Just last weekend, Li Minglei ran five kilometers by the Charles River in Boston, USA, and two years ago, he was wheeled off the plane by his wife. After being diagnosed with stage IV lung cancer, doctors in Beijing told him that his life might be only six months away.
Now, Li Minglei regularly comes to the Massachusetts General Hospital Affiliated to Harvard University to treat cancer. His improvement may not be called a medical miracle, but a common case of cancer treatment in the United States. Of course, he was lucky enough to have a mutation in the EGFR19 gene that led him into clinical trials of third-generation targeted drugs, and two weeks after the trial began, a turnaround occurred.
According to a market survey conducted by Shennoi, a Beijing-based overseas medical service, about 3,000 Chinese go to the United States each year for medical treatment, 70% of whom are cancer patients. It is not the first choice for patients to take part in clinical trials when effective drugs are available. However, once patients develop resistance to antineoplastic drugs, clinical trials of new drugs in the United States are likely to be their last resort.
At a hospital in San Diego, California, U.S., health care workers are analyzing scans of cancer patients. Figure /IC
At the famous MD Anderson Cancer Center in the United States, hundreds of clinical trials are conducted at the same time every day, and more than 90% of cancer patients ask their doctors, Can I participate in clinical trials of new drugs? Nowadays, there are also many advanced cancer patients who are seeking treatment from China.
67% of the treatment options were changed.
When Li Minglei, 38, visited a well-known third-class hospital in Beijing, doctors here told him that he belonged to stage IV lung cancer, can only be treated conservatively, there is no opportunity for surgery. He knew that the staging given by doctors meant that he had advanced lung cancer with distant metastasis. This plunged him into despair. During the next two courses of chemotherapy, Li Mingleis body was so fragile that he couldnt turn over on his own.
The World Health Organization (WHO) reports that lung cancer is the most common malignant tumor in the world, accounting for 19.4% of cancer deaths. Lung cancer is also the leading cause of death in China due to inadequate tobacco control. It is estimated that by 2025, the number of lung cancer patients in China will reach 1 million, becoming the largest number of lung cancer countries in the world.
Biopsies and genetic tests found Li Mingleis precise cause of cancer, the mutation of the EGFR19 gene. In China, this situation is almost not cured, he said. But in the United States, there was already a second-generation specific drug for EGFR19 mutation, Afatinib, and the third-generation drug, AZD9291, was in phase III. So he decided to go to the United States to take a chance.
Source: figure worm creativity
After a series of very professional medical records, Li Minglei chose the top Massachusetts General Hospital in the United States. On the second day of his appointment to Boston, he went to the hospital to see the doctor. The American doctor called him Dr. Lee and shook hands with him. The oncologist also appointed a surgeon to discuss the treatment plan.
Cai Qiang, founder and chairman of the Shennoi family, told China News Weekly that 67 percent of Chinese patients had undergone treatment changes after going to the United States for medical treatment. One reason is that clinical medicine in the United States is moving in the direction of precision medicine, where a patient is often treated by doctors from multiple disciplines who believe that no two lung cancer patients are treated the same way.
Another reason for the change of treatment is the difference in drugs. A large number of cancer patients have come to the United States to choose new treatments, because our latest drugs are available in the United States in 2011, the United States in 2012, 2013... We didnt have any drugs until 2016.
Cai Qiang, for example, said they introduced a skin cancer patient to the United States to see a doctor. As a result, American doctors found that Chinese medicine was used 30 years ago in the United States.
In fact, Chinese doctors have made no mistakes in treating patients on the basis of domestically marketed drugs, but the drugs are not advanced enough. Under the backdrop of new drug research and development, Chinese doctors are unable to make bricks without straw. Its like the U.S. is using the iPhone 6, and were still using the iPhone 3, one patient said after receiving satisfactory treatment in the U.S. Of course, this is just an inappropriate metaphor, in mobile phones, the Chinese are completely unwilling to lag behind.
Zhang Tianyin, a patient with cutaneous melanoma, was treated in a third-class hospital in Beijing. Li Tao, his attending doctor, suggested that he might consider going to the United States for clinical trials. Li Tao, who just attended the annual meeting of the American Oncology Society, told China News Weekly: We knew then that the United States already had new drugs for melanoma and was conducting phase III clinical trials. The results of phase I and phase II trials showed that the effect was very good. However, there are no such drugs or clinical trials in China, and I would recommend that patients who have the conditions to go abroad for medical treatment choose the latest drugs abroad.
Fortunately, Zhang Tianyin met the criteria for clinical trials. After entering the trial group, he was treated directly. Now it has been 67 years. He is satisfied with the results. Now, he doesnt feel hes experimenting, but sees the process as a complete treatment.
