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.
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.
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.
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.
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.