Why Are More Chinese Cancer Patients Seeking Treatment in the U.S.? A Surge in Cross-Border Oncology Care Driven by Clinical Trials and Precision Medicine

Editor’s Note: This article is reprinted from China Newsweek.(WeChat Official Account: chinanewsweekly), Author: Wang Sijing, republished with permission from VCBeat.

Three years ago, orthopedic surgeon Li Minglei noticed his left-sided chest pain worsening and decided to undergo a CT scan. After discovering a pulmonary nodule approximately 4 cm in size, he self-diagnosed cancer.

Just last weekend, Li Minglei completed a 5-kilometer run along the Charles River in Boston, United States. Two years ago, he had been wheeled off an airplane by his wife. After being diagnosed with stage IV lung cancer, doctors in Beijing told him that he might have only six months left to live.

Nowadays, Li Minglei regularly receives cancer treatment at Massachusetts General Hospital, affiliated with Harvard University. His improvement may not be termed a medical miracle but is rather an ordinary case among the many patients who travel to the United States for cancer therapy. Nevertheless, he was fortunate enough: the EGFR exon 19 mutation qualified him for a clinical trial of third-generation targeted therapy, and within two weeks of starting the trial, his condition began to turn around.

Market research conducted by Shengnuoyijia, a Beijing-based medical travel facilitator, reveals that approximately 3,000 Chinese patients seek medical treatment in the United States each year, with 70% of them being cancer patients. When existing medications remain effective, participating in clinical trials is not typically the patients’ first choice. However, once patients develop resistance to anticancer drugs, new drug clinical trials in the U.S. often become their last resort.

At the renowned MD Anderson Cancer Center in the United States, hundreds of clinical trials are conducted simultaneously each day, and more than 90% of cancer patients proactively ask their physicians, “Am I eligible to participate in clinical trials for new drugs?” Nowadays, the center also sees no shortage of late-stage cancer patients referred from China for treatment.

When 38-year-old Li Minglei sought treatment at a renowned Grade A tertiary hospital in Beijing, the physicians informed him that he had “Stage IV lung cancer, eligible only for conservative management, with no opportunity for surgical intervention.” He understood that this staging indicated advanced lung cancer with distant metastasis, which plunged him into despair. Over the course of the next two cycles of chemotherapy, his body was severely weakened by the chemotherapeutic agents, ultimately leaving him unable to turn over on his own.

According to a report by the World Health Organization (WHO), lung cancer is the most common malignant tumor worldwide, accounting for 19.4% of cancer-related deaths. Due to factors such as ineffective tobacco control, lung cancer is also the leading cause of cancer-related mortality in China. It is projected that by 2025, the number of lung cancer patients in China will reach one million, making it the country with the highest number of lung cancer cases globally.

Although the five-year survival rate for lung cancer in China is 16.1%, quite close to the 17% in the United States, China’s overall cancer treatment landscape reveals a disparity: while its cancer incidence rate approximates the global average, its mortality rate exceeds the world level. Data show that the five-year survival rate for cancer patients in the United States ranges from 60% to 70%, whereas in China it stands at only around 30%.

Biopsy and genetic testing identified the precise cause of Li Minglei’s cancer—an EGFR exon 19 mutation. He said, “In China, this condition was nearly untreatable. But in the United States, the second-generation targeted drug afatinib for EGFR exon 19 mutations was already available, and clinical trials for the third-generation drug AZD9291 had progressed to Phase III.” Thus, he decided to go to the United States to “try his luck.”

After meticulously preparing his comprehensive medical records, Li Minglei chose to seek treatment at Massachusetts General Hospital (MGH), which ranks among the top general hospitals in the United States. Upon arriving in the United States as scheduled, he visited the hospital to consult with his physician on the second day after reaching Boston. The American doctor addressed him as “Dr. Li” and rose to shake his hand. The oncology specialist also arranged a consultation with a thoracic surgeon to jointly discuss the treatment plan.

Contrary to the opinions of domestic physicians, U.S. doctors advised Li Minglei that after targeted drug therapy demonstrates efficacy, the remaining primary tumor lesions can be treated with surgical resection.

Cai Qiang, founder and chairman of Shengnuo Yijia, told China Newsweek that 67% of Chinese patients had their treatment plans modified after seeking medical care in the United States. One reason is that clinical medicine in the U.S. is moving toward “precision medicine,” where a patient is often treated by a multidisciplinary team of physicians. Under this paradigm, they believe that “no two lung cancer patients have the same treatment plan.”

