Research with ATMP's (Out of specification, OOS)

Exceptional cases

Section 11.5 of the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products states that, in exceptional cases, an ATMP which is OOS may be administered to the research participant, following a positive benefit/risk assessment by the manufacturer and the research physician:

Exceptionally, the administration of the cells/tissues that are contained in a cell/tissue based ATMP that is out of specification may be necessary for the patient. Where the administration of the product is necessary to avoid an immediate significant hazard to the patient and taking into account the alternative options for the patient and the consequences of not receiving the cells/tissues contained in the product, the supply of the product to the treating physician is justified.

When the request of the treating physician is received, the manufacturer should provide the treating physician with its evaluation of the risks and notify the physician that the out of specification product is being supplied to the physician at his/her request. The confirmation of the treating physician to accept the product should be recorded by the manufacturer. In a clinical trial setting, the manufacturer should immediately notify the sponsor of such events. In turn, the sponsor should inform the relevant competent authority. For marketed products, the marketing authorisation holder and the supervisory authority for the site of the batch release should be informed.

The manufacturer and the research physician are responsible for the administration of an ATMP which is OOS.

Topics to be included in the research file

For studies which may involve the administration of an ATMP which is OOS, the following topics should be included in the research file:

• A section in the protocol describing the OOS procedures. A detailed description of the possible OOSs of the ATMP and the various actions to be taken is not required.
• The expected OOS percentage should be substantiated. This may be included in the statistics section of the protocol. How data obtained after administration of an ATMP which is OOS will be included  in efficacy and safety analyses must also be indicated.
• The Participant Information Sheet (PIS) should mention that an ATMP which is OOS may be administered during the study. If possible, the PIS should also include an estimation of the (numerical) chance of an ATMP which is OOS based on existing manufacturing experience.
• In case of an ATMP which is OOS the research participant concerned should be informed adequately and timely about the product and consent to its administration.

Notifications

Notification to Member States concerned

An OOS administration of ATMPs is considered an unexpected event (CTR, article 53) as it may affect the benefit/risk balance of the clinical trial. In case of administration of an ATMP which is OOS, the sponsor has to notify the Member States concerned via CTIS. In case of a non-authorised ATMP the sponsor has to notify the Member States concerned within maximum 15 days after the administration of an OOS product via CTIS. For authorized products periodic reporting in CTIS is acceptable. This is laid down in chapter 6.1 of the CTR Quick guide for sponsors.

Of note, in case reporting via CTIS may lead to unblinding of the trial, these notifications need to be done outside of CTIS via mail to all national contact points of the Member States concerned.

The OOS notification is expected to consist of the following information:

• a description of the OOS including a risk analysis by the manufacturer on the impact on:
  • the risks and benefit of the product to the research participant;
  • the quality of the product, including the number of batches that are OOS and the total number of started productions as well as a reflection on the production process ('root cause analysis' and 'CAPAs')
• a letter of acceptance from the research physician to the manufacturer
• a detailed statement from the sponsor as to the use and administration of the product.

Notification to IGJ

If the ATMP which is OOS is produced and/or released in the Netherlands or if it is supplied to a research participant in the Netherlands, the sponsor should also notify the Dutch Health Care and Youth Inspectorate (IGJ) within 48 hours of supply of the product via the Medicine shortages and defects notification centre.