also required. The applicant does not always know what procedure should be applied (“contained use only” or deliberate release and contained use). If the framework to be followed is not clear to the applicant, it is strongly advised to request a national scientific-technical advice (STA) from the Federal Agency for Medicines and Health Products (FAMHP) prior to the submission of the clinical trial application.

BE 2018 In Belgium, depending on the characteristics and mode of administration of the medicinal product, it is possible that the GMO aspects of clinical trials with medicinal products for human use containing or consisting of GMOs do not require an authorisation under the deliberate release frameworks (Directive 2001/18/EC – Part B).



When there is no possible release of the GMO in the environment that may confer a risk to human health or the environment (e.g. in case of GM medication taken at home, no risk of shedding, spreading,…), or if proper management procedures and/or working practices are taken to prevent any possible release conferring a risk, then a ‘contained use’ procedure will generally be sufficient.



However, if there is a probability of possible release that may confer a risk to human health or the environment which cannot be avoided by proper management procedures or working practices, a notification under ‘deliberate release’ is also required. The applicant does not always know what procedure should be applied (“contained use only” or deliberate release and contained use). If the framework to be followed is not clear to the applicant, it is strongly advised to request a national scientific-technical advice (STA) from the Federal Agency for Medicines and Health Products (FAMHP) prior to the submission of the clinical trial application.



The SBB in collaboration with the Belgian federal agency for medicines are preparing a document “guideline” aiming to help applicants in determining the regulatory procedures they must follow

BG Administration of investigational medicinal products for human use that contain or consist of GMOs is notified under Directive 2001/18/EC as it is considered to involve release into the environment.



There is no clear procedure to distinguish whether a clinical trial of products containing genetically modified organisms (both for human and for veterinary use) should be considered contained use and when release into the environment.



It is not entirely clear to us how the provisions of the Directive 2009/41/EC should be applied when GMM is administered in hospital during clinical trial but the patients are not kept under contained conditions for the duration of the trial.



In application for clinical trials in Bulgaria, the applicant is required to provide information on the containment measures for each hospital (which should be registered as such under the Bulgarian legislation) where the medicinal product will be administered. That information is not considered formal notification. All applications examined so far involved only Class 1 activities. We expect that the current process on the interplay between EU medicine and GMO legislation will clarify most of the issues identified and common approaches will be adopted by the EU member states regarding clinical trials of GMO medicinal products.

BG 2018 Administration of investigational medicinal products for human use that contain or consist of GMOs is notified under Directive 2001/18/EC as it is considered to involve release into the environment.



There is no clear procedure to distinguish whether a clinical trial of products containing genetically modified organisms (both for human and for veterinary use) should be considered contained use and when release into the environment.



It is not entirely clear to us how the provisions of the Directive 2009/41/EC should be applied when GMM is administered in hospital during clinical trial but the patients are not kept under contained conditions for the duration of the trial.



In application for clinical trials in Bulgaria, the applicant is required to provide information on the containment measures for each hospital (which should be registered as such under the Bulgarian legislation) where the medicinal product will be administered. That information is not considered formal notification. All applications examined so far involved only Class 1 activities. We hope that the current process on the interplay between EU medicine and GMO legislation will continue and will further clarify most of the issues identified and common approaches will be adopted by the EU member states regarding clinical trials of GMO medicinal products.

CY Not Applicable. Not Applicable.

CY 2018 No investigation of GMOs for human use in Cyprus. N.R.

CZ Not applicable Not applicable

CZ 2018 not applicable not applicable

DE - With regard to the distinction between genetic engineering activities in containment and approvement of clinical trials with GMOs, an administrative agreement was reached in March 2015 between the relevant federal and competent authorities.

DE 2018 - -

DK None N/A

DK 2018 None N/A

EE Labour Inspectorate don't deal with this area Labour Inspectorate don't deal with this area

EE 2018 There is not such kind of premises N/A

EL No activities reported. No activities reported, therefore no associated challenges.

EL 2018 N/A N/A

ES CLINICAL TRIALS WITH GMOs ARE AUTHORISED UNDER DIRECTIVE 2001/18/EC CLINICAL TRIALS WITH GMOs ARE AUTHORISED UNDER DIRECTIVE 2001/18/EC

ES 2018 Differences in procedures between MS (Some MS have considered these activities as contained use and other MS as deliberate release). Harmonise procedures between MS.