Another reason for changes in treatment regimens lies in the disparity of available medications. “A significant number of cancer patients have traveled to the United States to adopt new treatment protocols, because our latest pharmaceuticals are those approved in the U.S. market in 2011; we lack access to drugs approved in the U.S. from 2012, 2013, and onward through 2016.”

Cai Qiang cited an example in which they referred a skin cancer patient to the United States for treatment, only for American physicians to discover that the medication used in China was one that had been employed in the U.S. three decades earlier.

In fact, the treatment plans formulated by Chinese doctors based on domestically approved medications are not erroneous; the issue is simply that the drugs are not sufficiently advanced. Given the lag in new drug development, Chinese doctors find themselves unable to perform miracles without the necessary resources. As one patient who achieved satisfactory treatment outcomes in the United States remarked, “It’s as if everyone in the U.S. is using the iPhone 6, while we are still stuck with the iPhone 3. Of course, this is an imperfect analogy, as Chinese people are certainly not willing to fall behind when it comes to mobile phones.”

Zhang Tianyin, a patient with cutaneous melanoma, was receiving treatment at a Grade 3A hospital in Beijing. His attending physician, Li Tao, suggested that he consider participating in clinical trials in the United States. Having just attended the American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Li told China Newsweek: “At that time, we were aware that the U.S. had new drugs specifically targeting melanoma undergoing Phase III clinical trials, and results from Phase I and II trials had demonstrated excellent efficacy. However, such drugs and related clinical trials were not yet available in China. For patients who have the means to seek medical care abroad, I would recommend they go overseas to access the latest therapeutic options.”

Fortunately, Zhang Tianyin met the eligibility criteria for the clinical trial. Since enrolling in the trial group, he has been receiving treatment continuously for the past six to seven years and is highly satisfied with the outcomes. He no longer perceives himself as participating in a trial but rather views the process as a comprehensive treatment regimen.

The lag in China’s new drug development is an undisputed fact. According to data from the U.S. Clinical Trials Registry, as of October 2015, a total of 201,149 clinical trials had been registered worldwide, with 48.53% conducted in the United States, while drug clinical trials carried out in China accounted for only 9.75%.

Taking anti-lung cancer drugs as an example, the United States has already initiated clinical trials for fourth-generation targeted therapies, while China remains reliant on first-generation targeted agents. This implies that once patients develop drug resistance, those being treated in China will have no alternative therapeutic options available.

The first step in the approval process for new drugs in China is to authorize the conduct of clinical trials. The Provisions for Drug Registration, issued in 2007, stipulated time limits for each stage of the review process, specifying that the review period for new drug clinical trial applications should not exceed 90 days. However, data from the China Food and Drug Administration (hereinafter referred to as the CFDA) revealed that in 2014, the average review times for Class 1.1, Class 3.1, and Class 6 new drug clinical trial applications were 14 months, 28 months, and 28 months, respectively.

In the United States, if an applicant submits an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (hereinafter referred to as the FDA) and does not receive a decision from the FDA to place the clinical study on hold within 30 days, the application is deemed approved.

In contrast to the United States’ “lenient entry, strict exit” approval system, China adopts the opposite approach. Applicants must undergo a two-tier review process by both national and provincial drug regulatory authorities; only after obtaining approval documents can they proceed with clinical trials.

China’s clinical trial regulations impose more detailed requirements on applicants’ pharmaceutical research data, mandating that all materials be submitted before Phase I clinical trials and that any deficiencies be fully rectified with a one-time submission within four months. In practice, however, it is often difficult to submit many study datasets prior to Phase I clinical trials for new drugs. In the United States, such documentation may be submitted incrementally as the research plan progresses.

To enhance the FDA’s operational efficiency and the quality of drug review and approval, the Prescription Drug User Fee Act (PDUFA), enacted in the United States as early as 1992, stipulated that new drug applicants could pay certain fees to the FDA, such as application fees and annual facility fees for prescription drug manufacturing sites. In return, the FDA was required to complete its review and approval processes within specified timeframes. This revenue stream enabled the FDA to hire more experts and reviewers across various disciplines and upgrade its information technology infrastructure, thereby significantly shortening approval timelines.

With more than 9,300 employees, the U.S. Food and Drug Administration (FDA) is one of the largest federal agencies in terms of staffing within the U.S. federal government. This stands in contrast to China’s semi-commercialized model. Public data show that in 2014, the administrative headcount of the China Food and Drug Administration (CFDA) headquarters was only 345, including just 10 inspection commissioners. Although the CFDA charged certain fees when accepting drug registration applications, all such fees were remitted to the state treasury and could not be used to optimize review resources.

