D7. Out of specification (OOS) ATMP
In some cases, an ATMP (advanced therapy medicinal product) does not meet the quality requirements as laid down in the specification of the Investigational Medicinal Product Dossier (IMPD). For example, a cell therapy product may contain fewer cells than specified and therefore falls 'outside the specification'. This ATMP is referred to as out of specification (OOS). In exceptional cases, an ATMP which is OOS may still be administered to the research subject following a positive benefit/risk assessment by the manufacturer and the research physician.
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 subject, 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 dealt with in the data analysis must also be established.
- The Subject Information Sheet should indicate that an ATMP which is OOS may be administered during the study.
- In case of an ATMP which is OOS the research subject concerned should be informed adequately and timely about the product and consent to its administration.
Notification to CCMO and IGJ
Notification to CCMO
The sponsor should notify CCMO of the supply and/or administration of an ATMP which is OOS regarding all participating centres. In the case of multinational research this includes the centres outside the Netherlands.
In the case of supply/administration to a research subject in the Netherlands, the sponsor should notify CCMO by email within 48 hours of delivery of the product via firstname.lastname@example.org, indicating 'Notification of ATMP which is OOS' and the relevant file number (NL number). The notification must include all relevant information available at that time. The sponsor may send relevant information not yet available at the time, at a later moment within a reasonable period of time. In that case, the sponsor should indicate in the notification when the remaining information is expected to be received by CCMO. Ultimately, CCMO should at least receive the following information:
- a description of the OOS with a risk analysis by the manufacturer on the impact on:
- the quality of the product, including the percentage of batches that is OOS on the total of started productions and a reflection on the production process ('root cause analysis' and 'CAPAs'),
- the safety and efficacy of the product in relation to the research subject;
- a confirmation of the research physician to the manufacturer to accept the product;
- a declaration from the sponsor as to whether or not the product has been administered.
In the case of supply/administration outside the Netherlands, the requirements as indicated above apply, except for the maximum period of 48 hours. There is no fixed term for the notification of supply/administration of an ATMP which is OOS outside the Netherlands.
Notification to IGJ
In case the ATMP which is OOS is produced and/or released in the Netherlands or in case it is supplied to a patient 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.