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On March 29, the State Council ’s research team on the joint prevention and control mechanism of the new coronavirus pneumonia epidemic also issued a “Notice on Regulating Medical Institutions to Launch Clinical Research on New Coronavirus Pneumonia Drug Therapy”, requesting that relevant Of clinical trials strengthen supervision and require:

“Implemented from the date of publication. The (the first subject has been enrolled) but not yet For clinical research, medical institutions should complete the project establishment, registration, and upload of information within 3 working days from the date of this article. Medical institutions that have not completed the deadline shall not continue clinical research work. “

According to reports, after this, 43 clinical trials have been actively withdrawn. However, the epidemic in China has basically reached the end of the state by the end of February, and the clinics that can be done have already been done.

The epidemic is a mirror. The epidemic has exposed the “Great Leap Forward” of domestic clinical trials and the turmoil of the chaotic situation. Although there are 589 clinical trials, except for vaccines, there has been no one so far. Achievements.

Second, what is the purpose of the clinical trial? Why is the quality of Chinese medicines not as good as India?

Clinical trials are intended to allow a drug to be approved for formal promotion and sale?

If this is the real purpose, there are actually many ways to achieve this purpose, not even through very complicated clinical trials. For example, SARS occurred in 2003, and in that year and subsequent years, China quickly approved a large number of drugs. According to the data, in 2005 alone, the Food and Drug Administration approved 11086 drug registration applications, including 1113 new drugs, 1198 varieties with changed dosage forms, and 8075 generic drugs.

This number is staggering, not to mention generic drugs. Even if new drugs are used, they are almost 10 times the number of new drugs approved in the United States each year.

The approved “new drugs” were still there, but Zheng Xiaoyu, the director of the Food and Drug Administration, was sentenced to death for taking bribes and was executed by injection in 2007.

Have there been any clinical trials for those “new drugs”? How credible is the result? I think the answer has been taken away by Zheng Xiaoyu.

So, The purpose of clinical trials is not to get a drug approved, but to know whether a drug is effective, safe, and reliable. This is a scientific question, we must follow the scientific method to answer.

As for the approval of drugs, this is an administrative issue. In theory, if you approve a clinical trial based on science, you can reduce the appearance of “Zheng Xiaoyu”. But if it is purely administrative means to approve new drugs, “Zheng Xiaoyu” is inevitable.

If it is said that before 2007, it was the “dark age” of China’s drug regulatory approval, then after 2007, China has been advancing on the road of “evidence-based approval”. In order to solve the burden left over by history, China has promoted the “consistency evaluation” of drugs, requiring that generic drugs be consistent with the quality and efficacy of the original drugs. If only relying on the means of administrative examination and approval, China’s medicines can leap forward rapidly in quantity and “catch up with the United Kingdom and the United States,” but they cannot even surpass India in terms of quality. If you adhere to the “evidence-based approval” road, although the speed will be a bit slower, but you can accumulate hair, reallyBecome a pharmaceutical powerhouse.

It should be said that the concept of “clinical trials” is still popular in China, and it is precisely because of this that after the outbreak of the new crown, hundreds of clinical trials suddenly appeared. From one aspect, this is the encouragement and expectation of “evidence-based medicine”, which is commendable; but from another aspect, it reveals the lack of awareness of the clinical trials of all parties.

Medical staff and patients in Wuhan Jinyintan Hospital.

3. Why is it that it is impossible to obtain data on the effectiveness of treatment in nearly 300 therapeutic clinical trials?

It seems that there are many pits in clinical trials. What issues should be paid attention to when conducting clinical trials? Or what can be done to improve the quality of clinical trials and increase the chances of success?

1. Retrospective studies, not real clinical trials

In the impression of many people, clinical trials are human trials, as long as there are data from human trials, they are regarded as clinical trial data. This is wrong.

This involves a “forward-looking” and “retrospective” question. “Prospective” means that the interventional treatment has not been carried out at the beginning of the study; and “retrospective” means that the interventional treatment has ended at the beginning of the study because it is only an analysis of the previous results.

For example, a registered intervention trial, the project name is “large-dose intravenous vitamin C in the new coronavirus pneumonia (COVID-19) Study on the improvement of acute patients in the acute exacerbation period “ (Registration number: ChiCTR2000032716) . In this study, there were 6 critically ill patients and 6 critically ill patients. However, although this study is an intervention study, it is “Retrospective studies” and “case studies”, even if it is found that some of the patients have improved, it is impossible to obtain therapeutically effective results.

