China has registered nearly 300 novel coronavirus pneumonia trials in addition to the higher threshold set by Reed sive in clinical trials. This will undoubtedly play a role in diversion.
But in the nearly 300 items, there are also many treatment methods such as Taijiquan, traditional Chinese medicine injection, soybean extract and so on. There are many doubts in the pharmaceutical industry and the general public.
So, how did these magic clinical trials come into being, and how did they become a pot of porridge?
Non traditional clinical trials
In fact, most novel coronavirus pneumonia clinical trials are not clinical trials that are commonly known in the public.
Clinical trials are generally divided into two types according to different initiators, one is industry sponsored clinical (IST), the other is investigator initiated clinical (IIT) initiated by researchers or academic institutions.
Cao Lijun, general manager of Beijing Zhongwei insurance agency, introduced to the interface news reporter that the research scope of the latter is often the field that the former has not been involved in, and the two sides complement each other in parallel, so as to better promote the depth and breadth of drug research, obtain more research data, and provide basis for evidence-based medicine.
At present, only ridcivir, faveravir, bdb-001 (C5a monoclonal antibody) and castem cell injection are reported to the drug evaluation center (CDE) of the State Drug Administration and approved for clinical trials.
Other clinical trials, such as chloroquine, toluzumab, klitschke, abidol or Taijiquan, are all clinical studies initiated by researchers. According to the bidding process, there is no need to report to the drug evaluation center of the State Food and drug administration, which is determined by its own nature, and does not determine the quality of its research simply because of the similarities and differences of the approval process.
The reason for the emergence of clinical research initiated by researchers is that Conan, a drug R & D practitioner, explained to the interface news reporter the profit-seeking nature of pharmaceutical enterprises, which makes some old drugs on the market, drugs with a small number of patients (such as rare diseases), or drugs with poor general payment ability of patients lack the motivation to continue research. In this case, some hospital doctors, specific research institutions and even regulators will initiate relevant clinical research. The scope of clinical research is often the fields that are not involved in the research sponsored by pharmaceutical companies, such as research on rare diseases, comparison of diagnosis or treatment methods, new uses of listed drugs, etc., which play a role in filling the gap.
But in China, the low quality of clinical trials has been criticized for many years.
After 2015, the requirements of the registered clinical trials initiated by the former State Food and Drug Administration for pharmaceutical enterprises are more stringent. However, the quality of the clinical trials initiated by the researchers is still uneven due to the fact that they do not need to be submitted to the drug administration and other regulatory agencies for review.
After the outbreak of new coronavirus, a large number of clinical studies initiated by researchers have emerged in a short time. Liu Yi, vice president of connective vein biology, analyzed the interface news reporter. The clinical research initiated by the researchers started relatively fast. In the early stage of the epidemic, it can promote the rapid start of a series of clinical trials, explore the treatment methods of different severe types of patients against new coronavirus, and guide the establishment of clinical diagnosis and treatment programs. However, it also quickly exposed the lack of effective coordination mechanism in clinical trials under the pressure of public health crisis.
The reason why the clinical research initiated by researchers is fast is that, from the process point of view, researchers only need to submit the design scheme to the hospital ethics committee for approval to carry out the research.
According to the (GCP) revised in 2018, the ethics committee shall be composed of medical professionals, non scientific professionals, non clinical trial unit members, and members of different genders, with at least 5 members. All members have training and experience in ethical review and are able to review ethical and scientific issues related to clinical trials.
In order to protect patients safety and reduce risks as much as possible, Conan said, the ethics committee has actually assumed the role of gatekeeper similar to the drug review center of the State Food and drug administration. Generally speaking, the ethics committee also needs statisticians and lawyers.
But looking at all kinds of treatment methods which are swarming in and out of the ordinary, we have to wonder whether some ethics committees play the role of gatekeeper or just a rubber stamp.
There are two major problems
Liu Yi believes that a large number of clinical trials in a short period of time will result in the limited clinical trial resources can not be effectively distributed and utilized, for example, the enrollment speed of truly valuable research can not be guaranteed. Due to the lack of effective clinical research management and sufficient clinical research resources, it can be predicted that some studies can not be completed as planned.
One of the important reasons is that because the sponsors of clinical trials are generally only clinical experts, and the degree of specialty of the pharmacy and preclinical data of the research drug itself is limited, some drugs have stepped into the clinical trial stage, and the basis for setting up the topic is not sufficient. At the same time, a large number of research samples are very small, and the research design is mostly open, which can not provide high-quality clinical evidence to guide drug use.
Novel coronavirus pneumonia clinical trials are the two major problems that many researchers have launched.
Drug screening is mainly based on pharmacology. Conan said that proof of concept and mechanism proof are necessary for drug development. For example, research on ridcivir is due to its antiviral drug mechanism, and its safety is also proved. Research on togzumab in the treatment of cytokine storm is also due to the approval of similar indications of this drug.
But at present, many clinical trials are lack of basic proof of concept, or its proof of concept is questioned.
The novel coronavirus pneumonia, the Chinese medicine, the soybean milk and the Chinese herbal medicine, and the soybean milk are basically lack of basic treatment for new crown pneumonia or the concept validation of the new crown virus.
