Multiple Barriers in Access, Payment, and Diagnosis: Is China's Rare Disease Treatment Dilemma Insurmountable?
How Many Rare Disease Patients Are There in China? In fact, there is currently no accurate answer to this question, as China has yet to establish an official definition of rare diseases. At present, a national rare disease registry system has not been established, and epidemiological surveys on rare diseases are lacking. Consequently, the number of patients and prevalence rates for specific rare diseases remain unknown, making it impossible to determine diagnostic criteria for rare diseases in China.
However, what is certain is that, given China’s large population base, the rare disease patient population is not rare. Nevertheless, individuals with rare diseases remain vulnerable and have long been neglected.
During the medical consultation process, due to healthcare professionals' lack of relevant knowledge and training, as well as hospitals' absence of corresponding diagnostic and treatment systems, rare disease patients in China are often diagnosed five years later than those in the United States.
Even after patients are fortunate enough to receive a confirmed diagnosis, 90% of rare diseases currently lack effective diagnostic and therapeutic options. In China, according to the “2019 Report on the Accessibility of Rare Disease Drugs in China,” 21 diseases included in the first batch of the National List of Rare Diseases face the dilemma of “drugs available abroad but not domestically.”
In terms of drug accessibility, orphan drugs in China are relatively scarce and primarily reliant on imports. These imported medications are prohibitively expensive, and the majority are not covered by the medical security system, rendering them unaffordable for most patients.
For patients with rare diseases, every challenge they encounter has no solution.
This also tells us that solving the challenges in diagnosing and treating rare diseases is not only a scientific issue, but more importantly, an economic issue, a public governance issue, and a matter of social civilization.
From an industrial perspective, the most viable business model is also the greatest public good when it comes to seeking solutions for rare diseases. How to break market failure, incentivize pharmaceutical companies to produce orphan drugs while remaining profitable and sustainable, and make rare disease treatments affordable for patients has become a significant challenge.
From September 20 to 22, 2019, the 8th China Rare Disease Summit (hereinafter referred to as the “Summit”) was held in Shenzhen. As the largest comprehensive forum in the field of rare diseases in China to date, it was hosted by the Shanghai Clover Rare Disease Family Care Center (abbreviated as “Rare Disease Development Center” or “CORD”) and supported by the Shenzhen Medical Association. Experts and scholars, clinicians, government officials, representatives from rare disease organizations, patient families, and pharmaceutical companies from both domestic and international arenas gathered together to engage in in-depth exchanges and seek further collaboration. The Summit aimed to strengthen industry communication and cooperation, advocate for the implementation of policies, and actively promote the development of rare disease initiatives in China through the exchange of diverse perspectives. During the Summit, VCBeat attended and documented this annual gathering of rare disease research in Shenzhen, summarizing the core advancements of the 2019 Rare Disease Summit, which mainly included:
Approval: The market launch of drugs for rare diseases in China is gradually achieving “zero time lag” with overseas markets.
Market Access: The “Three-No Status” Has Been Broken, but Patients Still Face a “Glass Door” to Actual Use
Payment: How to Construct a Diversified Payment System for Rare Diseases
Diagnosis: Missing Patient and Physician Data
Diagnosis and Treatment: Multidisciplinary Comprehensive Care Model Becomes a New Hope for Patients
China’s attention to rare diseases started relatively late. Previously, a major dilemma when discussing rare diseases was that “drugs were available overseas but not in China.” The First Batch of Rare Diseases Catalog, jointly released by five ministries including the National Health Commission and the Ministry of Science and Technology, includes 121 rare diseases. Globally, 162 drugs have been approved for these 121 conditions, but only 83 are marketed in China. Among these 83 marketed drugs, only 55 have indications specifically targeting these 121 rare diseases.
With the Center for Drug Evaluation of the National Medical Products Administration opening multiple “green channels” for the approval of rare disease drugs, the dilemma of “drugs available overseas but not in China” has been significantly alleviated.