Why? Because “retrospective” research may just select a limited group of people, and see only a few trees in the forest, which may or may not be representative. Only if a “prospective” clinical trial is carried out can the conclusion be obtained objectively.

A report on the clinical use of Kreuz and Abidor published in the Chinese Journal of Infectious Diseases has been mentioned in the media, calling it a clinical trial [1] . The study did not find that lopinavir ritonavir and abbidore have the effect of improving the symptoms of new coronary pneumonia or shortening the negative time of viral nucleic acid in respiratory tract specimens. However, this report is only a retrospective analysis, not a strictly designed clinical trial. Such research can only infer that the therapeutic effect of the drug may not be obvious, and it does not explain whether it is useless.

In contrast, there is a report in the media about the treatment of new coronary pneumonia with traditional Chinese medicine:

“Wuhan City Hospital of Integrated Traditional Chinese and Western Medicine has 1476 cases, including 662 cases of severe and critically ill patients. (Among them, 484 cases in the traditional Chinese medicine decoction group, 178 cases in the non-Chinese medicine decoction group) . 15 cases died in the Chinese medicine decoction group, and 56 died in the unused Chinese medicine decoction group. He introduced that the death risk of the Chinese medicine decoction group decreased by 87.7%, compared with the unused Chinese medicine decoction The difference in the decoction group is statistically significant. According to the calculation of the mortality rate, the mortality rate in the Chinese medicine decoction group is 3.1% (15/484) , non-Chinese medicine The mortality rate of the decoction group was 31% (56/178) , the difference between the two was as much as 10 times. “

This is also a retrospective analysis, not a clinical trial. If it is a clinical trial, when the treatment is divided into groups, it will ensure that the conditions and ages of the two groups of patients in the “Chinese medicine decoction group” and “unused Chinese medicine decoction group” are comparable. Otherwise, it is possible that critically ill patients have already been intubated, evenSpontaneous breathing is impossible, and of course I can’t drink Chinese herbal medicine decoction. The so-called “unused Chinese herbal medicine decoction group” is actually because the disease is more serious and the mortality rate is relatively high.

If the investigator believes that the conclusion of the retrospective study is reliable, a formal “prospective” clinical study is required to prove it.

2. A clinical trial without a control group (single arm trial), unable to draw conclusions

Since it is to obtain evidence of efficacy, clinical trials require controlled treatment. With the reference treatment as a reference, do you know whether the new treatment has better results? If the control treatment is a placebo, and the new treatment does not see a better effect, it means that the new treatment is used or not, and there is little difference.

To advance modern medicine, clinical trials not only need to be controlled, but also must use standard treatments that have been proven to be effective to ensure that new drug innovations are truly innovative, not standing still.

Only for a disease with a 100% mortality rate, if a drug can reduce the mortality rate, ethical considerations, you can not use control treatment. However, New Coronary Pneumonia is not a 100% fatal disease, and even people with asymptomatic, if there is no controlled treatment, really do not know how effective a certain treatment is.

In the clinical registry, 23 intervention trials are registered as single-arm trials. There is a study, “Evaluating the efficacy and efficacy of Danorevir sodium tablets combined with ritonavir in the treatment of patients with novel coronavirus pneumonia (COVID-19) Randomized, open, controlled clinical study of safety “ (Registration number: ChiCTR2000031734) . Even though the title of the subject contains “Controlled Trial”, the trial designThere is only one group:

It should be noted that for an unknown drug, it is indeed necessary to conduct a clinical phase one study to obtain information on the dosage and safety of the drug. This early study does not need to be controlled, but its purpose is not It’s not to verify whether it is effective.

3. Why do some clinical trials use “reducing viral negative time” as the end point instead of mortality?

The primary endpoint of clinical trials requires careful selection.

When designing a clinical trial, it is necessary to determine the main index of the investigation. If the treatment plan shows a clear advantage in this index, it can be said that the clinical trial “reached the main endpoint” and achieved success. This shows that the choice of this indicator is very critical.

For new coronavirus infections, this indicator can be the time that the virus turns negative, or it can be an improvement in clinical symptoms, or it can be mortality.

Obviously, if there are many mild patients enrolled in clinical trials, the mortality rate is not a good indicator, because even the control group will not be too high. Theoretically, the time for the virus to turn negative is a relatively reasonable indicator. Many clinical trials also use “reduce the time for the virus to turn negative” as the main endpoint of clinical trials.

