The latest version of clinical research emergency response guidelines

At present, the latest official guidance document for clinical research emergency response in China is the "Technical Guiding Principles for Clinical Trial Emergency Management (Trial)" jointly issued by the Drug Evaluation Center and the Medical Device Technology Review Center of the State Food and Drug Administration in March 2024. The latest supporting implementation manual commonly used in the industry at the practical level is the "Clinical Research Site Emergency Response Operation Manual (2024 Revised Edition)" updated by the Chinese Pharmaceutical Association in June 2024. The two documents together constitute the latest normative basis for the current domestic clinical research emergency response.

Last year, I was stationed at a tumor monoclonal antibody clinical trial site in a tertiary hospital in Shanghai, and I happened to encounter a grade 3 SAE where a subject developed laryngeal edema 10 minutes after administration. At that time, I read the 2021 version of the old guidelines, and the blinding process was very vague. The institution required that the ethics committee office be called to report first, but that day happened to be the weekend, and there was no one in the office. It took more than 20 minutes to find the ethics committee to sign to break the blinding. Fortunately, the subject was rescued in the end. Now I am scared to think about it. This new version of the guidelines is most praised by front-line practitioners because it directly resolves the dispute that has been quarreling for five or six years about "whether emergency blinding should wait for ethical approval first": as long as the situation is judged to be life-threatening to the subject, blinding can be broken immediately and rescued, and ethics can be supplemented within 24 hours. There is no need to get stuck in the regular approval process. In the past, the institutional group insisted on "complying first and then saving people", and the clinical group shouted "what's the use of compliance without people"? Finally, there is a clear boundary.

To be honest, many of the pitfalls filled in this update are real lessons learned from the past. For example, during a heavy rainstorm in Zhengzhou last year, the cold storage of experimental drugs in a clinical center lost power for 48 hours, and the follow-up of nearly a hundred subjects was interrupted. The old version of the guideline did not mention the rules for handling scenarios such as natural disasters and public health emergencies. At that time, the CRC of the entire center ran for three days to sort out the data and drug damage. This new guideline specifically adds relevant provisions, requiring all clinical trial centers to prepare for extreme scenarios in advance: cold storage must be equipped with generators, and sites that are more than 15 minutes away from the nearest emergency facility must be equipped with certified on-site first aid personnel. It even provides reference standards for remote follow-up of subjects and drug delivery processes in situations such as epidemic lockdown. This is indeed very down-to-earth.

Of course, not all questions have standard answers. For example, the currently hotly debated issue of “should AI emergency warning be included in mandatory requirements?” The guidelines are not one-size-fits-all. Several phase I head centers in Beijing have now used AI systems to monitor physical signs of subjects in real time. Once abnormalities in heart rate or blood pressure occur, they will immediately alert the CRC and researchers. A previous cell therapy center used AI to detect precursors of cytokine storms in subjects 15 minutes in advance, saving a life. ； However, many ethics committees in Guangzhou have always held objections. They feel that if AI misses the report or misdiagnoses, who will be held responsible? This time the guide only states that "qualified institutions are encouraged to explore digital emergency warning mechanisms, and the relevant data retention period shall not be less than 5 years after the end of the trial." There is no mandatory requirement, which can be considered as leaving space for centers at different stages of development.

Last month, I helped a county-level hospital center in Jiangsu and Zhejiang sort out emergency supply kits. Previously, their bags were stuffed with a bunch of useless experimental drug instructions and old version of ethics approval documents. According to the requirements of the new version of the guidelines, four items must now be placed on the outermost layer: the specific rescue drug margin corresponding to the experimental drug, the sealed blind envelope, the green channel docking card for the nearest tertiary emergency room, and the mobile phone number of the 24-hour contact person of the ethics committee. If something goes wrong, you can easily get it. There is another detail that is easily overlooked: this guide specifically mentions that the emergency procedures for cell therapy projects such as CAR-T and stem cells cannot be mixed with ordinary chemical drugs and monoclonal antibody projects. Previously, a center copied the allergy treatment procedures for chemotherapy drugs to deal with cytokine storms, which almost caused a serious incident. Now all cell therapy projects are required to make separate emergency plans and conduct at least two drills in advance with the emergency departments they are connected to.

The last time I chatted with an old PI who has been working for more than ten years, he said that the guidelines always cover the bottom line. People who do clinical research must have a strong balance in their hearts. Nothing is as important as the safety of the subjects. When it comes to emergency response, these words are really more effective than any number of rules. At present, many colleagues have complained that the cross-regional emergency coordination provisions for multi-center trials in the new version of the guide are still too rough. If SUSAR occurs in multiple centers across the country at the same time, each center still needs to coordinate on its own. Additional details should be released in the future. We are also waiting for updates.