Female college student passed away after receiving cellular immunotherapy, causing dispute again, expert: supervision needs attention

  Four years ago, the Wei Zexi incident caused concern. This college student suffering from synovial sarcoma received cellular immunotherapy in a hospital, but no effect was seen. The treatment time was delayed and eventually died prematurely.

Recently, Ms. Fan from Jiangxi told The Paper that on March 28, 2020, her 20-year-old daughter Zhang Fan (a pseudonym) died during treatment at Beijing Boren Hospital and was receiving a cellular immunotherapy called CAR-T. .

  Ms. Fan introduced to The Paper (www.thepaper.cn) that sending her daughter to Boren Hospital was specifically for CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy) treatment. She believed that Beijing Boren Hospital had no relevant medical qualifications, and In the case of "doctors practicing beyond the scope", the hospital will be sued.

  Ms. Fan said that Dr. Liu, one of the members of the expert treatment team, majored in pediatrics. “How can a pediatrician show my daughter leukemia?”

  In response, the staff of the Marketing Department of Gaobo Medical Group, a group of Beijing Boren Hospital, responded that they regretted the death of Zhang Fan. In the expert team equipped for Zhang Fan, there was indeed a doctor with inconsistent qualifications. Accept the relevant punishment, "Because Zhang Fan is relatively young, some treatment plans need to refer to the children's treatment plan."

The hospital stated that this did not affect Zhang Fan's treatment. In addition, Boren Hospital has carried out relevant filings for CAR-T clinical trials and has the corresponding qualifications.

  In addition to the controversy, some medical experts believe that the CAR-T products that have not yet been approved for marketing in my country are in clinical trials.

Under the craze of this medical project, my country currently has certain problems of lagging and insufficient management of the CAR-T project.

Sudden convulsion and coma after half a month of T cell reinfusion

  The medical records obtained by The Paper showed that Zhang Fan was diagnosed as "acute B lymphocytic leukemia" in April 2019 due to dizziness and fatigue.

Ms. Fan told The Paper that she had taken her daughter to a third-class hospital in Beijing to prepare for transplantation, because the blood index did not meet the transplant conditions of the hospital. On the advice of the doctors of the hospital, Ms. Fan took her daughter to Beijing Boren Hospital to receive CAR -T treatment.

  According to public information, CAR-T therapy refers to chimeric antigen receptor T cell immunotherapy, which is a new type of precision targeted therapy for tumor treatment.

In the laboratory, technicians use genetic engineering technology to activate human T lymphocytes, install the positioning and navigation device CAR, and transform the T cells into CAR-T cells.

CAR-T cells use positioning and navigation devices to specifically identify tumor cells in the body, and release a large number of effectors through immunity to effectively kill tumor cells.

Data show that CAR-T therapy is used for relapsed acute B-line lymphocytic leukemia or refractory acute B-line lymphocytic leukemia.

  Following the doctor's advice, on November 15, 2019, Ms. Fan took her daughter to Beijing Boren Hospital and was hospitalized on the same day. Medical records show that Zhang Fan received a bone marrow puncture at about 17 o'clock that day.

On November 16, the attending doctor An informed the patients and their families of the risks and costs of CAR-T, "and that 100% success rate cannot be guaranteed, and there is also the possibility of invalidity. The long-term efficacy cannot be guaranteed, and there may be less whole blood and less blood during treatment. Infections and even severe infections, convulsions, neurotoxicity, multiple organ failure and other life-threatening conditions".

  On November 19, Zhang Fan signed the informed and voluntary consent form for cd19-cart cell therapy.

It introduces the details of the clinical study and treatment procedures.

It is agreed that the preparation cost of cd19-cart shall be borne by the hospital, and other expenses during the hospitalization period shall be borne by the patient.

The car-t treatment informed and voluntary consent form signed by Zhang Fan

  According to medical records, on November 28, 2019, Zhang Fan was infused with mouse-derived cd19-cart cells from the hospital. Zhang Fan experienced repeated high fever on December 3, convulsions at 3 o'clock in the morning on December 12, and sudden breathing at 13 o'clock on the same day. Stop, "The probability of successful rescue is almost 0", and continue active treatment at the request of the family.

