The information which should be provided includes:

• Description of active substance
• Description of the finished product
• Mechanism of action and proposed use
• Summary of the status of the development of the product

Scientific evaluation and certification

The coordinating investigator should consider submitting all relevant quality and, where available, non-clinical data to EMA for scientific evaluation and certification of a new ATMP.

Information which could be submitted with the request form includes but is not limited to:

• The stage of development and in particular the stage of any study in pre-clinical or clinical setting whether planned, ongoing or completed.

• Starting and raw materials.
• Manufacturing process of the active substance(s).
• Data on characterisation of the active substance(s) (limited to the data necessary to adequately describe the active substance(s)).
• Description and composition of the finished medicinal product.
• Primary pharmacodynamic data supporting the rationale for the proposed therapeutic use.
• Data from at least one toxicity study.
• Data from non-clinical pharmacology studies (proof-of-concept studies).

Further information and the ATMP certification forms can be found on the EMA web site.

Quality of the ATMPs

The coordinating investigator should ensure that the following information is available:

• Detailed instructions for the handling and storage of the investigational product(s) at the clinical site
• Confirmation that required temperature has been maintained during transport and storage prior to administration

If the handling process is complex, the coordinating investigator should ensure that adequate training is given by qualified personnel e.g. the manufacturer.

Manufacturing of investigational ATMPs is laid down in the GMP requirements for Advanced Therapy Medicinal Products (EudraLex - Volume 4 - European Commission).

Where an ATMP contains human cells or tissues, the Investigational medicinal product dossier (IMPD) should contain an overview of:

• The confirmation that the donation, procurement and testing of the cells and tissues used as starting materials are in accordance with Directive 2004/23/EC or Directive 2002/98/EC.
• The confirmation that a traceability system is in place that enables the bidirectional tracking of cells/tissues contained in ATMPs from the point of donation, through manufacturing, up to the administration of the investigational product to the participant.

In case that an ATMP incorporates a medical device (“combined ATMP” and medical devices that are otherwise an integral part of the investigational ATMP, e.g. scaffolds), the IMPD should contain:

• Information on the characteristics, performance and intended use of the device.
• Information whether the medical device part(s) comply with the relevant general safety and performance requirements provided for under Regulation (EU) No 2017/745 on medical devices. When this is not the case (e.g. the medical devices used in an investigational combined ATMP are in an investigational phase as well), a justification should be provided as to the suitability of the medical device for the intended use, having due consideration to the relevant general safety and performance requirements.

More details on content of the IMPD is provided in EU Reg 536/2014 Annex I, section G.

Where applicable, the cover letter should contain a list of medical devices which are to be investigated in the clinical trial, but which are not part of the investigational medicinal product or products, including the CE-marked medical devices for the intended use.

Traceability

The manufacturer should provide the coordinating investigator with detailed instructions to ensure traceability from sourcing, manufacturing, packaging, storing, transport to delivery to the clinical trial site, of the cells/tissues contained in the investigational ATMP.

Sponsor must document administration to the participants, reconciliation and destruction or final disposition. Traceability data should be documented in each step, as well as the location of the traceability records.

In case the manufacturer ceases to exist, the coordinating investigator should discuss custody of the traceability data with the Reference Member State (RMS).

Protocol

In addition to the usual requirements for a clinical trial protocol, the following should be considered by the coordinating investigator in relation to the content of the protocol but not limited to:

• Information on the follow-up strategy expected for the ATMP (including follow-up after the end of the trial, long-term follow-up and remote follow-up). The safety profile for some investigational ATMPs may not be fully elucidated, with respect to long-term effects in particular. The duration of the biological activity of a given ATMP should be taken into consideration when determining the need of participant follow-up. In long-term follow-up of participants, the reporting of adverse events during the follow-up period should be clearly specified as part of the long-term follow-up arrangements. If the coordinating investigator plans to gather follow-up data from sources other than visits of the participants to the clinical trial site, the process of gathering data should be clearly explained (e.g. use of digital tools or phone calls, visits of the clinical  trial participants to a local physician).
• The process for reporting adverse events (see Safety reporting).
• If there is any variability inherent in the use of the ATMP then the protocol should define the appropriate degree of flexibility that may be used for the handling of any variability, for example, the acceptable range of cell numbers and cell viability at the time of administration to participants.

If medical devices are to be investigated in the clinical trial but are not part of the IMP, the protocol should contain summary information on the characteristics, performance and intended use of the device, as well as its regulatory status (e.g. CE-marked).

Informed consent

In addition to the usual requirement for consent the participants should receive the following information:

• The expected benefits and risks of the ATMP, including the risk of treatment failure and effects of the treatment on the future use of the other therapies for the diagnosis or treatment of the disease.
• The irreversible nature of the ATMP, if applicable.
• The risks to close contacts and off-springs.
• Where applicable, if the treatment could compromise future pregnancies.
• The need for long-term follow-up and/or arrangements for remote follow-up, if applicable.
• The presence of the sponsor (or a representative thereof) during the collection of cells/tissues or the administration of the ATMPs.

If presence of the sponsor (or a representative thereof) is envisaged before the start of the clinical trial, this should be explained in the informed consent. If, exceptionally, the presence of the sponsor (or a representative thereof) has not been foreseen from the outset of the clinical trial but is justified for reasons related to the protection of the clinical trial participants or to detect and prevent errors in the extraction of cells/tissues and/or administration, the clinical trial participants should be informed a posteriori.

Safety reporting

In addition to the usual reporting requirements for adverse events and serious adverse events from principal investigator to the sponsor (medical monitor), the following safety issues should be specifically considered (non-exhaustive list):

• Adverse events possibly related to the product administration process (surgical procedures; or other).
• Adverse events possibly related to medical devices that form part of the product or are used for application of the product.
• Adverse events possibly due to unexpected reactions such as hypersensitivity, immunological, toxic; or migration of cells from the target site and ectopic tissue formation.
• Adverse events possibly related to product failure (including lack of efficacy).
• Adverse events possibly related to mandatory concomitant medication (e.g. immunosuppression).

The process for reporting adverse events should be outlined clearly in the protocol.

Follow-up

The sponsor should ensure follow-up procedures including (non-exhaustive):

• Follow-up for the protection of the participant i.e. clinical follow up.
• Follow up for the purpose of collection of specific data (which might not involve all participants) i.e. safety follow-up and efficacy follow-up.
• Remote follow-up.
• Long-term follow-up.

Where long-term follow-up of participants is necessary, the coordinating investigator should discuss the long-term follow-up with the reference member state. The length of the observation period should be based on a risk-assessment.  

Patient alert cards

Alert cards should contain – as a minimum – the name of the participant, an investigator contact number and information regarding the medical treatment received.

The cards should be approved by authorities through CTIS.

Monitoring

In addition to usual risk considerations, the monitoring plan should consider that:

• For ATMPs that contain cells or tissues of human origin, monitoring activities should also cover compliance with the traceability requirements.
• The arrangements for long-term follow-up of participants (as described in the protocol) should be verified, if applicable.

Documentation and archiving 

After termination of the trial, the coordinating investigator and the principal investigators will archive all essential documentation and ensured storage for 30 years after the expiry date of the product, unless a longer time period is required in the clinical trial authorisation.