FI 1) Decision whether the clinical trial is contained use or deliberate release; and



2) classification of the GMM; and



3) interplay of various regulations concerning GMOs, pharmaceuticals, occupational safety, waste treatment, and patient rights. Commission working group is already considering the interplay of pharmaceutical and GMO legislation, and this hopefully clarifies the situation.However, it is likely not to solve all the issues. It would be worth examining whether GMO medicinal product production and clinical trials should be legally separated from GMO directives. Also, the linkages between occupational safety, patient rights and waste treatment issues outside hospital environment (e.g. in homecare) should be considered.

FI 2018 1) Decision whether the clinical trial is contained use or deliberate release; this is easier when the medicinal product has already a marketing approval as the shedding issues have been examided during the approval proecess.



2) classification of the GMM; and



3) interplay of various regulations concerning GMOs, pharmaceuticals, occupational safety, waste treatment,



and patient rights. Commission working group is already considering the interplay of pharmaceutical and GMO legislation, and this hopefully clarifies the situation. However, it is likely not to solve all the issues. It would be worth

examining whether GMO medicinal product production and clinical trials should be legally separated from GMO directives. Also, the linkages between occupational safety, patient rights and waste treatment issues outside hospital environment (e.g. in homecare) should be considered.

FR néant néant

FR 2018 Difficulté à apprécier l'utilisation confinée et disséminée dans le cas d'essais cliniques sur des personnes humaines Le périmètre d'application de la Directive pour les essais cliniques sur des personnes humaines pourrait être clarifié

HR not applicable /

HR 2018

HU In Hungary the requirements for GMO submission in clinical trials could be accepted under the deliberate release directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EC.



No. of authorisation of investigational medicinal products for human use that contain or consist of GMOs under deliberate release directive 2001/18/EC last 3 years: 3 clinical trials. No relevance.

HU 2018 No challenges were encountered. -

IE Not applicable Not applicable

IE 2018 n/a n/a

IT Challenge 1: difficulties for the stakeholders. They are due to different interpretations of the definitions given in Directive 2009/41/EC and in Directive 2001/18/EC (e.g. GMM vs. GMO in which the last includes also the first or to interpret the means of “deliberate release” in a context of “contained use”) and to different approaches used throughout Europe to assess the risk for the humans and environment.



The different interpretations lead EU Member States to follow different procedures and users/sponsors to comply to different rules in order to get the same type of authorizations in different Countries.



Challenge 2: difficulties for the user and the sponsor related to different approaches among the EU Countries.



Though the Directive 2009/41/EC lays down common measures for the contained use of GMMs, the installations, in which a clinical trial is carried out, and the contained activities, by which the IMPs containing or consisting of GMMs, are administered, can be subject, in several European Countries, to authorizations issued according to Directive 2001/18/EC.



The above mentioned not harmonized approach could entail that a deliberate release authorization is issued notwithstanding the user risk assessment reports and proves a priori that there is no deliberate release in the environment of GMMs.



Challenge 3: to avoid misunderstandings among the involved stakeholders and GMM CA whether an application, for a clinical trial in which an IMP consisting of GMM is used, has to be or not submitted to get an authorization to deliberate release according to the Part B of the Directive 2001/18/EC).



Part of these cases can be found among the clinical studies listed on the website of the Joint Research Center (http://gmoinfo.jrc.ec.europa.eu/gmo_browse.aspx) that were submitted, in compliance with the article 6 of the Directive 2001/18/EC, assuming and giving for sure that an intentional deliberate release of GMM occurs although this in conclusion is not or would not be confirmed.

Challenge 4: find a simplified approach, where possible, according to the Directives provisions.



Without prejudice to the right of each European Country to apply on their territory the legislation that is considered more appropriate, it is presumable that an harmonized approach could result more adequate in terms of human resources and time spent by the CAs to assess the notification and by the premises holder, user and sponsor to prepare the notification.



Challenge 5: to establish the relevant cases for which a risk assessment by a notification has to be submitted or not if a medicine used in the clinical trial has obtained the marketing authorization by EMA centralized procedure.