Ms. Fan told The Paper that since then, her daughter did not wake up until her death on March 28, 2020.

  The medical records on December 15 showed that Zhang Fan was diagnosed as acute B lymphocytic leukemia with BCR-ABL (P190) fusion gene positive, IKZF1 gene mutation, central nervous system leukemia; neurotoxicity, intracranial leukemia after CD19-CART treatment Increased blood pressure, suspected cerebral hemorrhage, foramen magnum hernia; cytokine release syndrome, multiple organ dysfunction (liver, heart, lung, kidney, coagulation function) after CAR-T treatment, in addition to respiratory failure, lung, Intestinal infections and other problems.

Expert team members have doctors who are qualified in pediatrics, and the hospital was fined

  From when her daughter convulsed and fell into a coma, Ms. Fan began to question Beijing Boren Hospital.

Ms. Fan believes that there are problems in the treatment process of Beijing Boren Hospital. “There is a lack of important inspections, and the rescue is not timely.” A mediation issued by the Beijing Fengtai District Medical Commission in February 2020 was obtained by The Paper. The closing letter shows that on December 19, 2019, Zhang Fan’s family applied to the Medical Dispute Mediation Committee for medical dispute mediation. Beijing Boren Hospital agreed to mediate and submitted all materials on December 19, 2019.

On the same day, the Fengtai District Medical Commission accepted the case.

After mediation, the patient did not approve the mediation plan.

  "At that time, the mediation result said that Boren Hospital was asked to compensate 40,000 yuan for humanitarian purposes. We could not accept it." Ms. Fan told The Paper, but she did not submit a medical appraisal to the Medical Association.

  The marketing department of Gaobo Medical Group, a group of Beijing Boren Hospital, responded to this. At that time, Ms. Fan requested a compensation amount of 3 million yuan, and Ms. Fan did not apply for medical appraisal. “We cannot compensate without responsibility. So much money."

  After reporting to the Medical Research Commission, Ms. Fan also reported the problem to the Beijing 12345 hotline and the Fengtai District and Beijing Municipal Health Commissions. Ms. Fan insisted on questioning that Beijing Boren Hospital does not have CAR-T treatment qualifications and has " "Doctors practice medicine beyond the scope".

  Ms. Fan said that when she came to Boren Hospital, she hung the expert number of a doctor surnamed Liu, and later learned that the doctor's main specialty was pediatrics. "How can a pediatrician show my daughter leukemia?" The Paper Search found, Beijing According to the doctor's profile on the official website of Boren Hospital, the doctor surnamed Liu has been engaged in pediatric clinical work for more than 20 years.

Good at diagnosis and treatment of children's blood system diseases and tumor diseases.

  The recordings obtained by The Paper show that at the end of July 2020, the Medical and Political Department of the Health and Health Commission of Fengtai District once replied to Ms. Fan that Beijing Boren Hospital was suspected of using health technicians to conduct diagnosis and treatment activities outside of their specialties. The case has been filed and the follow-up procedure has been entered.

On September 14, 2020, the government service hotline personnel reported that the relevant department has imposed a fine of 3,000 yuan on Beijing Boren Hospital and ordered the hospital to make corrections immediately and request the hospital to prohibit health technicians from engaging in treatment activities other than their specialties , It is forbidden to use non-health technical personnel to engage in medical and health technical work.

In this regard, Boren Hospital stated that Dr. Liu, one of the members of Zhang Fan’s expert treatment team, is indeed qualified in pediatrics and has participated in rounds. The hospital explained that “because Zhang Fan is relatively young, some treatment plans need to refer to children’s treatment plans.” , The hospital accepted the punishment from the District Health Commission and will avoid this situation from happening again in the future.

  Regarding the CAR-T qualification issue, Beijing Boren Hospital explained that Fengtai District and the Beijing Municipal Health Commission have both visited the hospital for investigations on the CART qualification and the case. The hospital followed the requirements of the Fengtai Health Commission and the Beijing Municipal Health Commission’s Medical Administration Division. Communicate with the Science and Education Department. The director of the Science and Education Department came to the hospital for investigation. The competent department replied after the research: The CAR-T clinical research carried out by Beijing Boren Hospital has been registered in the "Chinese Clinical Trial Registration Center" and "Medical Research Registration Information" The system" has been registered.