In 2018, a total of 13 drugs for 10 rare diseases were approved for market launch through the priority review and approval process. Twenty drugs for 12 rare diseases were included in the List of Clinically Urgent Overseas New Drugs (Batch I), released by the Center for Drug Evaluation of the National Medical Products Administration in 2018. In 2019, an additional 14 rare disease drugs were included in the List of Clinically Urgent Overseas New Drugs (Batch II).
At the 8th Rare Disease Summit, Gao Chenyan, Director from the Center for Drug Evaluation (CDE) of the National Medical Products Administration, provided a comprehensive explanation of how the CDE encourages the research and development of drugs for rare diseases.
First, regarding regulatory review, for products already marketed overseas, if there are no ethnic differences, overseas clinical trial data may be used directly to apply for drug registration.
Second is priority review and approval. Since the implementation of the new priority review policy in 2016, a total of 909 drug products have been included in the priority review program, among which 121 are drugs for rare diseases.
The third pathway is conditional approval for marketing. “For rare disease drugs that address conditions seriously endangering life and for which no effective treatments are currently available, conditional marketing approval may be granted, provided that existing clinical data demonstrate efficacy and allow prediction of clinical benefit. Meanwhile, after conditional approval is granted, the applicant must promptly complete the clinical trials required by the national drug evaluation agency. Among these, rare disease therapeutic drugs already approved for marketing overseas may be granted conditional marketing approval.”
Minister Gao Chenyan stated, “At our Center for Drug Evaluation (CDE), communication meetings regarding applications for products that are urgently needed clinically and have already been marketed overseas are classified as Class I meetings. Once a drug enters the CDE, the approval process is very rapid. For any product listed in the catalog of drugs with urgent clinical needs, we will apply a special marker to flag it for expedited review through a dedicated channel. Specifically, technical reviews for rare disease medications must be completed within three months.”
In the first three years, when discussing the speed of new product launches in China, we often cited AstraZeneca’s lung cancer drug TAGRISSO (Tagrisso), which set an approval record at the time with its entire market launch approval process taking no more than seven months. This year, however, that record was broken by a rare disease medication: Spinraza, a treatment for spinal muscular atrophy, completed its market launch approval process in China in just 173 days, only two years after its initial approval in the United States.
We can anticipate that more than 30 drugs for rare diseases will be launched in China over the next three years, with approval timelines becoming progressively shorter.
Notably, at the 8th Rare Disease Summit, Director Gao Chenyan also disclosed recent progress in the review and approval of gene therapies.
Minister Gao Chenyan stated, “This year, the National Medical Products Administration (NMPA) has decided to carry out regulatory science research on drugs, medical devices, and cosmetics, launch and implement the China Drug Regulatory Science Action Plan, and identify the first batch of nine key research projects. The first project listed is the regulation of cell and gene therapy products. I am leading the implementation of this project. Our objectives include facilitating the research and development and registration in China of products such as gene therapies, and we are exploring new pathways to accelerate their market approval.”
The activation of the "green channel" for the review of orphan drugs has enabled multiple therapies to reach the market rapidly, but it has also brought a series of challenges.
First, in terms of clinical trials, the small patient population, low geographic concentration, and low diagnostic rate for rare diseases pose significant challenges to trial completion.
Recently, real-world studies have become a hot topic. The "Basic Considerations for Real-World Evidence Supporting Drug Development (Draft for Comments)" released in May 2019 also pointed out that drugs for rare diseases are one of the several scenarios where real-world evidence supports drug development and regulatory decision-making.
However, real-world studies require multi-source data collection and high-granularity structured data processing. Given the small patient population with rare diseases, how to leverage data to support real-world studies remains an area requiring continuous exploration by all stakeholders.
Li Yangyang, Managing Director of Management Consulting at IQVIA China, believes that while the acceleration of regulatory approval is a positive development, it also presents a double-edged sword for the subsequent market launch of rare disease drugs. Faster time-to-market implies that corresponding clinical data will be more streamlined. With conditional approvals and the direct adoption of overseas clinical data, an increasing number of rare disease drugs are being launched in China based on Phase II clinical trials, without substantial sample size data. As the speed of market entry increases, the supporting evidence becomes increasingly simplified, posing significant challenges for subsequent national reimbursement listing, pricing, and market access. Payers perceive increased uncertainty in their assessments, including uncertainties regarding clinical value, budget impact, and patient benefits.
