European Union: Latest Updates On Good Clinical Practice For Advanced Therapies In The EU

Last Updated: November 14 2019
Article by Alexander Roussanov and Lincoln Tsang

On 16 October 2019, the European Commission published the Guidelines for Good Clinical Practice (GCP) specific to advanced therapy medicinal products (ATMPS) covering gene therapies, cell therapies and tissue engineered products. These Guidelines are available at the website of the European Commission.

Background

The European Commission was legally required to adopt the GCP Guidelines specific to ATMPs (the Guidelines) by Regulation (EC) No 1394/2007 (ATMP Regulation) with the technical input from the European Medicines Agency ("EMA"). The Guidelines were adopted after a period of public consultation with the targeted stakeholder consultation in the second half of 2018.

The Guidelines reflect the experience gained by the European Commission and the EMA in the field of ATMPs and in the assessment and authorisation of this type of medicinal products. Due to their complex nature, ATMPs present specific practical operational and regulatory challenges related to GCP compliance.

Why is this significant?

All sponsors of clinical trials involving an investigational medicinal product, including an ATMP, are required to comply with the GCP.

The general GCP requirements developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ("ICH") apply also to clinical trials conducted with ATMPs. There is, however, a need for the specific Guidelines that reflect the specificities of ATMPS. This is also recognised in Article 4 of the ATMP Regulation which requires the European Commission to develop these Guidelines.

The Guidelines do not seek to replace or supersede the ICH GCP but serve to complement the basic requirement with certain adaption specific to ATMPs. The Guidelines state explicitly that to the extent there is a difference in the requirements imposed by the ICH GCP and the Guidelines, the content of the Guidelines prevails.

The objective of the Guidelines is to address areas of GCP compliance in which there is a need to take into account the specificities of ATMPs. These areas include:

  • the specific manufacturing constraints and the short shelf-life of the ATMPs;
  • the specific mode of administration, the need for related training of the clinical trial team and the challenges surrounding the use of placebo;
  • the need for long-term follow-up of the patients and monitoring of the effect of the ATMPs;
  • specific requirements for retention of samples;
  • traceability of ATMPs that contain cell or tissues of human origin;
  • challenges around the feasibility of blinding of the investigator, the investigator's team or the patients.
  • challenges around the generation of relevant non-clinical data before the conduct of the clinical trial.

The key elements of the Guidelines

The Guidelines address key issues, including selection of patient population, clinical trial protocol design, requirements for pre-existing non-clinical data, manufacturing of ATMPs, safety reporting, samples retention and use of medical devices.

The Guidelines explicitly refer to the European Commission Guidelines on Good Manufacturing Practices for ATMPs. These Good Manufacturing Practices also apply to investigational ATMPs. For the sake of brevity, the blog post does not discuss these aspects.

The Guidelines also refer to the requirements of Directives 2004/23/EC and 2002/98/EC concerning the donation, procurement and testing of human cells and tissues used as starting materials. The protection of the personal data of patients and the related requirements of Regulation (EU) 2016/679 ("GDPR") are also referred to.

Selection of the study population

The Guidelines highlight that patients should be included in the clinical trial only if the anticipated risk-benefit balance of the investigational ATMP is at least as favourable as the risk-benefit balance of existing treatment options. This is particularly important if the effects of the investigational ATMP are long-lasting or irreversible.

The Guidelines also acknowledge that the use of a staggered approach based on the age of the patients may not be suitable for clinical trials involving ATMPs. This is particularly the case for ATMPs for the treatment of conditions that occur at very early age where the treatment would not be effective in the later stages of the disease. In such cases, the requirement for prior studies in adults may be waived, subject to certain conditions.

The selection of patient population should also consider risks of sensitisation of patients and pre-existing immunities.

Choice of comparators and controls

In absence of availability of an active comparator, the effects of the investigational ATMP may be compared to the best standard of care. A comparison between patients' biomarkers levels pre- and post-treatment can also be considered.

The use of placebo in clinical trials that involve invasive procedures for the administration of the investigational ATMPs or the collection of tissues and cells would be acceptable only when it is ethically and scientifically justified. Patients receiving placebo should not be subject to these invasive procedures unless the related risk and burden for the patients is minimal.

Dosing of the patients

The Guidelines acknowledge that in some circumstances does escalation may not be necessary or appropriate. This includes situations in which there are no toxicity concerns or the re-administration of the medicinal product is possible or ethically justified. In these cases, the exploratory dose should be a therapeutic dose for the specific patient.

Safety reporting

The safety reporting mechanisms set out in the Protocol should take into account the specific characteristics of the investigational ATMP. The safety reporting mechanisms should specifically consider, among other key elements, the adverse events that are possibly related to:

  • the product administration process or intervention; and
  • any medical device used in the conduct of the clinical trial.

Determination of the end of the clinical trial

In light of the potentially long-term effects of the investigational ATMP and the related need for long-term follow-up and monitoring of the patients, it may be challenging to identify the end of the clinical trial in the Protocol. The Guidelines highlight the importance of clear determination of the event that marks the end of the clinical trial and to outline to follow-up activities taking place after this moment.

The duration and the nature of the follow-up activities should be clearly described in the clinical trial documentation, along with the related scientific and medical justification. Patients should be fully informed of all aspects of these activities and provide their related informed consent.

Requirements for pre-existing clinical data

The Guidelines acknowledge that in the specific case of ATMPs, non-clinical data may not be available or even possible to generate. According to the Guidelines, the rationale for not conducting a non-clinical development should be justified by the sponsor and discussed in the related clinical trial documentation, including the Protocol, the Investigator Brochure and the Investigational Medicinal Product Dossier ("IMPD").

Use of medical devices

If the investigational ATMP incorporates a medical device, the IMPD should contain information concerning:

  • characteristics, performance and intended use of the device;
  • compliance with Regulation (EU) No 2017/745 on medical devices, where applicable; and
  • suitability of the medical device.

The Guidelines indicate that the clinical trial could involve the use of investigational medical devices. This includes medical devices that are not CE marked. This is somewhat surprising, as previous experience suggests that the use of investigational medical devices in clinical trials for investigational non-ATMP medicinal products is discouraged or even not permitted by the competent authorities of the EU Member States.

Samples retention

The Guidelines acknowledge that it may be challenging to retain samples of the investigational ATMP due to limited shelf life or scarcity of the materials, especially in the case of autologous or allogenic ATMPs. In these circumstances, the sampling strategy set out in the Protocol may be adapted with the related justification.

Patient monitoring

ATMPs exhibit unique biological characteristics and functions. The safety profile may not be fully characterised particularly with respect to their long-term effects. Therefore, long-term follow-up of the trial subjects to assess potential delayed adverse events is necessary. The Guideline also recognises the practical challenges of instituting long-term follow-up of trial subjects who may reside in a long distance away from the trial site and are unwilling to return to the trial site for follow-up. The need to monitor remotely is contemplated.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Authors
 
In association with
Related Topics
 
Related Articles
 
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Mondaq Free Registration
Gain access to Mondaq global archive of over 375,000 articles covering 200 countries with a personalised News Alert and automatic login on this device.
Mondaq News Alert (some suggested topics and region)
Select Topics
Registration (please scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions