Restricted access to treatment is one of the three most common challenges posed on patients with rare diseases. Even if they can be diagnosed, most patients still have difficulty in the accessibility and affordability of medicines. Fortunately, progress has been made on this front. Over the past few years, with the efforts of government, hospitals, enterprises and social organizations, more than 70 drugs for rare diseases have been launched in China by the end of 2021, over 40 of which have been incorporated in the National Reimbursement Drug List, reflecting the government's philosophy of putting people and lives first. As a pioneer in rare diseases diagnosis and treatment, PUMCH has made its contribution to the establishment of the national supply guarantee system for orphan drugs by strengthening the pharmacological management, expanding the access, and promoting the research and development of orphan drugs.
Strengthen the Pharmacological Management for Rare Diseases
Due to a small patient population and a drug development process characterized by great difficulty, heavy investment and long time-to-market, large-scale clinical trial for rare disease has become a huge challenge, posing an enormous barrier to the full evaluation of drug efficacy before marketing. "With relentless efforts in enhancing pharmacological management, PUMCH has established a quality control system for pharmacy services in alignment with our high standards to promote the improvement of rational use of orphan drugs." Zhang Bo, Director of Department of Pharmacy said.
Mitotane tablets have been approved for the treatment of adrenocortical carcinoma (ACC) in Europe and the United States but have not been marketed in China. To address the needs of Chinese patients, a team headed by President Zhang Shuyang filed an application to the authority in March 2019 for a lump-sum import of mitotane tablets after a thorough study of policies and purchase channels as well as preparation of declaration documents.
To ensure the rational use of mitotane tablets, a range of departments and offices joined forces and drafted more than ten documents, including the “Clinical Practice Guidelines”, “Administrative Measures”, and “Informed Consent for Drug Use” for the temporarily imported drug Mitotane, and established a multidisciplinary ACC treatment team. A broad spectrum of innovative pharmacy services has been offered based on the all-round management of personalized medicine and the standard of care on various dimensions, such as the formulation of treatment plans, clinical effectiveness assessment, drug interactions, adverse reaction monitoring, plasma concentration monitoring and result interpretation.
Recently, the “Expert Consensus on Mitotane for Adrenocortical Carcinoma Treatment (2021)”, which was developed by experts from the MDT team of PUMCH based on evidence-based and empirical research, was ranked the top 5% of high-quality consensus in STAR 2021 China Guidelines/Consensus Rating. It is the first pharmacology-related expert consensus on mitotane for ACC treatment in the international community, providing a reference for promoting the standard and rational use of mitotane for ACC as well as clinical practice.
To promote precision and safety of medication for rare diseases, the hospital has established a dedicated platform and conducted studies on plasma concentration and other related topics. During the clinical practice, the rare disease team found that mitotane has a narrow therapeutic range and high inter-individual pharmacokinetic variability, but limited evidence concerning affecting factors in large inter-individual variability of the pharmacokinetics of mitotane is available. To address this question, an analysis was conducted by the clinical team of the Rare Diseases Collaborative Group at PUMCH consisting of departments such as pharmacy, endocrinology, and urology departments to study the factors affecting blood mitotane concentrations in Chinese patients with ACC, with a focus on the role of mitotane metabolizing enzyme genotype polymorphisms. The results of the study, recently published in “Frontiers in Oncology”, indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in patients, with wild-type patients at high risk to be below the therapeutic range of mitotane when treated with conventional drug doses. This study marks another important achievement of the multidisciplinary collaboration in rare diseases at PUMCH, providing a reference for further guiding the rational clinical application of mitotane.
The Department of Pharmacy has also developed management documents including medication risk management plans and is strictly implementing rational medication use in line with patient lists and physician prescription qualifications. Meanwhile, pharmacists are urged to fully inform patients about drug use, take the initiative to monitor medication use and conduct patient education. With breakthroughs made in the temporary import declaration, introduction, and clinical use of rare disease drugs, PUMCH has gained valuable experience along the way.
Explore the Accessibility of Orphan Drugs
The low accessibility of orphan drugs is one of the key limits on the clinical treatment of rare diseases. Although 86 out of the 121 rare diseases identified by the “First Catalogue of Rare Diseases” have therapeutic medicines by the end of 2021, 9 of them still have no drugs available in China. To overcome this challenge, PUMCH, supported by the National Health Commission, National Medical Products Administration, and other relevant regulators, is exploring new models such as lump-sum import of rare disease medicines, expand the compassionate use of clinical trial drugs, and set up green channels for urgently needed drugs, opening doors to hope for patients.
In 2019, the hospital completed China’s first intrathecal injection of nusinersen administration for adult SMA patients, after removing the barriers on the pathway for the lump-sum import of mitotane, an urgently needed orphan drug. On April 21, 2022, with the concerted efforts of the People's Hospital of Tibet Autonomous Region (TAR) and PUMCH, Mr. Sang, an adult Tibetan patient suffering from SMA, became the first person in Tibet who received the intrathecal injection of nusinersen administration.