However, due to the problem of false negatives in viral nucleic acid testing, whether it is due to sampling operations or kits, the proportion of false negatives in the report can be as high as 40%. For a 50-person clinical trial, 20 people can have false negatives in one test, and 8 people can have false negatives in two consecutive tests, becoming a misdiagnosis. If two negative transitions are used as the main indicator, it is clear that these eight misdiagnoses will greatly interfere with the conclusion of the trial.

Redesivir clinical trials conducted at home and abroadDifferent conclusions have been drawn. Although the main endpoint of the two trials was the improvement of clinical symptoms, the specific criteria for improvement were different. In the international experiment, the final use was not the standard that was originally formulated, but was revised later. Some people may be surprised by this, and feel that the researchers are suspected of opportunistic. In fact, this is allowed, as long as it is modified before blinding [Patricia2], theoretically it will not affect the conclusion of the study. Of course, Under normal circumstances, it is necessary to communicate with FDA in advance and modify the main endpoint after being approved, otherwise the research data will also be questioned.

4. The sample size of the clinical trial determines the different results at home and abroad caused by the test such as Redshive and others

If you want to compare the height of the mountain and the height of people, because the gap is too large, you only need to compare one mountain and one person; if you want to compare the height of the residents of two countries, you ca n’t just find a few people to compare, Use this to get a reliable answer.

How many people are needed for clinical trials? It depends on how different the experimental group is from the control group.

The domestic lopinavir / ritonavir clinical trial for severe new coronary pneumonia has obtained a negative result [2] The mortality rates of the lopinavir-ritonavir group and the conventional treatment group at 28 days of treatment were 19.2% and 25.0%, respectively. From the data point of view, the two groups are still slightly different. The mortality rate in the Tonavir group was lower, but this difference was not statistically significant.

If there is a difference of 19.2% and 25.0%, how many subjects would theoretically be necessary to see the therapeutic effect of lopinavir-ritonavir? 1600 people. How many people were actually included in this clinical trial? 199 people. The gap between 1600 and 199 people is the gap between failure and success.

Let ’s take another look at the reduxill clinical trial. Experiments abroad were successful, and a total of 1063 people were enrolled. The test conducted in China died, and naturally it did not get a positive result. How many people were enrolled? 236 people, only reached half of the expected number of participants.

In 310 interventional new crown clinical trials in China, not all projects have a control group. In those clinical trials with control groups, how many people were enrolled based on statistical considerations? I believe this will be a pessimistic answer.

A registered clinical study mentioned earlier, “High-dose vitamin C combined with traditional Chinese medicine for the treatment of common and severe new coronavirus pneumonia (COVID-19) Efficacy and safety “ (Registration number: ChiCTR2000032717) , according to the submitted plan, the study will be enrolled in a total of 60 Patients, but divided into 6 groups, each group has only 10 people:

Studies like this abound.

In the epidemic situation, the World Health Organization joint investigation team conducted an inspection in China. After making a positive evaluation of China ’s national epidemic prevention efforts, it also found problems in the in full swing “clinical trials”: There are many people infected with the virus, but as a large number of patients are discharged from the hospital, and there are too many clinical trials at the same time, recruiting patients becomes more and more difficult.

When conducting an investigation in China, Bruce Elward, the foreign team leader of the WHO joint investigation team and senior adviser to the Director-General of the World Health Organization, believed that the only hope was the clinical trial of ridsivir. The opinions expressed at that time were misunderstood by many people, who felt that the WHO officials were also unreliable, and the test results had not yet come out. How dare to endorse the effectiveness of the drug? Actually, what he wants to say is not to support the effectiveness of redoxir, but to the disappointment of most of the clinical trials that are being carried out. The design can be seen from the failed seedlings , Because it is impossible to get a definitive answer to whether there is a cure.

5. The biggest reason for the failure of clinical trials: the experimental drugs are not effective, and there are no special drugs

Among all the reasons for the failure of clinical trials, the efficacy of drugs is not good enough and should be the most importantthe reason.

If Ridesivir is a special effect medicine, the difference between the treatment effect and the control group is the difference between Seco and person height, you do n’t care if you have 400 or 200 people in the group, or even like the design of many trials. In that case, 40-50 people are enough.