Of course, the lack of proof of concept is not unique to Chinese prefix drugs and therapies, as are many antibiotics, stem cells and other drugs / therapies.
A typical case is novel coronavirus (Carolyn Ju monoclonal antibody) and Thymosin used in the treatment of severe pneumonia patients with 2019 new coronavirus infection associated with lymphocytic reduction, registered in the Wuhan golden Yin Tan Hospital. The trial was conducted in PD-1.
Its not surprising that some people in the industry will question whether the idea of using PD-1 treatment is reversed and it may aggravate the patients condition instead.
In the design of clinical trials, there are also many cases of poor quality. The most typical is still soymilk therapy, which not only has a small number of patients in each team of the whole clinical trial, but also has a surprisingly small number of patients in the control group. It is difficult to see the effectiveness of the control group of two people, whether from the perspective of probability or statistics. Similar clinical trials designed only for dozens of cases are not rare.
However, the latest search on the Chinese clinical trial website found that the status of the clinical study application had been changed to investigator withdrawal.
A large number of clinical research samples are very small, and the research design is open, so it is unable to provide high-quality clinical evidence to guide drug use. Liu Yi pointed out.
She believes that novel coronavirus pneumonia novel coronavirus pneumonia trial is challenging: first, from pathophysiology to disease diagnosis, the disease itself is still in a gradual process of cognition, such as the new clinical trial scheme of the new crown pneumonia involving the participating organisms. Different treatment objectives of patients with the same severity need to be discussed separately and judged by different clinical evaluation indicators. Finally, for the special clinical diagnosis and treatment status of the epidemic, the feasibility and operability should also be fully considered in the research design.
However, whether the statistical efficacy and methods of clinical trial design are accurate and feasible, and whether the selection of clinical end points for drug dosage and observation indicators can not only be compared with statistical methods, but also have guiding significance for clinical practice. In many cases, these need to be completed by a strong team of statisticians. However, at present, whether most of the first-line doctors have this professional ability should be put on a question mark.
In addition, in the special period of the current epidemic situation, there are more difficulties in the actual operation, which affect the quality of a clinical trial. According to Cao Lijun, there are a large number of basic and routine work to be completed in clinical trials, while hospitals often do not have enough full-time personnel; many researchers have a large number of clinical front-line work, and their energy is limited in facing a large number of project management work.
In fact, in the clinical trials carried out by pharmaceutical companies, clinical contract research organizations (cros) are often employed to design and operate clinical trials. However, it is reported that there are not many clinical trials initiated by researchers with cro participation, which is mainly related to the research scale, funding and researchers concept of clinical trial quality.
Specifications should be more detailed
There is no doubt that the low-quality clinical trial program will produce low-quality research results. The interface news reporter learned a data from the industry before: at present, domestic researchers have submitted more than 150 research papers to be published, but the number of papers to be reviewed is as high as 90, while American researchers have submitted more than 90 articles, but only a dozen of them have been rejected. At present, the number of patients available for study in the United States is far lower than that in China.
However, novel coronavirus pneumonia can be summarized, and the following factors are summarized: administrative intervention, financial driving, research needs and human relationship are the main factors that have been approved, run and approved by various clinical trials of low quality new crown pneumonia.
More realistically, the chaotic clinical trials will also cause harm to the patients in the epidemic. If some patients are enrolled in some obviously unreasonable drug clinical trials, it is unknown whether they will delay the treatment and whether the researchers can do well in the protection of the subjects.
It is not that the chaos has not been ignored.
The World Health Organization (who) has previously held a global research and Innovation Forum on the new coronavirus related clinical trials in China. Soumya Swaminathan, whos chief scientist, said these efforts would be futile if Chinas trial design did not have strict criteria for research parameters, such as the control group, randomization and the measurement of clinical results.
The novel coronavirus pneumonia clinical study of novel coronavirus pneumonia is also being put forward in the latest issue of the new clinical guidelines for clinical trials of new coronavirus pneumonia, which includes the restriction that the drugs used should be marketed drugs, and the dosage should not exceed the dosage and dosage of the existing drug instructions. The concentration of substance can be converted to the effective concentration of human body by in vitro experiment, it is clear that the medical institution is the main body responsible for clinical research, and it is proposed that the hospital can hire IDMC (independent data monitoring committee) of medical personnel and patients independent of drug suppliers and participating in clinical research work according to needs, and regularly evaluate the research progress before the end of clinical research.
However, for detailed drug screening, clinical endpoint and other specific issues, the above notice did not provide normative guidance.
Liu Yi suggested that resources should be concentrated to solve major clinical diagnosis and treatment problems, and high priority topics could be recommended jointly by regulatory agencies, clinical experts and public health experts; referring to the international operation during the Ebola epidemic, a master protocol should be established as soon as possible to study multiple therapies, multiple diseases or both, Promote standardized clinical research programs, so as to abandon some clinical trials with defects in research design.
She also said that the quality and qualifications of researchers and ethics committees need to be strictly reviewed and controlled. Under the condition that the clinical trials initiated by all researchers cannot be supervised uniformly, the regulatory measures for high-risk clinical trials can be formulated. Give clear guidance on the project establishment, implementation, data management, results publication, and supporting hardware and software of clinical research. Finally, there should be legal support for the punishment of the adverse consequences caused by the violation or fraud of clinical trials.