On Friday 12th April 2019, I had the opportunity to attend a seminar on good cellular therapy practices organized by the Spanish Ministry of Health and the Spanish Competent Authority, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) representing our consulting firm, Pharmity.
Speakers from the Ministry of Health, AEMPS, the Cell Theraphy Network (TerCel) and patients’ associations gave an overview of the current status of ATIMP in Spain and Europe with special focus on cell therapy.
It was highlighted on multiple occasions during the seminar, that Spain is the leading country in clinical research with advanced therapy medicinal products (ATMP) (800 clinical trials were authorized in Spain in 2018) and that clinical trials are fundamental tools to make these medicines available to patients.
This article will summarize the overarching principles in ATIMP/ATMP regulations and guidelines relevant to Good Clinical Practice (GCP) that were not covered in detail during the aforementioned seminar.
The Spanish Royal Decree (RD) 1090/2015 defines “ATIMP” as an investigational medicinal product which is an advanced therapy medicinal product as defined in point (a) of article 2(1) of Regulation (EC) No 1394/2007:
‘Advanced therapy medicinal product (ATMP)’ means any of the following medicinal products for human use:
Important consideration should be given to the classification and definition of the medicinal investigational product at its very early stages of development. Companies can consult AEMPS to determine whether the medicine they are developing is an advanced therapy medicinal product (ATMP). The criteria for ATMPs are set out in Regulation (EC) nº 1394/2007 (Article 17)2.
The main regulation for ATMPs in the European Union (EU) consists of Regulation (EC) No 1394/2007 which was developed as a lex specialis of Directive 2001/83/EC3 to provide the regulatory framework specific for ATMPs in terms of authorization, supervision and pharmacovigilance.
The specifics of ATMPs were implemented into other legal texts and guidelines by the European Commission (EC). The scientific and technical requirements specific to ATMPs concerning quality, safety and efficacy were introduced by the Commission Directive 2009/120/EC4 to amend Annex I of Directive 2001/83/EC.
The Annex 2 of the EU guidelines for Good Manufacturing Practice (GMP)5 was updated by the European Commission with respect to the specific requirements of ATMPs to comply with Article 5 of the ATMP regulation and a guideline on good clinical practice to ATMPs was developed.
Furthermore, other scientific and procedural guidelines and guidance documents for ATMPs have been developed by the European Medicines Agency (EMA).
Table 1 lists all the aforementioned EU documents and the main legislation and reference guidance for ATMPs in Spain.
There are three main types of authorization that can be granted in Spain:
Regulation (EC) nº 1394/2007 specifies that “Advanced therapy medicinal products which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient, should be excluded from the scope of this Regulation whilst at the same time ensuring that relevant Community rules related to quality and safety are not undermined”1. Each EU member state regulates the medicine products that have not been industrially manufactured. In Spain this is regulated by Royal Decree (RD) 477/20146.
Clinical Trials using ATIMPs are conducted under the same clinical trials regulations as all other clinical trials; however, such trials shall additionally comply with the guidelines for good clinical practice which are specific for advanced therapy medicinal products (Table 1. Regulations and Guidelines for ATMP).
The overarching principles related to ATIMP clinical trials are as follows5:
The sponsor should ensure that an ongoing risk analysis, based on existing knowledge of the type of product and its intended use, is performed and provided to the investigator involved in a clinical trial with that ATIMP, through the investigator brochure or updates to it and to the patient through the informed consent or updates to it.
The risk analysis for each ATIMP clinical trial should contemplate, among other things, the need for, the duration and the nature of follow up5.
Where an ATIMP contains human cells or tissues, the sponsor of the trial, the manufacturer and the investigator/institution where the product is used should ensure that there is a traceability system in place to link the donor/source to the donation, to link the donation to the product and then to link the product to the subject. The traceability has to work in both directions from source to subject and from subject to source.
GCP contains requirements for accountability of IMPs that contributes to the traceability of the ATIMP from the manufacturer onwards.
Traceability requirements should also be compatible with the requirements in Annexes 2 to the GMP Guidelines7 (Manufacture of biological active substances and medicinal products for human use) and to the GMP Guidelines as amended for the specific requirements of ATIMPs.
The guideline on traceability referred to in Article 15(7) of the Regulation No 1394/2007 should also be applicable to clinical trials on ATIMPs.
In the event that the clinical trial is suspended or prematurely ended or the product development discontinued, the sponsors retain their obligation to ensure that the traceability system is maintained (including where the ownership of the ATIMP is transferred to another legal entity; the new owner should take responsibilities for maintaining the traceability). In case of bankruptcy or liquidation of the sponsor, and in the event that the ownership is not transferred to another legal entity, the relevant traceability records related only to ATIMPs shall be transferred to the national competent authority.