Over the years, PUMCH has stayed committed to pooling the efforts to continuously improve the accessibility of medication and address the challenges that patients with rare diseases face. For instance, after the approval of vyndaqel capsules for the treatment of transthyretin cardiac amyloidosis (ATTR-CA), the first prescription for a wild-type ATTR-CA patient in China was issued at PUMCH. Aldurazyme, a drug for mucopolysaccharidoses, was quickly put into clinical use through the DTP pharmacy (pharmacy that provides more valuable professional services directly to patients). The first clinical use of Icatibant at PUMCH opened a new era in the treatment of hereditary angioedema in China. The first national prescription of the innovative rare disease drug Crysvita at PUMCH filled the gap in the clinical treatment of X-linked hypophosphatemia (XLH) in China; The new phase III clinical drug iptacopan solved the dilemma of abrupt discontinuation for patients with paroxysmal nocturnal hemoglobinuria by expanding compassionate use of clinical trial drugs. Clobazam, a drug for rare epilepsy, was also prescribed for the first time at PUMCH.
As a patient living with scleroderma, a.k.a. systemic sclerosis, a rare autoimmune disease, Xiaohe is taking on hospital-made drugs. When patients like him were facing a major disruption in medication access due to travel restrictions in Beijing caused by the pandemic, PUMCH and the China Alliance of Rare Diseases co-launched a green corridor for scleroderma patients in urgent need of medication, which allows patients to make appointments online and after their medical records and medication needs are verified, volunteers will collect and mail the medicines for them. This practice has been deeply appreciated by many patients because “this has really helped them out during the pandemic”.
President Zhang Shuyang said, "the mission of a doctor is to save lives. In this 'ice-breaking journey' of rare disease medication, there are many innovative mechanisms and pathways that can serve as a role model so that patients in a similar place will benefit. This has not only demonstrated that PUMCH ‘puts people at the center and makes utmost effort for patients' with the care and support of all sections of society; it is also a testament of the superiority of the socialist system under the leadership of the CPC."
Advance the Development of Rare Disease Medicine
Since the development of rare disease medicine is still in its infancy in China, there is a huge gap in clinical trials. Over the past nine years, the number of clinical trials of rare disease drugs registered on the website of the NMPA remained at a low level.
"Clinical trials on rare disease drugs are completely different from those for conventional drugs. There is also a glaring disparity in the requirements on the clinical trial design because the former is much more challenging." Said Han Xiaohong, director of the Clinical Pharmacology Research Center. To overcome the dilemma of insufficient orphan drugs, the hospital adopts a two-fold approach: first, developing innovative drugs for rare diseases; second, discovering the new mechanisms of existing drugs and assessing their suitability for treating rare diseases by leveraging the advantages of PUMCH as a clinical institution.
The benefits of orphan drugs are not just limited to rare diseases; they can be extended towards common illnesses. The study of rare diseases can also lead to a deeper understanding of common diseases among doctors. For example, drugs developed to treat familial hypercholesterolemia are now widely used for patients with coronary atherosclerotic heart disease," said Professor Tian Zhuang of the Department of Cardiology, "the pathogenesis of rare diseases is more homogeneous than that of common diseases, so drugs developed for rare diseases are more purpose-made. The pathogenesis of common diseases is complex, but there may be some similarities with those of rare diseases. That’s why some of the rare disease drugs can also be used to treat common diseases.”
Glycogen storage disease is a spectrum of glucose metabolism disorders caused by genetic defects, which may cause liver and kidney failure, or even life-threatening conditions. In the 1980s, the Department of Pediatrics of PUMCH introduced uncooked corn starch therapy, which slowed down the disease progress, but the starch must be taken with cold water, four times a day, which means patients need to get up in the middle of the night. Moreover, the dosage is excessively high and requires lifetime use. In 2006, Researcher Wang Wei began to review literature and seek solutions, and in 2015, she met Professor Qian Feng of School of Pharmaceutical Sciences at Tsinghua University at an academic salon organized by the hospital. Through cooperation with enterprises, her invention is expected to become the world's first orphan drug that can maintain stable blood sugar in glycogen patients.
The past few years have witnessed the fast growth of the supply guarantee system for orphan drugs thanks to the care of the government and society for rare diseases. Dozens of rare disease drugs have been included in the National Reimbursement Drug List. Fast-track review and approval are provided for novel, innovative and modified new drugs marketed overseas that are urgently needed in clinical practice. The NMPA has also released the “Technical Guidelines for Clinical Development of Rare Disease Medicines” on January 6, 2022. These actions speak volumes about how the government care for every vulnerable group, leaving no one behind and giving up on no one, as the guardian of families affected by rare diseases.
China's first compassionate use of orphan drug was carried out at PUMCH
Written by: Hong Chengwei and Chen Mingyan
Picture courtesy: Sun Liang
Translator: Liu Haiyan
Editor: Wang Yao