Approval of backlog 17 thousand pieces
Take anti-lung cancer drugs for example, the United States has begun clinical trials of the fourth generation of targeted drugs, and China is still in the first generation of targeted drugs. This means that once a patient develops resistance, there will be no other drugs available for treatment in China.
The first step in approving new drugs in China is to approve clinical trials. The Regulations on the Administration of Drug Registration issued in 2007 sets a time limit for each step of examination and approval. Among them, the time for examination and approval of clinical trials of new drugs must not exceed 90 days. However, in fact, data from the State Food and Drug Administration (hereinafter referred to as the Food and Drug Administration) show that in 2014, Chinas 1.1 class of new drugs, 3.1 class of new drugs. The average time for clinical trials of drugs and 6 types of new drugs was 14 months, 28 months and 28 months.
In the United States, if no FDA decision to suspend clinical trials is received within 30 days after an application for a new drug has been submitted to the Food and Drug Administration (FDA), it means approval.
China is just the opposite. The applicant must be examined and approved by the national and provincial drug regulatory authorities at two levels, and the approval is obtained before the clinical trial can be carried out.
Chinese clinical trials require more detailed information on the applicants pharmaceutical research. All materials should be submitted prior to Phase I clinical trials and all materials should be supplemented at one time within four months. But in fact, for clinical trials of new drugs, many research data are difficult to submit before phase I. In the United States, these data can be submitted gradually with the development of the research plan.
In order to improve the efficiency of FDA and the quality of drug approval, the Prescription Drug Reporter Payment Act promulgated by the United States in 1992 requires that new drug applicants pay a certain application fee to the FDA, an annual fee for the production site of prescription drugs, etc., and the FDA must complete the review and approval within a limited time. This revenue allows the FDA to hire more experts and reviewers in different fields, update information technology facilities, and significantly shorten the approval time.
FDA, which has more than 9300 employees, is one of the largest number of government employees in the federal government. But it is different from the semi commercialized mode in the US. Public data show that in 2014, the administrative establishment of the Chinese Food and Drug Administration was 345, of which only 10 inspectors. Although the Food and Drug Administration charges certain fees when accepting drug registration applications, these fees are all turned over to the state treasury, and can not be used to optimize the resources for review.
According to the Drug Review Report 2015 issued by the Food and Drug Administration, although about 120 drug review center staff completed 9,601 review tasks in 2015, there is still a backlog of 17,000.
Under the situation of insufficient manpower, new drugs, vaccines and medical devices in China lag behind Europe and the United States. For example, the first HPV vaccine to prevent cervical cancer was approved by the FDA in 2006 and has entered many countriesmarkets. However, due to the delayed approval of the vaccine in China, many Chinese women have chosen to leave the country for vaccination in private clinics. It was not until July 18 that the first HPV vaccine was approved for sale in China, a process that took nearly 10 years.
In order to speed up the review of some drugs used to treat critical diseases, the FDA has set up four special approval channels, including fast track, priority review, accelerated approval, and breakthrough therapy. Cai Qiang said that these special channels examine and approve much faster than usual, sometimes only take three months.
In 2012, the fifth Amendment to the Prescription Drug Reporter Payment Act emphasized improving FDAs rapid approval channels, including training inspectors for such drugs, and offered priority to review orphans. The third generation of targeted drug AZD9291, which was launched in November 2015, depends on fast approval channels.
On November 6, 2014, Li Minglei took the first second-generation targeting drug, Afatinib, which had been on the market in the United States for a year and had not been introduced in China. Li Minglei clearly remembered that five weeks after taking the drug, PET-CT showed that metastatic lesions on the spine and ribs disappeared, and primary lung lesions shrank by 60%.
But less than a year later, doctors found that Li Minglei had developed resistance to Alfatinib, and biopsy showed that he had mutations in the resistance gene. But this is in line with the AZD9291 clinical trial standard, which was then in phase III.
Li Minglei spent only one month from applying for trial to formal entry. Before applying, the doctor fully informed him of the risks and possible side effects of the drug, and he signed the consent without hesitation.
This authorization agreement also needs to be examined and approved by the Third Party Ethics Committee.
In China, ethics committees are attached to hospitals, and censorship is a mere formality. Cai Xuliu, general manager of Jingwei Legendary Pharmaceutical Technology Co., Ltd, told China News Weekly: Sometimes doctors emphasize free medication, but do not fully inform the risks of medication.
As director of the third-party inspection company, Cai Xuliu found that some hospitals would gather patients together, with a doctor telling dozens of patients about the risks and benefits of the trial, and then letting the patient decide whether to sign the consent. This may affect patients.
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In the United States, clinical trials are free, but the cost of testing is higher than usual. As a result, patients participating in clinical trials often receive more detailed consultation from doctors, and medical staff are willing to spend more time fully understanding the patients compliance and coordination. Doctors also leave contact information for patients in emergencies. Nurses often call patients to ensure that they are followed up on medication, adverse reactions and help them fill out test forms.