There are multiple bottlenecks in the diagnosis and treatment of rare diseases, and according to Dr. Huang Rufang, founder of the Shanghai Clover Rare Disease Family Care Center (CODR), the two most critical issues are approval and reimbursement.
“By bridging these two aspects, the entire diagnostic and treatment loop for rare diseases can potentially be set in motion.”
Previously, rare diseases in China were in a “three-no” state: no official definition, no special policy support, and no medical insurance reimbursement. Policy breakthroughs are now eliminating this “three-no” status for rare diseases in China.
In 2018, five ministries and commissions jointly formulated and released the First Batch of Rare Diseases Catalog. Regarding medical insurance reimbursement, data from the 2019 Report on Accessibility of Rare Disease Drugs in China shows that only 55 drugs with clearly registered indications for rare diseases were available in China, covering 31 types of rare diseases. Among these 55 drugs, 29 were included in the National Basic Medical Insurance, Work-Related Injury Insurance, and Maternity Insurance Drug List, covering 18 types of rare diseases.
The core challenge in including rare disease drugs in the national medical insurance scheme lies in their high pricing. Due to the small patient population, higher prices are adopted by pharmaceutical companies abroad to incentivize R&D, supported by commercial insurance or policy measures. However, in China’s healthcare payment system, the out-of-pocket expense ratio for patients is relatively high, reaching 30%. According to the China Health Statistical Yearbook, the per capita healthcare expenditure is 1,685 yuan, which creates a substantial gap compared to the prices of most rare disease drugs.
Beyond medical insurance coverage, rare disease drugs still face numerous hurdles in “business access,” and the “last mile” of drug accessibility remains fraught with challenges.
Barriers such as hospital procurement restrictions, physician prescribing limitations, outpatient reimbursement caps, and the slow implementation of tiered diagnosis and treatment, coupled with drug shortage crises, have resulted in poor medication accessibility for patients with rare diseases, even after these drugs are included in the national medical insurance scheme.
Taking procurement restrictions as an example, due to the high prices of orphan drugs, hospitals are often reluctant to purchase them out of consideration for drug-to-revenue ratios and medical insurance cost containment. This has resulted in a situation where orphan drugs, despite being included in the national medical insurance coverage, still fail to gain access to hospital formularies.
Dr. Chen Hao, Director of the Center for Pharmaceutical Policy and Management Research at Tongji Medical College, Huazhong University of Science and Technology, described this barrier as a “glass door.”
Overall, payment for rare disease treatments faces challenges such as the absence of commercial insurance, high thresholds for basic medical insurance coverage, and a high proportion of out-of-pocket expenses. However, this issue is not insurmountable; diverse payment models are emerging within the industry. Commercial insurance, pharmacy services, outcome-based insurance, financial installment plans, charitable drug donation programs, and special funds are providing more possibilities for financing rare disease treatments.
Wang Zhenyao, Dean of the China Philanthropy Research Institute at Beijing Normal University and former Director-General of the Department of Social Welfare and Charity Promotion under the Ministry of Civil Affairs, stated, “On September 16, the China Critical Illness Assistance Project, supported by the China Philanthropy Research Institute, was launched. At related meetings, I learned of a set of data showing that 120 million participants have joined Shuidichou’s critical illness mutual aid plan, raising RMB 20 billion for patients with serious illnesses. We must not overlook the power of public welfare; assistance for rare diseases also requires a joint effort combining government and social resources.”
In addition to social assistance, replicating the U.S. payment system to make commercial insurance a key component of China’s rare disease payment framework has also become a hot topic of discussion.
