Table 2 Comparison of regulatory mechanisms for the provision of OOS products in the regions of the United States, European Union, and Japan
| Â | United States | European Union | Japan |
|---|---|---|---|
Legal handling of the OOS product | Unapproved product | Commercial product | Unapproved product |
Regulatory mechanism of OOS product provision | Expanded sccess | GMP guidelines on exceptional release of OOS ATMPs | Clinical trial |
Eligible patients | No specific requirements exist for defining eligible patients for providing OOS products for ethical purposes Expanded access may be appropriate when all the following apply: Patients have a serious or immediately life-threatening disease or condition No comparable or satisfactory alternative therapy exists to diagnose, monitor, or treat the disease or condition Patient enrollment in a clinical trial is not possible Potential patient benefit justifies the potential risks of treatment | Considering the alternative options for the patient and the consequences of not receiving the cells/tissues contained in the product, OOS product administration is necessary to avoid an immediate significant hazard to the patient | In principle, the target patients for clinical trials are those defined for the purpose of collecting data for regulatory approval. No specific requirements exist for defining eligible patients for clinical trials aimed at providing OOS products for ethical purposes |
Responsibilities of the HAs | FDA will review a treatment IND/Protocol submitted by a physician or company and authorise the use of the OOS product FDA supervises it in accordance with Expanded Access regulations | Supervisory Authority and EMA requires the MAH to report each OOS provision (within 48Â h from the supply) EMA will inform the Committee for Advanced Therapies Rapporteurs of each authorised OOS product. If a trend is detected, the need for regulatory actions will be considered | PMDA will review a CTN of OOS trial submitted by the MAH and authorise the use of the OOS product. The HA does not request a report for each OOS provision PMDA supervises it in accordance with GCP |
Responsibilities of the MAH | Submit Treatment IND/Protocol to FDA Follow-up of the patient who received the OOS product in accordance with REMS Report safety information to the HA in accordance with IND requirements | Establish standard operating procedures for providing OOS products. OOS products may be provided only if the requirements of the guidance are met Submit a Quality Defect report to the HA Conduct pharmacovigilance activities in the same manner as those for commercial products | Submit a CTN of OOS trial to PMDA Conduct an OOS trial in accordance with GCP, evaluate the safety and efficacy of OOS products, and report safety information to the HA |
Responsibilities of treatment physicians | Confirm patient eligibility Request the MAH to provide the OOS product Obtain patient IC Monitor and follow-up the patient according to the treatment protocol Report safety information to the MAH and HA according to IND requirements | Confirm patient eligibility Request the MAH to provide the OOS product Obtain patient IC Monitor and conduct patient follow-up Report safety information to the MAH and HA (same with that required for commercial products) | Confirm patient eligibility Request the MAH to provide the OOS product Obtain patient IC Monitor and follow-up the patient according to the clinical trial protocol Report safety information to the MAH and HA according to GCP requirements |
Responsibilities of medical institutes | Conduct EC review for the use of the OOS product to the patient (including the protocol and ICF) | Conduct EC review for the use of the OOS product to the patient (including the ICF) | Conduct IRB review for conducting an OOS trial (including the protocol and ICF) Conduct an OOS trial in accordance with GCP |