BA/BE Exempted From IND Requirements
Not all BA/BEs meet the requirements of IND exemption (that is, there is no need to submit an IND application and perform clinical trials in accordance with IND requirements). For example, BA/BE involving cytotoxic drugs does not meet the requirements of IND exemption.
The guidelines followed by the US IND and BA/BE safety reports are 21 CFR 312.32, 312.64(b) and 320.31(d)(3). The requirements and time limits of the two security reports are not consistent. The former focuses on reports of suspicious and unexpected serious adverse events (SUSAR), while the latter focuses on reports of serious adverse events (SAE).
U.S. IND Clinical Trial Safety Report
US IND clinical trials report SUSAR in accordance with the requirements of ICH E2A. 21 CFR 312.32 clearly stipulates the reporting time limit and requirements:
- That is to say, the SUSAR that requires death or life-threatening needs to complete the report within 7 natural days of the knowledge, and complete the follow-up report within the following 8 natural days.
- For other SUSARs, the first report is completed within 15 natural days of the knowledge, and the new or updated follow-up information is reported within 15 natural days of the knowledge.
BA/BE Safety Report Exempted From IND Requirements
The main reasons for the difference between the BA/BE safety report exempted from the IND requirement and the IND safety report are:
- In BA/BE clinical trials, the number of subjects participating is relatively small, and they are usually healthy subjects. The time of drug exposure is relatively short, and the probability of SAE is small. Therefore, we need to focus on every SAE that appears;
- U.S. regulatory agencies consider that SAEs are rare in BA/BE, and there is no need to make relevance judgments.
- At the same time, based on previous observations, most of the SAEs received are usually listed in the safety reference information such as the instruction manual of the reference preparation, which does not meet the definition of “unexpected” stipulated by the regulatory authorities. (For generic drug BA/BE trials, the US FDA believes that the instructions of the marketed reference drug can be used as safety reference information for the tested drug product)
Therefore, 320.31(d)(3) BA/BE requiring IND exemption should report all SAEs, not just SUSAR.
Time Limit and Requirements For BA/BE Safety Reporting Exempted From IND Requirements
- The sponsor will notify the FDA and all clinical investigators within 15 natural days of the learned SAE, and the follow-up information must be reported within 15 natural days of the learned;
- If the FDA issues a query, additional information or data is required, and the sponsor or the CRO company will reply to the relevant information within 15 natural days;
- For unexpected deaths or life-threatening adverse reactions, it is required to notify the clinical safety coordinator of the Generic Drug Office of the Center for Drug Evaluation and Research (CDER) within 7 days of learning (email, telephone or fax is recommended);
- If the complete report can be submitted within 7 days, there is no need to submit an additional report within 15 natural days of the notification
The SAE here includes expected and unexpected, including SAEs that occurred in the test formulation and reference formulation group.
BA/BE Safety Reporting Methods Exempted From IND Requirements
- Adopt FDA Form 3500A
- Need to indicate:
2) “Follow up Bioavailability/Bioequivalence safety report” for followup information
3) “7-day Bioavailability/Bioequivalence safety report” for unexpected fatal or lifethreatening adverse reaction report
- Guidance for Industry and Investigators SafetyReporting Requirements for INDs and BA/BE Studies
- 21CFR 320.31(d)(3)
- 21CFR 312.64(b)