The latest revision of clinical research emergency response guidelines

The first is to refine the "prioritization of subjects' rights and interests" from a principle requirement to an implementable mandatory clause. The second is to add emergency response modules in new fields such as public health emergencies, cell therapy, and real-world research. The third is to adjust the flexibility boundaries of emergency blinding, incident reporting and other processes, which solves the common industry pain point of "more principles and less practical operations" in the old version of the guideline.

When I went to Guangzhou last month to attend a closed-door meeting on clinical research ethics, Director Zhang from the Ethics Office of the Third Hospital of Sun Yat-sen University complained about the 2019 version of the old guidelines, saying that their center had previously received a Phase III trial of an oral drug for COVID-19, and a subject developed severe liver damage after taking the drug and had to be hospitalized. This revision directly writes the rules for handling such scenarios into mandatory clauses: All research-related adverse event treatment costs must be advanced by the sponsor within 24 hours, and subjects must not be required to use medical insurance or commercial insurance for any reason. Sponsors who violate regulations will be directly included in the list of research dishonesty, and will not accept any new drug clinical trial applications for three years, fundamentally blocking the room for blame.

Speaking of the most controversial clause in this revision, it has to be the adjustment of emergency blindness breaking authority. Previously, the old version required that any blinding operation must be approved by the ethics committee and must obtain written approval before execution. Experts from the ethics camp have always insisted on this requirement, saying that once the blinding authority is relaxed, it is easy for researchers to break the blinding at will in order to cover up adverse events, destroying the blinding integrity of the study, and the final experimental data collected cannot be used at all. But front-line researchers have long been complaining. I stayed at a cancer clinical research center in Suzhou for two weeks last year, and happened to encounter a subject who went into anaphylactic shock after taking an experimental drug. At that time, the main researcher wanted to break the blind to confirm whether the experimental drug or a placebo was used, so that he could adjust the emergency plan. No one answered the call to the ethics committee, and he waited for more than 40 minutes before he could contact the ethics secretary, which almost delayed the first aid. Therefore, this revision directly gave two sets of parallel plans: If there is a life-threatening emergency, the lead researcher can directly break the blinding, as long as the reasons for breaking the blinding and the treatment process are compiled into written materials and submitted to the Ethics Committee for filing within 24 hours. ； If it is a non-life-threatening situation, the normal ethics approval process still needs to be followed, and the demands of both parties are taken into account.

Oh, by the way, the previous old version of the guidelines was basically written around interventional clinical trials. In the past two years, there have been more and more real-world research and cell therapy projects, and there is no corresponding clause in emergency situations. Last year, there was a real-world research project in a province in East China. The hospital's system was hacked and the medical and research data of more than 2,000 cancer patients were leaked. At that time, the project team was in a hurry and did not know who to report to or whether to notify the subjects. In the end, it took almost two weeks to send the notice, and many subjects complained to the provincial drug administration. This revision specifically adds an emergency response chapter for non-interventional research, making it clear that as long as the personal information of subjects is leaked, all involved subjects must be notified within 72 hours, and reported to the provincial drug regulatory department and ethics committee. A specific notification template and reporting process are also attached, which saves a lot of trouble.

I just updated the emergency SOP for a CAR-T cell therapy project last week, and I directly applied the treatment process for cell therapy in the new version of the guide. The previous version did not break down the adverse reaction treatment of different research types. This time, the hierarchical treatment and reporting requirements for specific adverse reactions such as cytokine release syndrome and neurotoxicity after cell reinfusion are clearly listed, so we don’t have to cross the river by feeling the stones by ourselves. In addition, it was previously required that the leader of the emergency team must have a senior professional title. Many county hospital research centers simply cannot recruit enough people. This time it has also been changed. As long as there is an intermediate professional title with more than 3 years of experience in clinical research emergency response, they can also serve as team leaders. The only requirement is that they must participate in at least two national-level emergency trainings every year. This is quite down-to-earth.

To be honest, many researchers in the past felt that the guide was just for show, and they had to rely on their own experience to deal with problems. The content of this revision is basically based on the pitfalls that the industry has encountered in the past five years. Each item is supported by corresponding actual cases, making it more practical. Anyway, when I was training the team recently, I would repeatedly tell everyone, don’t wait for something to happen before you flip through the guide. Go through it twice when you have time, so that you won’t panic when something happens.