In the realm of commercial insurance, a key solution involves collaborating with insurers and pharmacy benefit managers (PBMs) on outcome-based insurance products. The primary approach entails linking insurers, pharmaceutical manufacturers, and direct-to-patient (DTP) pharmacies to provide patients with tools such as installment payment plans and outcome-based insurance coverage, thereby making high-cost medications more affordable.
While several companies have launched efficacy insurance products in the field of specialty oncology drugs, there are still few solutions available for rare diseases with smaller patient populations.
"In installment payment plans, domestic companies have partnered with pharmaceutical firms to provide interest-free installment services for patients with rare diseases."
In China, doctors capable of diagnosing and treating rare diseases are even rarer than the patients themselves. At the Rare Disease Summit Forum, a panelist remarked during a discussion, “I once heard a joke: In China, specialists in rare diseases are even scarcer than rare disease patients.”
It is estimated that there are only about 20 hospitals in China with the capacity to diagnose and treat rare diseases, and they are concentrated in developed cities.
In an interview, Director Huang Rufang stated, “We are not afraid of doctors lacking diagnostic skills, as they can refer patients to specialists. What we fear most is doctors telling patients that their condition is hopeless. A lack of expertise can be addressed through referral, but a misdiagnosis amounts to a death sentence for the patient.”
Diagnosing rare diseases is more challenging than treating them. Eighty percent of rare diseases are genetic disorders, which are typically chronic and degenerative. Due to limited awareness and experience among most clinicians, the misdiagnosis rate for these conditions remains high. Furthermore, patients are often lost during prolonged referral processes, resulting in low diagnostic rates for rare diseases.
Qi Ming, Director of the Center for Genetics and Genomics at The First Affiliated Hospital, Zhejiang University School of Medicine, and jointly appointed professor at Sir Run Run Shaw Hospital, Zhejiang University, stated in an interview, “China faces a critical shortage of genetic counselors for the diagnosis of rare diseases. Compared with the United States, China’s medical education system lacks two disciplines: preventive medicine, and genetics and genomics. The absence of standardized training systems and professional certification has resulted in an extremely limited number of physicians in China qualified to diagnose rare diseases.”
Addressing these issues requires concerted efforts from multiple stakeholders, including patient organizations, hospitals, enterprises, and the government.
Specifically, one effective approach to improving the diagnostic rate of rare diseases is to organize patients into groups that can play a more significant role. For instance, patient organizations can help promote and coordinate regional multidisciplinary team (MDT) consultations for specific rare diseases. Representatives from these organizations may also participate in Rare MDTs or encourage other patients to enroll in registry studies (observational studies) and adhere to scheduled follow-up visits. Furthermore, patient organizations can filter out misleading diagnostic and therapeutic information for their members, disseminate accurate information, standardize channels for medication access, and prevent patients from resorting to unverified folk remedies that could delay treatment or exacerbate their condition. In addition, patient organizations can compile directories of national rare disease diagnosis and treatment centers and the outpatient schedules of rare disease specialists to guide patients in seeking medical care.
Another effective approach relies on primary healthcare institutions. Physicians at these facilities need to undergo systematic training in rare disease knowledge to enhance their awareness and diagnostic capabilities. Furthermore, the primary healthcare system should establish an efficient referral network that connects patients with patient advocacy organizations and hospitals equipped to manage rare diseases.
At the conference, Professor Rao Li from West China Hospital of Sichuan University proposed an ideal clinical pathway for patients with rare diseases. First, primary care hospitals should promptly report suspected cases to higher-level hospitals upon patient presentation. Subsequently, these higher-level hospitals should establish dedicated units to manage referred patients, offer online consultations, and screen individuals who meet the diagnostic criteria for rare diseases. Furthermore, a green channel for specialized rare disease outpatient services should be provided for referred patients identified through online consultations as meeting the diagnostic criteria. Finally, after the patient’s visit to the specialized rare disease outpatient clinic, a multidisciplinary team (MDT) of experts will discuss and determine the next steps in diagnosis and treatment based on the patient’s clinical condition.
