Source丨21New Health21 original work
Author/Wu Yinggang
Editor/Xu Xu
Image/Figureworm
Recently, thanks to the national "first mover and first pilot" concession policy, fludrocortisone acetate tablets landed in Ruijin Hainan Hospital of Hainan Boao Lecheng International Medical Tourism Pilot Zone, and patients with rare diseases with 21-hydroxylase deficiency who have faced drug difficulties for many years have finally achieved access to medication.
According to Ruijin Hainan Hospital official micro introduction, 21-hydroxylase deficiency (OHD) is the most common type of congenital adrenal hyperplasia (CAH), most patients will occur in the neonatal period, mild symptoms are manifested as milk refusal, vomiting, diarrhea, fatigue, if not treated in time, there will be adrenal crisis, resulting in coma, and even death.
Relevant data show that 21-OHD accounts for 90%~95% of CAH patients, the internationally reported incidence rate is 1/10000~1/20000, and the domestic incidence rate is 1/16466~1/12200. Compared with other rare diseases, 21-OHD can be controlled and treated, and the lost glucocorticoids and mineralocorticoids can be supplemented by rational administration of hydrocortisone and fludrocortisone, respectively.
21st Century Business Herald learned that fludrocortisone is an important part of the treatment of 21-OHD combination drugs, unlike other expensive rare disease drugs, fludrocortisone has only a few thousand yuan per year to treat, and has been listed abroad as early as 1954, but this cheap drug has only entered China through the policy "green channel".
Cheap "blessings" and "curses"
Before fludrocortisone landed in Lecheng, domestic patients could only obtain drugs through daigou.
An industry veteran told the 21st Century Economic Herald that the price of fludrocortisone tablets is relatively low, about 1,000 yuan a bottle, some patients a year 2 ~ 3 bottles may be enough, currently in Japan, South Korea, Southeast Asia and other regions are in use, but has not entered China, domestic has not yet been approved for marketing.
It is understood that fludrocortisone acetate tablets were first marketed in Canada in 1954 and have been approved for marketing in 33 countries and regions around the world, which is a variety of the WHO Essential Medicines List in 2019. But why is this drug not yet available in China?
The above-mentioned industry veterans said that mainly because the number of rare disease patients is small, if the price of drugs is too cheap, the profit margin may be insufficient for pharmaceutical companies, and accessibility will decline. "If a rare disease drug costs 1.5 million yuan a year, as long as there are 10 patients, the annual revenue of pharmaceutical companies can reach 15 million, but low-cost drugs will not." In addition, after low-cost drugs enter the country, they may also face competition from generic drugs in the future, and the income of pharmaceutical companies will be further reduced. ”
A few years ago, a survey of the clinical use of 42 hospitals in 12 cities in China showed that the shortage of cheap drugs in hospitals was as high as 342 varieties, and 131 of them were in a long-term out-of-stock state, most of which were cheap life-saving drugs, such as protamine necessary for heart surgery, tabazole (methimazole) for the treatment of hyperthyroidism, anti-cancer drug cyclophosphamide, anti-heart failure drug cediran, etc.
According to the analysis of relevant researchers from the School of Pharmacy of Tongji Medical College of Huazhong University of Science and Technology, the reasons behind the shortage include rising raw materials and production costs, resulting in the supply of some cheap life-saving drugs.
But the reasons for the shortage of cheap drugs for rare diseases seem to be somewhat unique.
Feng Wenwen, a researcher at the Institute of Materia Medica, Peking Union Medical College of China, once said that as the only mineralocorticoid, fludrocortisone has a wide range of potential uses, and is expected to reach between 50 million and 100 million yuan in the domestic market after marketing.
However, the above-mentioned industry veterans said that due to the lack of understanding of the Chinese market, some foreign rare disease companies may not consider entering the Chinese market, 21-OHD patients are expected to have 7~90,000 people in China, many patients with weight gain, the amount of drugs may also increase, so in fact, sales are not small.
According to analysis, internationally, some pharmaceutical companies' rare disease drugs have rarely considered entering China after the patent period, which may be considered that Chinese patients are few and have insufficient purchasing power, and part of the reason is that these companies have occupied most of their energy to serve the European and American markets and lack motivation to expand unknown markets. Behind these problems is actually related to the lack of flow survey data for rare diseases in China, which is very important for pharmaceutical companies to understand the Chinese market, and at present, many rare diseases in China can only estimate the number of patients, which will inevitably have deviations and do not have the accuracy of official statistics.
Wu Kun, head of rare diseases of Pansy, told the 21st Century Business Herald: "Since 2020, we have begun to unite with all parties to promote the landing of fludrocortisone in Lecheng, and in the process we are very strongly aware that the lack of natural medical history and relevant flow regulation data in the field of rare diseases makes it difficult for pharmaceutical companies to clearly understand the reality of the disease in the mainland, which is an important constraint for foreign marketed drugs to enter the Chinese market." ”
According to relevant studies, the epidemiological investigation of common diseases in mainland China is relatively perfect, but the epidemiological data of rare diseases are very lacking. At present, most of the rare disease databases and epidemiological data referenced in China are derived from Western developed countries, but due to differences in national conditions, ethnicity and disease spectrum, it is difficult to completely copy and reference. The long-term existence of the problem of uncountable and unclear patients with rare diseases will affect the in-depth understanding of this group from all walks of life, and also affect the enthusiasm, timeliness and accuracy of policy formulation.