However, in China, most of the leading clinical trials are conducted by qualified doctors in hospitals of Grade Three A. They are usually chief physicians and the busiest group of people in the whole hospital. In fact, as long as researchers can fully participate in clinical trials, they will do very well. But basically, they have little time to participate. Cai Xu Liu said.
Since there are only more than 400 medical institutions in China that can carry out clinical trials, mainly the third-tier hospitals, and drug research and marketing rely on hospitals, Chinese pharmaceutical companies are afraid to offend these hospitals and doctors.
Unlike the weak position of pharmaceutical companies in China, the majority of clinical trials in the United States are dominated by pharmaceutical companies. Because any American doctor can participate in clinical trials. Wang Changyu told China News Weekly that he was the director of research and development for Pfizers cancer immunity department in the United States.
Cai Xuliu said: Many of the clinical trials in China are designed by outsourcing service agencies (CRO) and hospitals, and some pharmaceutical companies are not as good as CRO specialty. Some pharmaceutical companies even indicate in the contract with CRO that clinical trials must be ensured.
Today, Wang Changyu, who founded Huamin Biotechnology Co., Ltd. in Chengdu, feels that trust is the biggest gap between Chinese and American clinical trials. The United States pays attention to credit, and the only check when you declare is to see if there are any errors in your conclusions and inferences, and will not question your test procedures and results.
Because in the United States, very subtle procedural changes, once a test program is established, require voluntary reporting to the FDA, even if a patients infusion time changes from one hour to two hours. However, it is not uncommon for Chinese doctors to fill in the signature, post supplement inspection record, or even post supplement test paper.
Wang Changyu even heard, What kind of data the drug companies need, what kind of data the hospital can give you. Some clinical trials modify the original data directly to ensure the drug is effective, according to an industry insider. Some hospitals will drop the control group and the experimental group; some researchers will directly modify the patients medical records; some hospitals will be patients to participate in clinical trials, his tumor size a little larger and the final evaluation of the results of a little smaller, the efficacy of the drug will therefore appear.
These circumstances are unthinkable in the United States. Because once the FDA finds that clinical trials are falsified, drug companies, research institutes, and CROs will pay a huge price. The U.S. based on the credit system, if the clinical results are falsified, the agency in the U.S. is definitely not going to be able to do more, equivalent to a blacklist. Wang Changyu said that because of the fierce competition between pharmaceutical companies in the United States, if the opponents data is found to be fraudulent, pharmaceutical companies will often take the initiative to report. But in China, reporting is not good for anyone, so its better to make money together.
In June 2013, the FDA announced that the review of the new drug, Apixaban, developed jointly by Bristol-Mercedes-Squibb and Pfizer, would be delayed for three months. The reason is that a Chinese clinical research center manager and another inspector changed the original records to cover up evidence of violations of clinical research quality management standards. This eventually led FDA investigators to question 24 data from 36 Chinese research centers.
Although Chinas Food and Drug Administration issued the 722 documents on July 22, 2015, the most stringent data verification requirements in history, by contrast, the cost of counterfeiting in China is still small. The 1622 acceptance numbers listed at that time required self-examination, if they could not submit the self-examination report within a month, they would choose to withdraw the application. In the end, more than 80% of the applications were withdrawn.
After taking AZD9291 for about two weeks, Li Ming-lei found that his breathing was smooth again and his bones were no longer painful. Unfortunately, he enjoyed only three months of free trial treatment, and AZD9291 was approved for sale in the United States. Since then, it has cost more than $10,000 a month. This is a huge financial burden for patients at their own expense.
In general, U.S. drug companies invest about $50,000 to $100,000 per patient in clinical trials, it was revealed. It takes 10 years to develop a new antitumor drug, which costs 2 billion to 3 billion dollars. The cost of R&D in foreign pharmaceutical companies ranges from $4 billion to $10 billion per year, whereas the top ten foreign pharmaceutical companies average two or three approved drugs per year.
According to a 2015 ranking of R&D investment by domestic pharmaceutical companies, only HK$1.3 billion is spent most on R&D among listed pharmaceutical companies with a market value of more than 10 billion.
Today, Li Minglei can return to work, but he needs to go to the United States every three months to review and prescribe drugs. The historic city of Boston is a famous higher education and health care center in the United States, and has become a promising place for Li Minglei. His American doctor is not worried that he will develop resistance again. He himself believes that, despite the high cost of traveling to the United States, the constant development of new drugs can give him a head start in the race against cancer.
Clinical trials are often the last stroke of cancer patients for life. In Li Mingleis view, the standardized, rigorous and meticulous drug testing process in the United States has not only given him a bright future in precision medicine, but as a Chinese doctor, he has also found the dignity of being a patient in the medical environment in the United States.