Therefore, Boren's CAR-T clinical research project is in compliance with relevant laws and regulations.

  In addition, Ms. Fan questioned that the doctor asked her daughter to sign the informed and voluntary consent form for cd19-cart cell therapy. At that time, no one emphasized that it was a "clinical trial", and Ms. Fan wondered why it took more than 70 to participate in the trial. Ten thousand yuan.

Bills for Zhang Fan’s treatment cost more than 700,000 yuan in total

  In this regard, Boren Hospital reported to The Paper that the patient was fully aware of it, and related conversations were conducted before admission, and the patient signed an informed consent.

In response to the cost issue, the hospital insisted that the cost of CAR-T is not included in Ms. Fan's expenses, but the cost of blood disease inspections is relatively high.

  After "stopping the cold winter", how should cellular immunotherapy be regulated?

  In 2016, college student Wei Zexi passed away after receiving cellular immunotherapy, triggering public opinion controversy. Various types of clinical application of "cellular immunotherapy" in medical institutions were stopped by the former Health and Family Planning Commission, requiring autoimmune cell therapy technology to follow clinical research. Regulations are implemented.

  But for several years, this medical technology is still developing rapidly.

  In 2017, the FDA (U.S. Food and Drug Administration) took the lead in approving the world’s first and second CAR-T therapies. Kymriah from Novartis and Yescarta from Gilead’s Kite Pharmaceuticals were approved to treat specific types of acute lymphocytes. Tumors and large B-cell lymphomas.

Among them, Kymriah is priced at 475,000 US dollars, and Yescarta is priced at 373,000 US dollars.

  In October 2018, the Nobel Prize in Physiology or Medicine was awarded to James Allison, an immunologist at the University of Texas at Austin, and Shusuke Moto, a professor at Kyoto University in Japan, in recognition of their discovery of cancer treatments that suppress immune regulation.

  In 2019, the National Health Commission solicited opinions on the "Administrative Measures for Clinical Research and Translational Application of Somatic Cell Therapy", filed management of somatic cell clinical research, and allowed clinical research to prove safe and effective somatic cell therapy projects to be filed in relevant medical institutions Enter the conversion app.

Some media believe that cell therapy has gone through the "stop the cold winter."

  An immunology expert who did not want to be named introduced to The Paper that CAR-T is currently a hot topic in my country's medical field. There are more than a dozen organizations working on CAR-T and many companies have applied for it.

However, the expert said frankly that, under the enthusiasm, my country currently has certain problems of lagging and insufficient management of CAR-T projects.

  According to the above-mentioned experts, there are currently no CAR-T products approved for marketing in my country, and they are all in the clinical trial stage.

There are two types of clinical trials, one is approved by the National Food and Drug Administration, and the other is initiated by the hospital investigator and approved by the health care provider. Both are legal.

  "Re-approval, but lack of follow-up process-based supervision and management." The expert believes that this problem exists in both CAR-T clinical trial projects approved by the Food and Drug Administration or the health department. The approval is strict, but In the process of follow-up implementation, there is little or no supervision and management. “The supervisory authority should intervene in every case and manage it at any time. If it is not approved, it will be fine.”

  However, the expert said frankly that the China Food and Drug Administration is already in an "overloaded state." Vaccines, chemical drugs, biological preparations...many fields need to be managed by them, and the field of cell therapy is relatively new and highly specialized, making it difficult to achieve Good supervision.

In addition, the expert stated that some experts currently participating in CAR-T cell review are themselves "consultants" or "technical developers", which is not conducive to CAR-T development and management.

The expert suggested that an independent institution should be established to strengthen supervision in the field of cell therapy.

  A doctor from a tertiary hospital in Guangdong province told The Paper that CAR-T clinical trials are currently concentrated in private hospitals, and there are almost no public hospitals. “The ethics committee can’t approve, and the leaders don’t dare”.

The doctor believes that the reason why public hospitals dare not operate at present is the lack of relevant laws and policies, and "the rules have not been set."

Under what circumstances can patients be accepted for clinical trials?

Is there any insurance to protect the rights of patients?

If the trial does not go well, how to maintain the doctor and the hospital?

These issues have yet to be improved.