If Ridesivir is a specific drug, it does not care about the standard of clinical symptom improvement, whether it is the standard used in Chinese research, or the standard in foreign research, and there is no need to carefully modify the standard. The advantages of drug therapy are shown.

Unfortunately, we are faced with an era of no special drugs. Lopinavir / ritonavir is an anti-HIV drug, not a drug designed for the new coronavirus tailor-made; Redcive is an anti-Ebola virus drug, nor is it tailored for the new corona virus It is designed; chloroquine is an anti-malarial drug, and it is also not designed for the new coronavirus tailored.

It is because it is found that the efficacy of the drug is not good during the clinical research process, so it is necessary to adjust the trial. When the clinical trials of ridacive in foreign countries expand the scale of enrollment, it can be understood that ridacive does not have the effect of specific drugs. Now the US FDA grants Radecivir an emergency use authorization to approve the treatment of the new crown, and does not consider it a special effect drug. However, ridacive can be part of the “cocktail” treatment [Patricia3], combined with other drugs to achieve better results.

“Three Stooges, Top Zhuge Liang”. Therefore, in the era when there is no special medicine, combination therapy is an inevitable way out. The domestic lopinavir / ritonavir clinical trial failed, but the results of a phase 2 clinical trial from the University of Hong Kong showed that the use of “interferon beta 1b + ribavirin + lopinavir / ritonavir (Kreitz) “triple therapy can accelerate the rehabilitation of patients with mild to moderate new crowns! The research was published in the May 8th Lancet [3] .

The main indicator of this study is the time for the nasopharyngeal swab to turn negative. From the beginning of treatment to two consecutive negative nucleic acid tests, treatment with the triple regimen only takes 7 days, while the use of lopinavir / ritto The control treatment of navir takes 12 days. Of course, in terms of treatment effect, the sooner the triple plan is used, the better the effect. The treatment starts within 7 days after the symptoms appear, and the effect is very obvious, but if after 7 days, becauseWorried that interferon β1b may cause immune hyperreactivity, the treatment plan is only ribavirin + lopinavir / ritonavir, and the treatment effect is not obvious.

Four, three suggestions for clinical trials in China

The effectiveness of clinical trials is not good, and it is easy to completely negate. However, a clinical trial is a scientific experiment. Strictly speaking, as long as it is a serious experiment, there are no absolutely failed trials, only trials that have not yet succeeded. Even if the efficacy of the treatment group is worse than the control, it can prove that this is a wrong path, and other treatment methods are needed.

Although scientific research is meaningful, in the face of infectious diseases that have a huge impact on humans, it is imperative to find effective treatment options as soon as possible.

Viruses bring disasters to humans, but they also bring opportunities, but if you ca n’t cherish opportunities, then that is the greatest disaster for humans. How to seize the opportunity, benevolence sees benevolence, wise sees wisdom.

For more than 300 clinical trials of “therapeutic” new crowns conducted in China (These 300 are clinical trials that clearly label interventional treatment of new crown viruses , More than 200 other retrospective and other forms of clinical trials) , perhaps the more meaningful question should be: How can we do better?

As an “inner person” who has been engaged in clinical research in the United States for decades, I think the following points should be used as suggestions:

1. It is necessary to make full use of the advantages of the Chinese system and concentrate on implementing promising multi-center major experiments

As mentioned earlier, for clinical trials, the sample size is a key factor in determining whether the trial can obtain a positive result. After the outbreak of the new crown, there were tens of thousands of patients diagnosed in Wuhan.The family feels that there are not many people enrolled in the group, but the fact that China Redcliffe dissatisfied with patients did happen.

Not all patients are suitable for one drug, and all clinical trials will set the conditions for patient enrollment. The number of patients who can be enrolled in a certain hospital is actually very limited. If only the investigator initiates the clinical trial, it is limited to the hospital where the investigator is located, and a sufficient sample size cannot be obtained.

Because of this, the clinical trials of new drugs in the world are generally carried out in multi-centers, and pharmaceutical companies are needed to support them. Multi-center clinical trials, if successful, can also explain the universality of treatment.

On the other hand, most of the new Guan’s therapeutic drugs are old drugs and new drugs, and many are drugs without patent protection. It is difficult for pharmaceutical companies to support the cost of clinical trials. It is for this reason that almost 300 clinical trials of new crowns are almost all trials initiated by researchers.