In these cases, the risks to consider could be different for a new clinical trial if compared to those assessed in order to obtain the marketing authorization. This last aspect need to be assessed on a case by case basis by the Italian GMM CA and it is also for this reason that in Italy, to conduct a clinical trial for which a deliberate release can be excluded, the GMM CA issues the authorizations for the premise and the GMM contained activity performed in it. Harmonization of the different point of views of the different Countries at European level should be the primary aim. The work and the documents, produced by Commission Services, focused to optimize the interplay between the GMO, GMM and the medicinal products legislation, are to consider as very useful approaches for the Italian GMM CA and the involved stakeholders.



Challenge 1: could be faced and settled amending the Directive 2009/41/EC and Directive 2001/18/EC with ad hoc provisions focused on clinical trials in which IMPs are administered.



Challenge 2 and 3: provide the user a clear information, previously shared with the involved National CAs, to be published on the CAs institutional web sites.



With regard to the challenge 3, an additional analysis shared at European level could further simplify the approaches followed by involved CAs, users and sponsors. The scope is also to keep the European Commission and Member States informed about the type of Clinical Trials authorized under the Directive 2009/41/EC and to publish the relevant information on the Commission web site.



Challenge 4 and 5: could be dealt importing at national level the approach reported in the mentioned documents produced by Commission service or producing harmonized documents among the European Member States.

IT 2018

LT - -

LT 2018 - -

LU Directive not yet transposed Transposition of the directive is ongoing

LU 2018 Directive not yet transposed Transposition of the directive is ongoing

LV - -

LV 2018 - -

MT Not applicable. Not applicable.

MT 2018 N/A N/A

NL -- --

NL 2018 -- --

PL risk assessment sharing procedures across Member States (for example ERA, notification, etc.)

PL 2018

PT The legal framework of the GMOs clinical trial – deliberate release into the environment of GMOs or contained use of GMOs - is defined on a case-by-case basis taking into account the specificity of the GMO clinical trial. Therefore the clinical trials don´t fall exclusively whitin the scope of Directive 2009/41/EC or Directive 2001/18/EC.



There were no activities notified and/or authorised regarding clinical trials using medicinal products for human use that contain or consisit of GMOs under Directive 2009/41/EC - contained use of GMOs.



However under Directive 2001/18/EC there were submitted and authorised three notifications in 2016 for deliberate release into the environment with GMOs for clinical trials on medicinal products for human use.



The CA had difficulty determinated whether the administration of investigational medicinal products for human use that contains or consist of GMOs - clinical trials, fall under the scope of Directive 2009/41/EC or under the scope of Directive 2001/18/EC.



We considered that should be a harmonisation of the guidance and the procedures for the evaluation and notification of clinical trials with GMMs at Union level. The CA would like to see clarity on the legislative framework concerning clinical trials with GMMs.

PT 2018 The legal framework of the GMOs clinical trial – deliberate release into the environment of GMOs or contained use of GMOs - is defined on a case-by-case basis taking into account the specificity of the GMO clinical trial. Therefore the clinical trials don´t fall exclusively within the scope of Directive 2009/41/EC or Directive 2001/18/EC. The CA would like to see clarity on the legislative framework concerning clinical trials with GMMs.

RO Not applicable. Not applicable.

RO 2018 Not applicable Not applicable

SE No challenges experienced yet. n.a.

SE 2018 - -

SI - -

SI 2018 Administration of investigational medecinal products for humans that contain or consist of GMOs is notified and/or authorised under Directive 2001/18 in Slovenia. -

SK ---- ----

SK 2018 --- ---

UK Unfortunately we cannot provide this information as it is not specifically recorded. Some class 2 activities have definitely been notified and we would estimate that this would be between 10-15 for the reporting period. There is no notification required for class 1 activities which likely accounts for the bulk of work involving administration of IMPs.



Nothing in addition to the issues raised by the industry relating to the lack of consistency across member states in relation to the requirements to notify and which regulatory route (CU v DR) It is our understanding that the EC working groups on GMO-Pharma interplay are trying to address some of these issues through provision of better information and guidance on risk assessment for certain types of vectors etc. At a national level the CA is discussing with the medicines regulator to see if there are ways to streamline clinical trials whilst complying with requirements under the different regimes.