The "2015 Annual Drug Evaluation Report" released by the China Food and Drug Administration (CFDA) shows that although approximately 120 staff members at the Center for Drug Evaluation completed 9,601 review tasks in 2015, a backlog of 17,000 applications remained.

Due to insufficient manpower, new drugs, vaccines, and medical devices in the Chinese market have lagged behind those in Europe and the United States. For instance, the first HPV vaccine for cervical cancer prevention was approved by the FDA and launched in many countries as early as 2006. However, due to delays in its approval in China, many Chinese women chose to travel abroad to receive vaccinations at private clinics. It was not until July 18 this year that the first HPV vaccine was finally approved for marketing in China, a review process that took nearly ten years.

To expedite the review of certain drugs used to treat critical conditions, the FDA has established four special approval pathways: Fast Track, Priority Review, Accelerated Approval, and Breakthrough Therapy. Cai Qiang noted that these special channels “are much faster than the standard review process, sometimes taking only three months.”

In 2012, the United States enacted the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA), emphasizing improvements to the FDA’s expedited review pathways, including training for reviewers handling such drugs, and proposing priority review for orphan drugs. The market approval of the third-generation targeted therapy AZD9291 in November 2015 was facilitated by these expedited review pathways.

On November 6, 2014, Li Minglei took his first dose of the second-generation targeted therapy afatinib. At that time, the drug had already been on the market in the United States for one year but had not yet been introduced in China. Li Minglei clearly remembered that after five weeks of treatment, PET-CT scans showed the disappearance of metastatic lesions in the spine and ribs, as well as a 60% reduction in the primary lung tumor.

But within a year, doctors discovered that Li Minglei had developed resistance to afatinib. Biopsy results revealed the emergence of drug-resistance gene mutations. Fortunately, his condition met the enrollment criteria for the AZD9291 clinical trial, which was then in Phase III.

It took Li Minglei only one month from applying to participate in the trial to being formally enrolled. Prior to his application, the physician thoroughly informed him of the drug’s risks and potential side effects, and he signed the informed consent form without hesitation.

This informed consent form is also subject to review and approval by an independent ethics committee.

In China, ethics committees are affiliated with hospitals, and their reviews often become a mere formality. Cai Xuliu, General Manager of Beijing Jingwei Chuanqi Pharmaceutical Technology Co., Ltd., told China Newsweek: “Sometimes, doctors place particular emphasis on the provision of free medication but fail to adequately inform patients of the associated risks.”

As the director of this third-party audit firm, Cai Xuliu discovered that some hospitals would gather patients together, having a single physician explain the risks and benefits of the trial to dozens of patients before asking them to decide whether to sign the informed consent form. “This practice may lead to mutual influence among patients.”

In the United States, although investigational drugs used in clinical trials are provided free of charge, patients’ examination costs are often higher than usual. Consequently, patients participating in clinical trials typically receive more thorough consultations from physicians, with healthcare professionals willing to devote additional time to fully assess patient adherence and cooperation. Physicians also provide contact information for emergencies, while nurses regularly call patients to ensure timely monitoring of medication adherence and adverse reactions, as well as to assist them in completing trial-related forms.

However, in China, clinical trials are predominantly led by physicians from accredited Grade 3A hospitals, who are typically chief physicians and among the busiest professionals within their institutions. “In fact, clinical trials in which investigators can fully participate tend to be conducted very well. But in reality, they rarely have the time to engage,” said Cai Xuliu.

Given that there are only over 400 medical institutions in China qualified to conduct clinical trials, predominantly Grade A tertiary hospitals, and given that drug development and sales rely heavily on these hospitals, Chinese pharmaceutical companies are reluctant to offend these institutions and their physicians.

Unlike the relatively weak position of pharmaceutical companies in China, most clinical trials in the United States are led by these companies. “Because any physician in the U.S. can participate in clinical trials,” Wang Changyu told China Newsweek. He previously served as R&D Director of the Oncology Immunology Division at Pfizer in the United States.

Cai Xuliu stated, “Many clinical trial protocols in China are jointly designed by contract research organizations (CROs) and hospitals, with some pharmaceutical companies lacking the professional expertise of CROs.” Some pharmaceutical companies even include clauses in their contracts with CROs requiring that the clinical trials be guaranteed to pass.