There are many reasons behind this problem, including the vast territory of the continent and the large differences in economic level, medical resources and policy base between regions. There are many types of rare diseases, and the number of patients with single diseases is very small, and the distribution is scattered; Conventional field investigation methods are not suitable for rare diseases, and epidemiological analysis methods for rare diseases are lacking.
From foreign experience, many countries have collected rare disease research and nursing data in the form of rare disease registration. The Medical Information Research Center of Shandong Institute of Medical and Health Science and Technology Information has combed that several rare disease registration agencies have been established in the UK to carry out rare disease registration and patient data collection; Germany has proposed to establish a national rare disease registry and provide an information portal on rare diseases; France proposed to use the construction of a national rare disease database to carry out a national registration of patients who cannot be diagnosed; Australia has proposed a coordinated and cooperative approach to data collection to facilitate surveillance of rare diseases and accumulate knowledge.
Medication dilemma in children
In addition to fludrocortisone, hydrocortisone, another drug used to treat 21-OHD, is also worth paying attention to.
The above senior people introduced, hydrocortisone is also an important component of the combination of drugs, belongs to glucocorticoids, the main problem of domestic hydrocortisone is the lack of children's dosage form specifications, mostly 20 mg / tablet, but children generally need 5 mg, so parents will divide the drug into 4 tablets, each tablet 5mg, need to be particularly careful.
According to Caixin, hydrocortisone is insoluble in water and needs to be taken in multiple doses, and parents need to rack their brains with small pills, such as grinding the medicine into powder or smashing the medicine into a noodle shape, mixing it in water, shaking it well and taking it in milliliters, but even so, the amount of medicine is still difficult to accurately control.
Luo Feihong, chief physician of the Department of Endocrinology and Metabolism of the Children's Hospital of Fudan University, once said that hydrocortisone can not achieve the effect of eating less, and eating more is prone to side effects and inhibiting children's bone growth. Moreover, overdose of hormonal drugs may lead to obesity, so patients often need to purchase overseas 10mg, 5mg and other specifications of hydrocortisone tablets through various channels.
It is understood that in addition to 5mg, smaller products have also been listed abroad. In September 2020, the FDA approved Eton Pharmaceuticals' hydrocortisone oral granules, which are available in 4 strengths: 0.5mg, 1mg, 2mg, and 5mg, enabling clinicians to administer it individually according to the needs of patients.
In fact, not only hydrocortisone, dosage form has always been a dilemma faced by domestic children's drugs.
Relevant researchers of the Health Development Research Center of the National Health Commission have released an article analyzing that among the more than 3,500 kinds of chemical preparations approved by the State Food and Drug Administration, only more than 60 kinds are exclusively for children, accounting for less than 2%, and the dosage forms and specifications for children in the mainland are small, and the survey report shows that 90% of the clinical basic drugs in the mainland do not have special dosage forms for children, more than 95% do not have safe packaging for children's medication, are not equipped with special measuring instruments, and the phenomenon of "medication by breaking, dose by guessing" is very common.
The difficulty of research and development and low product profits may be important reasons for the lack of motivation of pharmaceutical companies. The person in charge of a company that has been focusing on children's drugs for a long time once said that the production process of children's drugs is often more demanding, and the specifications are small and the process is complex, and most of them need to add flavor correctors, and the cost is relatively higher. In addition, common diseases in children are seasonal, and at low incidence, production lines are idle and amortization costs increase; Since the number of children is not as good as that of adults, the age group and special dosage forms and specifications further lead to market refinement, and the market size is limited. Therefore, improving the return on investment of enterprises is the key to stimulating enterprises to improve the motivation of children's drug research and development.
In this regard, in May 2022, the General Department of the State Food and Drug Administration publicly solicited the Regulations for the Implementation of the Drug Administration Law of the People's Republic of China (Revised Draft for Comments) (hereinafter referred to as the "Draft for Comments"), encouraging innovation in the research and development of children's drugs, and clearly proposing that for the first approved new varieties, dosage forms and specifications for children, as well as increasing the indications or dosage of children, a market exclusivity period of up to 12 months will be given, during which the same varieties will not be approved for marketing.
The Draft also encourages R&D and innovation in the use of drugs for rare diseases, and clearly states that new drugs for rare diseases approved for marketing will be granted a market exclusivity period of up to 7 years under certain circumstances, during which the same varieties will not be approved for marketing.
In addition to the encouragement of market exclusivity, the "Pediatric Orphan Drug Priority Review Voucher (PRV) Program" in the United States may also be worth learning.
In 2012, the PRV program was created to incentivize rare disease drug development, and holders of the voucher can use it for marketing applications for any of the company's other drugs, requiring priority review from the FDA. In addition, the holder of the voucher can also transfer or sell the voucher to other pharmaceutical companies. Statistics show that as of April 30, 2018, the FDA has issued a total of 19 priority review coupons, of which 14 are granted to rare pediatric disease products.
Allowing the transfer and sale of this coupon may significantly increase the enthusiasm of enterprises to develop rare disease drugs.
In August and September 2022, two rare disease gene therapies from Bluebird Bio were approved by the FDA for marketing, each receiving a PRV. In November 2022 and January 2023, Bluebird Biotech cashed out for $102 million and $95 million, respectively, selling PRV to Dutch immunology company argenx and multinational giant BMS.
However, in December 2020, the United States reportedly decided to stop the PRV program after September 30, 2026.