Clinical Research Emergency Response Guide

Hierarchical triggering, clear rights and responsibilities, dual-track parallelism, and traceability closed loop. The priority for handling all emergencies is always "subject safety first, research compliance bottom line is not loosened", and there is no gray space that can be compromised.

Last month, I helped a tertiary tertiary institution to review the emergency incident of an anti-tumor phase I trial last year. It still feels pity when I think about it: the seventh subject enrolled at that time developed a grade 3 allergic rash accompanied by fever 72 hours after the drug was administered. The project team panicked immediately and wanted to hide it from the institution and give it to the subject first. Paying some money to settle the matter, but also fearing that omissions would affect subsequent trial approvals, the two parties struggled to delay the 12-hour reporting golden period. In the end, not only did the subjects' adverse reactions become grade 4, but they were also directly punished by the ethics committee to suspend the project for 6 months. The initial investment of millions was almost in vain.

Let me first explain to you "what is an emergency?" There are actually two schools of thought in this industry, and there is no absolute right or wrong. One group of researchers who came from the drug regulatory system advocates "zero threshold triggering". As long as there is a deviation from the protocol, an SAE (serious adverse event), a subject complaint, or a problem found in a surprise inspection by the institution, the emergency process must be entered regardless of the severity. The advantage is that items will never be missed, but the disadvantage is that it can easily cause a waste of resources - I have seen a project because a subject complained that the follow-up subsidy was delayed for three days, and a dozen relevant persons in charge were invited to hold a two-hour emergency meeting. It was purely unnecessary. The other group, the operators from SMO (clinical research site management organization), prefers "graded threshold triggering", dividing events into three levels: red, yellow and green: red is SAE, data fraud, ethical violations and other flaws, and emergency response must be initiated immediately. ； Yellow refers to small deviations from the plan and delays in trial supplies. First evaluate the impact on subject safety and data integrity before deciding whether to go through the entire process. ； Green refers to common issues such as rescheduling of follow-up visits and late issuance of subsidies, which can be handled by the CRC itself and reported. At present, most leading institutions in China are actually trying to find a balance between the two factions. The trigger line of several top three institutions that I cooperate with is basically "whether it affects the safety of subjects or the core compliance of research." Both sides can be taken into consideration.

Just knowing when the trigger is triggered is not enough. After all these years of dealing with it, the biggest headache is not the incident itself, but the fact that no one takes the blame when something goes wrong, and all the characters kick each other's butts. Many project teams' emergency lists are written in vague terms, including "relevant person-in-charge contact" and "operation team coordination". When it comes time to make a decision, no one responds. My experience is that the emergency list must be written down to everyone: the PI (principal investigator) is the first responsible person and has full authority over medical decision-making. ； Institutional office’s docking and human management compliance reporting path ； CRA (clinical research assistant) manages data traceability and traces ； The CRC (Clinical Research Coordinator) assists in the implementation of subject communication. Even who will send formal emails to ethics and who will call the provincial bureau for reporting needs to be decided in advance. Don’t wait until the moment of urgency and ask each other, “Who will do this?” Oh, by the way, one more thing to mention here. Many project teams will leave all the communication between subjects to CRC. In fact, they have stepped on a big mistake - when serious adverse events occur, a research doctor must be present to communicate. CRC has no clinical qualifications, so it makes many mistakes. I have encountered CRC casually telling subjects "this rash must be caused by the experimental drug." In the end, when the subject made a claim, this sentence was directly used as evidence, and it took almost half a year to resolve.

The so-called dual-track parallelism, to put it bluntly, means that emergency response and compliance reporting are carried out at the same time. Don't do anything like "process first and then report" or "complete the process first and then manage the subjects." If either side is delayed, big trouble will occur. When the COVID-19 epidemic first broke out, a phase II trial in the respiratory department happened to be under lockdown and could not deliver experimental drugs to the enrolled subjects. The project team responded very quickly: they first contacted community volunteers to deliver the drugs to the subjects, and at the same time arranged for researchers to follow up remotely to monitor physical signs. ； The other side immediately reported the deviation from the plan to the ethics and provincial bureau, explained the situation and submitted an adjusted dosing plan. Both sides advanced simultaneously. In the end, not only did no safety issues arise, but because the treatment was promptly approved by ethics, the progress of the trial was not delayed much. By the way, there are also different operating ideas regarding subject compensation. Some institutions advocate that regardless of the causal relationship, as long as the subject feels unwell during the trial, the medical expenses should be paid in advance to avoid disputes. ； Some institutions advocate making a causal determination first, confirming that it is trial-related, and then go through the compensation process to avoid malicious insurance fraud. Everyone can choose according to the risk level of their own project. There is no unified standard answer.

Finally, there is the closed loop of traceability. Many people think that everything will be fine once the incident is handled and reported. In fact, the most critical step has just begun. Be sure to do a root cause analysis. Don't write empty words like "the staff lacks sense of responsibility" and "unfamiliar with the process" every time you review. Dig to the bottom of the cause: For example, the allergic rash incident mentioned before was finally discovered because the entry criteria omitted the clause "Exclusion of people with a history of severe drug allergy." After the project team directly modified the entry, the more than 20 subjects who were subsequently enrolled never had similar problems again. After changing the process, all employees need to be trained. It is best to lead the entire research team to do 1-2 simulation exercises of the same scenario, otherwise it will still be chaotic next time when similar things happen.

To be honest, the emergency guide is not just a window-dressing material to welcome inspections. It is something that each project team must go through and even practice with all relevant personnel before starting. I really waited until the knife holder was on my neck before I thought of reading the manual. By then it was already too late. The conditions of each institution and each trial are very different, and there is no need to impose a unified template. The bottom line of subject safety and compliance can be maintained. The one that suits your project is the best.