14/15 December 2023
What happens to an ATMP that is just out of specification? Can it still be released based on a risk assessment? Don't the current guidelines even provide this possibility?
As a fictitious example: Is a product that might have to contain at least 50,000 cells according to the specification no longer effective if it contains only 48,000 cells? May I then still apply the ATMP to the patient, if it can be life saving? Who will do the assessment and decision on release - manufacturer, physician or both? How do you document such a process?
This topic occupied not only the participants of an expert workshop on 25 June in Vienna, conducted by the ATMP Interest Group of the ECA Foundation, but experts and authorities worldwide.
An example from practice is already available from the USA. It concerns Kymriah, a Novartis product that received FDA approval in 2017. Due to the complexity of the manufacturing process, Novartis has batches of this product that do not meet the specification. These were deviations due to cell variability and the number of inactive cells in the treatment of relapsed large B-cell lymphoma. However, due to the severity of the disease, some physicians wanted to use these OOS batches on their patients, as this would be preferable to non-treatment in the context of a risk assessment. Subsequently, in consultation with the FDA, the corresponding doses were made available free of charge for treatment as part of a compassionate use program.
The EMA recently published a Questions and Answers paper entitled "Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products" as a first guidance to these questions, particularly taking into account Section 11.5 of the ATMP Guidelines, which states that in special circumstances the administration of a cell/tissue-based ATMP that does not meet the specifications laid down in the marketing authorisation may be considered in order to avoid an immediate significant risk to the patient. The document addresses questions of responsibility, documentation and notification to the EMA and also states that the patient must be informed in an understandable way, but that this does not relieve the manufacturer of his responsibility.