Nowadays, Wang Changyu has founded Huamian Biotechnology Co., Ltd. in Chengdu. He believes that trust represents the biggest gap between Chinese and U.S. clinical trials. “The United States emphasizes credibility. During the application process, the sole review focuses on whether there are any errors in the conclusions and inferences presented in the submitted documentation, without questioning the trial procedures or results.”

In the United States, once a clinical trial protocol is finalized, even minor procedural changes must be proactively reported to the FDA—for instance, if a patient’s infusion time is extended from one hour to two hours. In contrast, it is not uncommon in China for physicians to retroactively sign documents, backdate examination records, or even fabricate laboratory test results after the fact.

Wang Changyu has even heard it said, “Pharmaceutical companies can get whatever data they need from hospitals.” An industry insider revealed that some clinical trials directly alter raw data to ensure drug efficacy. In some cases, hospitals swap the control and experimental groups; researchers may directly modify patients’ medical records; and certain hospitals deliberately overestimate tumor sizes before patients enroll in clinical trials, only to report smaller measurements during final outcome assessments, thereby artificially “demonstrating” the drug’s therapeutic effect.

Such scenarios are inconceivable in the United States. Once the FDA discovers fabricated clinical trial data, pharmaceutical companies, research institutions, and CROs face severe consequences. “The U.S. operates on a credit-based system; if an institution falsifies clinical results, it will inevitably be forced out of the market, effectively being blacklisted,” said Wang Changyu. Due to intense competition among pharmaceutical companies in the U.S., firms often proactively report competitors’ data fabrication. “In China, however, whistleblowing benefits no one; it is more advantageous to collaborate for profit.”

In June 2013, the FDA announced that the review process for apixaban, a new drug jointly developed by Bristol-Myers Squibb and Pfizer, would be delayed by three months. The reason was that a manager at a clinical research center in China and another monitor had “altered source records to conceal evidence of violations of Good Clinical Practice (GCP).” This ultimately led FDA investigators to question data from 24 of the 36 clinical study sites in China.

Although the China Food and Drug Administration (CFDA) issued the “722 Document” on July 22, 2015, imposing the “strictest data verification requirements in history,” the cost of fraud in China remained relatively low by comparison. At that time, 1,622 application serial numbers were listed for self-inspection; applicants who failed to submit their self-inspection reports within one month were required to withdraw their applications. Ultimately, more than 80% of the applications were withdrawn.

After taking AZD9291 for about two weeks, Li Minglei found his breathing becoming smooth again and the bone pain subsiding. “Unfortunately,” he only enjoyed three months of free trial treatment before AZD9291 was approved for marketing in the United States. Since then, a month’s supply has cost more than $10,000. For self-paying patients, this represents a significant financial burden.

It has been revealed that, generally speaking, U.S. pharmaceutical companies invest approximately $50,000 to $100,000 per patient in clinical trials. The development of a new anti-tumor drug typically takes 10 years and costs between $2 billion and $3 billion. Foreign pharmaceutical companies spend $4 billion to $10 billion annually on R&D, while the top ten foreign pharmaceutical companies have an average of two to three drugs approved each year.

A 2015 “Ranking of R&D Investment by Domestic Pharmaceutical Companies” showed that among listed pharmaceutical companies with a market capitalization exceeding RMB 10 billion, the highest R&D expenditure was only HK$1.3 billion.

At the national level, the United States invested $79.1 billion in pharmaceutical development and research as early as 2005, with the government contributing $27.8 billion and enterprises contributing $51.3 billion. In contrast, the Chinese government’s funding for clinical research is significantly insufficient, with the majority of funds coming from sponsorships by pharmaceutical companies and manufacturers. In 2011, the Chinese government invested $1 billion in biomedical research, while its investment in clinical research amounted to only $250 million.

Nowadays, Li Minglei has been able to return to China for work, but he needs to travel to the United States every three months for follow-up examinations and prescription refills. Boston, a historic city renowned as a hub for higher education and healthcare in the U.S., has become a place of hope for Li Minglei. His American doctors are not concerned about the recurrence of drug resistance. He himself believes that although receiving treatment in the U.S. is costly, the continuous development of new drugs allows him to stay one step ahead in his race against cancer.

Clinical trials are often the last resort for cancer patients fighting for their lives. In Li Minglei’s view, the standardized, rigorous, and meticulous drug trial process in the United States not only revealed the promising future of precision medicine but also, as a Chinese physician, allowed him to discover “the dignity of being a patient” within the American healthcare environment.