Late last year, Novartis explained how in certain circumstances, it was providing out-of-specification (OOS) doses of its cell therapy Kymriah (tisagenlecleucel) under a compassionate use program in the US.
As the company dealt with manufacturing issues, the OOS product was provided at no cost but was still “expected to maintain the risk/benefit profile observed in clinical trials,” a spokeswoman told
In light of this development, on Tuesday the European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT), together with the GMDP Inspectors Working Group and the Blood Products Working Party, released a questions and answers (Q&A) document on how companies should go about using OOS batches of authorized cell or tissue-based advanced therapy medicinal products (ATMPs).
EMA explains how the administration of such OOS batches of ATMPs “may be considered to avoid an immediate significant hazard to the patient,” although manufacturers must provide an evaluation of the risks to the treating physician.
“The manufacturer of the OOS batch should always be at the centre of the investigation of the root causes leading to the OOS result and of the evaluation of the risks. In cases where the manufacturer, importer and marketing authorisation holder (MAH) are different legal entities, there should be a written agreement between the parties which lays down the respective roles including also with regard to the communication with the treating physician and competent authorities,” EMA says.
When a patient is administered an OOS batch, the manufacturer should, within 48 hours, inform EMA and the competent authorities responsible for granting the manufacturing authorization to the site manufacturing or importing the product within the EU.
In addition, the manufacturer/importer/MAH should contact the National Authority of the treating site(s) to check if they also have to be informed.
And although the Qualified Person cannot certify an OOS batch, the Q&A explains how “the manufacturing/importing site should - as a minimum - keep records of all details concerning the manufacture, testing, transport and storage of the product, the request of the treating physician and the analysis of the risks provided by the MAH/manufacturer.”
Pharmacovigilance reporting obligations or other obligations to follow up on patients treated with the ATMP (such as with a registry) continue to apply for OOS batches, EMA adds. Patients should also be informed about the OOS ATMP in lay language, the Q&A says.
“It is stressed that document(s) designed to inform patients can neither transfer any responsibilities to the patient nor discharge the responsibilities of the MAH or the manufacturer,” EMA adds.
Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products