Improving the diagnostic rate of rare diseases relies on physicians who directly diagnose and treat these conditions. However, given the limited expertise and cognitive capacity of individual clinicians, hospitals can enhance diagnostic accuracy by establishing Multidisciplinary Teams (MDTs) for rare diseases. In the field of oncology, many large hospitals have already implemented MDTs for comprehensive care. The concept of rare disease MDTs has emerged in recent years, focusing on patient-centered care that leverages multidisciplinary expertise to develop standardized, individualized comprehensive treatment plans for rare diseases.
RareMDT is an essential organizational model in the diagnosis and treatment of rare diseases. Given the high proportion of genetic disorders among rare diseases, many of which involve gene mutations, geneticists are typically required to participate in the diagnostic process. This involves utilizing genetic testing and integrating insights from specialist physicians.
Professor Xu Kaifeng from Peking Union Medical College Hospital (PUMCH), affiliated with the Chinese Academy of Medical Sciences, introduced at the conference that PUMCH has conducted years of research on multidisciplinary teams (MDT). Even for less complex disease cases, physicians from pathology, radiology, surgery, and genetics departments participate in diagnosis and treatment. The hospital’s multidisciplinary team collaborates not only within the institution but also with external partners. Professor Xu stated, “The management of rare diseases is not solely the responsibility of a single institution; a national collaborative network is also crucial.” In the fields of tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), PUMCH has established a highly mature global collaborative network.
At the forum, Dr. Wang Jian from Shanghai Children’s Medical Center, affiliated with Shanghai Jiao Tong University School of Medicine, stated that precise diagnosis and treatment of rare genetic diseases require multidisciplinary involvement from obstetrics, pediatrics, genetic diagnostics, and radiology, integrating both “phenotype” and “genotype.” Obstetricians need to be familiar with genetic testing reports and promptly refer fetuses for further evaluation. Subsequently, pediatricians make definitive diagnoses of genetic disorders. Radiologists then identify imaging abnormalities based on imaging data. Finally, geneticists should possess the ability to assess the pathogenicity of rare genetic variants. To date, Shanghai Children’s Medical Center has diagnosed and treated more than 10,000 cases of genetic disorders, covering over 400 types of genetic diseases, among which at least 50 are rare genetic diseases reported for the first time in China.
Professor Rao Li from West China Hospital presented the standardized workflow of the hospital’s Rare Disease Clinic at the forum. These standardized and scalable processes have enabled West China Hospital to achieve significant success in implementing multidisciplinary teams (MDTs) for various rare diseases. To date, the hospital has conducted 500 rare disease MDT cases, covering more than ten specialized areas, including amyloidosis, hypertrophic cardiomyopathy, pituitary tumors (such as acromegaly and Cushing’s disease), and other rare conditions.
In the field of diagnosis and treatment of rare diseases, the government has successively introduced relevant policies since 2018. In May 2018, five national ministries and commissions jointly released the First Batch of Rare Diseases Catalog, which covers a total of 121 rare diseases. In February 2019, the National Health Commission announced the establishment of a National Collaborative Network for the Diagnosis and Treatment of Rare Diseases to strengthen the management of rare diseases across China and improve diagnostic and therapeutic standards. On March 1, 2019, China implemented preferential value-added tax (VAT) policies for the first batch of 21 rare disease drugs and four active pharmaceutical ingredients (APIs). Referencing the policy for anticancer drugs, VAT on imports was reduced to 3%, while domestic sales could opt for a simplified VAT calculation method at a rate of 3%.
Zhu Kun from the Social Development Research Center of the Chinese Academy of Fiscal Sciences shared his insights on improving the safeguard mechanism for rare diseases: “First, establish a registration system based on the definition and catalog of rare diseases. Second, use the establishment of a multi-party cost-sharing mechanism as a breakthrough to gradually improve the drug supply guarantee mechanism and diagnosis and treatment guarantee mechanism. In addition, it is necessary to strengthen legal research and promote the inclusion of rare disease safeguards into the legal framework. Finally, the safeguard mechanism for rare diseases requires joint efforts from the government, enterprises, and society.”