The social organization capabilities China has demonstrated during the fight against the epidemic have attracted worldwide attention. How to make full use of the support of the government and society for research, conduct effective coordination, and organize large-scale clinical trials, rather than small-scale trials that do not have a clear answer, relevant domestic authorities should have this wisdom.

It is worth mentioning that the clinical trial of lopinavir / ritonavir triple therapy in Hong Kong with positive results was conducted in 6 public hospitals in Hong Kong, and a total of 127 patients with new coronary pneumonia were enrolled. This does not sound like much, but the number is already 80% of all diagnosed patients in Hong Kong at the time. Imagine if the focus is not on the focus of the clinical trial, is it still possible to successfully obtain a positive result?

2. How to choose those clinical trials that have no prospects: the anti-viral component has a half-inhibitory concentration of 100 uM or more, and basically can not be approved

If you want to concentrate, you have to choose. What are the trade-off criteria? It should also be based on experimental data.

In vitro experiments, the in vitro antiviral activities of redoxivir and chloroquine (semi-inhibitory concentration) were 0.77 uM and 1.13 uM, respectively [Patricia4]. The lower the value, the better, which means that as long as the drug concentration is very low, it can achieve the inhibitory effect.

In general, only data from in vitro tests cannot be used as evidence to support clinical trials. even thoughA drug has been used for other clinical treatments, and it can only provide evidence of safety. It does not guarantee the success of clinical trials. This is like an anti-cancer drug approved for melanoma. If there is no clinical trial for lung cancer, I don’t know if it can be used to effectively treat lung cancer.

However, under the special circumstances of the epidemic, there is simply no time to conduct animal experiments first to verify, and only rely on the data of in vitro cell tests as the basis for whether to conduct clinical trials and whether to preferentially choose.

The results of current clinical trials confirm that even uM-level active substances have very limited clinical antiviral effects. So, if a “magic” antiviral component has a half-inhibitory concentration of more than 100 uM, then it ’s better to wash and sleep. Do n’t take up clinical resources and snatch patients.

Sometimes, inaction is the biggest contribution to society.

3. Professional things, let professional people do it

It is undeniable that clinical doctors have a lot of treatment experience, which must be respected. However, this does not mean that any clinician can professionally lead large-scale clinical trials. Organization of such clinical trials also requires professional personnel to carry out, for example, there is now a CRO company specializing in such business.

So, national, social, and hospital support for clinical trials should consider how to effectively combine doctors and clinical CRO companies to obtain higher quality clinical trial results. This should be a trend, but how to supervise and ensure transparency also requires wisdom.

On the other hand, first-line doctors should be encouraged to participate in clinical research. If the clinical research is initiated by the investigator, the number of participants in the trial should be reasonable without affecting the key clinical trials. This kind of test is only an early test, and it is generally impossible to obtain a rigorous conclusion, but it can make a certain evaluation of the clinical effectJudgment became the basis for large-scale clinical trials.

An important reason for the clinical trials of drugs such as ridxivir carried out in China that cannot accurately judge the number of people enrolled is that there is no previous trial results as a basis. And it is also based on the experience of Chinese clinical trials that foreign clinical research adjusted the number of enrollment in time to ensure that the trial can obtain a positive result.

The epidemic is now under very effective control in China, but it cannot be said that the epidemic has completely ended. At present, local cases still occur in some areas. At the same time, because of the widespread epidemic in the world, importing cases is also under pressure from China.

In the face of these cases, China still has the opportunity to continue some clinical research. Without sudden outbreak pressure, I hope China can calmly carry out newer and promising clinical trials and cherish precious opportunities.

References:

1. Chen Jun, et al., Study on the effectiveness of lopinavir, ritonavir, and abidol for the treatment of new coronavirus pneumonia. Magazine, 2020. 38 (00): p. E008-E008.

2.Cao, B., et al., A Trial of Lopinavir-Ritonavir in Adults Hospitalizedwith Severe Covid-19. N Engl J Med, 2020. 382 (19): p. 1787-1799.

3.Hung, IF-N., etal., Triple combination of interferonbeta-1b, lopinavir & # x2013; ritonavir, and ribavirin in the treatment of patientss admitted to hospital with COVID- 19: an open-label, randomised, phase 2trial. The Lancet.

This article comes from the WeChat public account: CC Weekly (ID: cancer-weekly) < / span> , author: Zhang Hongtao (Associate Professor, University of Pennsylvania School of Medicine)
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