The traceability procedures and the documentation process should be described in the clinical trial protocol and amended as needed which is sent to the competent authority for approval.
The system should allow full traceability from the donor to the recipient through anonymous coding systems.
There are specific considerations for consent for ATIMPs. The subjects and their legal representatives as applicable, should be informed by the investigator of the specific issues arising from ATIMPs (Table 2).
As regards to the keeping of records, the rules as set out in Directive 2001/20/EC8 and 2005/28/EC9 apply. The traceability records should be kept by the sponsor of the trial and investigational sites for a minimum of 30 years after the expiry date of the product, or longer if required by the terms of the clinical trial authorization or by the agreement with the sponsor (this requirement differs for ATIMP as compared with other medicinal products).
Before, during and after completion or termination of the trial, each party should hold the necessary information available at all times to ensure bidirectional traceability, linking the donor information at the procurement site to the ATIMP and the clinical trial subject information at the clinical trial site to the ATIMP, whilst ensuring the data protection legally required for both the donor and the clinical trial subject.
The requirements for notification of adverse events and adverse reactions by the investigator and the sponsor in the context of clinical trials are laid down in Articles 16 and 17 of Directive 2001/20/EC and their implementing guidelines. New events related to the conduct of the trial or the development of the ATIMP and likely to affect the safety of the subjects such as serious adverse events (SAEs) associated with trial procedures, and significant hazard to the subject population should be reported according to the existing timelines for expedited reporting (this requirement differs for ATIMP as compared with other medicinal products).
The sponsor should provide information and training to the investigator on any additional protocol and/or product specific requirements for the reporting of adverse events and this reporting process should be outlined clearly in the clinical trial protocol. Table 3 details the safety issues that are of special concern for ATIMPs.
Differentiated causality assessment concerning the safety issues mentioned above should be described in the clinical trial protocol and implemented in the adverse event reporting system.
The need for, the duration and the nature of follow-up should be determined by the sponsor for each clinical trial based on the nature of the ATIMP, the current state of knowledge regarding that ATIMP and a risk analysis, including the risk for close contacts and offsprings.
The sponsor may wish to discuss the duration of follow up with the competent authority, AEMPS. This follow up should be aligned with the specific requirements of the product under development, should be described in the protocol, and amended as needed in accordance with the evolving experience with the ATIMP and should make it clear which follow up activities should take place prior to and after the end of the clinical trial. The rationale for the chosen follow-up, including the available supporting information, should be documented and kept as an essential clinical trial document.
The follow up should be considered from the following aspects:
All subjects participating in a clinical trial with an ATIMP should receive from the investigator an alert card, which has been previously agreed by the sponsor and approved by the Ethics Committee, containing as a minimum; the name of the subject, the investigator contact number and information regarding the medical treatment received.
Subject alert cards should inform treating physicians about the product used and any other source of data available in case of safety/efficacy issues, and of the need to inform the competent authority, the investigational sites and the sponsor in the event of certain serious adverse reactions.
The protocol should define the end of the trial and which follow up should take place after the end of the trial. The safety and efficacy follow up involving active data collection (study visits) should form part of the clinical trial whereas clinical follow up and passive data collection may take place after the end of the trial.
Where follow up after the end of the trial is required, in particular when this occurs over a long term, the sponsor needs to ensure that there is a process in place for follow up of the subjects treated with the product – even in cases where the product development is discontinued or the (former) sponsor ceases to exist as a legal entity. This process should be described in the protocol, which should be amended as needed.
Where a subject is withdrawn from a trial at their own request or based on a decision of the investigator, the follow up should be maintained depending on the consent of the subject.
Table 4 lists the main sources where information regarding ATMP/ATIMPs can be located in Spain.
The EU legal framework for ATMPs sets high regulatory standards, including manufacturing in compliance with GMP and the centralized procedure for obtaining a marketing authorization, which requires among others, conducting clinical trials. This puts an enormous regulatory burden on the manufacturers of ATMPs, who are mainly represented by academic institutions with limited regulatory expertise, budget and staff.
The development, regulation, and clinical use of the vast majority of ATMPs are still evolving. As a consequence, defining appropriate regulatory standards taking into account the complexities inherited in these products is crucial.
For the field to advance, developers and regulators need to collaborate to continuously monitor and evolve methodologies and regulations for ATMPs. This was a clear message sent by AEMPS during the seminar on cell therapy that took place last 12th April 2019 in Madrid.
If medicines traceability is critical, for ATMPs it takes higher priority. Traceability along with an ongoing risk-assessment (and risk minimization strategies) and a well-established post-marketing surveillance are fundamental pillars when talking of ATMPs.
Author: Dr Leire Zúñiga, Director and Principal GCP Consultant
PHARMITY, 22nd April 2019