Enlightenment of COVID-19 Treated by Botanical Drugs on the Development of Drugs for Rare Diseases in China

Li Qiao,Wang SuWang AiliWu DiChen Yuwen

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 10016,China;2.Affiliated Hospital of Liaoning University of Traditional Chinese Medicine,Shenyang 110032,China)

Abstract Objective To study the feasibility of developing botanical drugs to treat intractable diseases and play an important role in dealing with major public health crises.Methods From January 1990 to May 2021,a bibliographic search was carried out on the use of botanical drugs,rare disease drugs,related registration management policies and regulations in PubMed and CNKI.The following keywords were searched in the database: Rare disease policies and regulations,orphan drugs,botanical drugs for intractable diseases,botanical drugs for the treatment of new coronary pneumonia,traditional Chinese medicine,and emergency guidelines for major public health crisis.Other data were obtained from “Chinese Pharmacopoeia” and relevant Chinese government websites for sorting and analysis.Results and Conclusion Based on 39 Chinese corresponding policies and regulations,challenges and opportunities of developing and researching drugs for treating rare diseases were found out after the analysis and comparison.Based on the study of national policies on drugs for rare diseases,the priority review and approval procedures in the drug registration,as well as China’s emergency guidelines and policies for major public health events,some problems in the use of drugs for rare diseases are found out.Therefore,it is recommended to actively adopt the property rights protection system,explore the folk prescriptions of traditional Chinese medicine and the potential of hospital preparations,and the registration review strategy of giving priority to the use of botanical drugs for rare diseases.Thus,the international status of botanical drugs for rare disease and the influence of responding to major public health events can be enhanced.

Keywords: COVID-19;botanical drug;intractable disease;rare disease;public health event

1 Introduction

The botanical drugs played an important role in the fight against novel coronavirus pneumonia(COVID-19) of this major public health event.As an intractable disease,COVID-19 is in the category of febrile disease in the theory of Chinese medicine.It is an rare infectious disease encountered by humans in the category of epidemics and traditional Chinese medicine.There are many similarities and differences between traditional Chinese medicines for intractable diseases and rare disease drugs (orphan drugs) in European countries and the United States.Firstly,both have the characteristic of a single and individualized treatment plan.Secondly,rare diseases are only defined by the prevalence rate,while traditional botanical drugs for intractable diseases are based on the difficulty of diagnosis and treatment theories and methods.Based on the research on China’s rare disease drugs,the priority review and approval procedures in the drug registration,and emergency guidelines and policies on major public health events,some problems in the use of rare disease drugs are sorted out.Then,some recommendations are made such as actively adopting the property rights protection system,exploring the folk prescriptions of traditional Chinese medicine and the potential of hospital preparations,and the strategy of giving priority of registration approval to promote the international status of traditional botanical drugs and the infiuence of responding to major public health events.

1.1 COVID-19 belongs to the category of intractable diseases in traditional Chinese medicine

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2)infection.On March 11,2020,the World Health Organization (WHO) announced that COVID-19 caused a global pandemic.As of May 22,2021,COVID-19 had spread to more than 200 countries and regions around the world.The number of confirmed infections worldwide has exceeded 23.14 million,of which 3.45 million lost their lives[1].At the end of December 2019,a new type of coronavirus pneumonia broke out in Wuhan,China.Under the strong leadership of the Chinese government and the efforts of medical staff,the situation of the novel corona virus has been effectively controlled.In the treatment of new coronary pneumonia,traditional Chinese medicine has played a huge role.The research and development of Anisodamine is a good example[2].However,as to the whole world,the pandemic situation is still not optimistic.The research and development of related traditional Chinese medicine for the new coronavirus pneumonia has broad prospects in the future,which will bring new changes to modern medical theories.

At the same time,it is extremely necessary for China’s regulatory authorities to have an effective mechanism to support drug development,review,use and supply under emergency situations to solve urgent clinical needs and curb the pandemic.Before the developing the highly accessible and safe antiviral chemicals,traditional Chinese medicine has played a nationally recognized safe and effective role in the treatment of COVID-19.There is no doubt that coronavirus pneumonia can be recognized as a difficult and complicated disease in the traditional Chinese medicine system.As to difficult and miscellaneous diseases,there is a medical term rare diseases in western countries.The drugs used to treat rare diseases are called orphan drugs abroad.There are similarities and differences between drugs for intractable diseases in traditional Chinese medicine and drugs for rare diseases (orphan drugs) in Europe and the United States.Both have the characteristic of single treatment plan with personalized medicine,and the number of patients is small.Rare diseases are only defined by the prevalence rate.Traditional Chinese medicines for intractable diseases are based on the difficulty of the theory and methods of diagnosis and treatment.

1.2 Introduction of rare disease

Rare diseases,also known as orphan diseases,refer to diseases with a low incidence and a relatively small number of patients.And orphan drugs are drugs used to treat,diagnose,and prevent rare diseases or symptoms.The WHO defines a rare disease as a disease in which the number of patients is 0.65% to 0.1% of the total population.But not all countries and regions strictly follow this definition.The definition of rare diseases in some countries will vary according to the country’s total population and incidence[3].According to a report by the US FDA at the “World Rare Disease Day Conference” in 2011,there are more than 250 million people with rare diseases worldwide,and more than 7 000 rare diseases have been discovered.About 80% of them are genetic diseases,and more than 50% affect children[4].Unfortunately,there are only a few rare diseases that can be treated with medicines,and they are very expensive.The media also reported that an injection for a rare disease is 700 000 yuan,an infusion is 7 000 yuan[5],which is unbearable for most patients.

Since 1980,the development of orphan drugs has attracted widespread attention from the public.Many countries and regions have successively established relevant institutions and formulated special laws and regulations to promote the development of orphan drugs.The core is about establishing a good system of orphan drugs[6].For example,as early as 1983,the United States took the lead in legislating drugs for rare diseases.Later,Japan,the European Union and some other countries and regions also issued relevant policies and regulations on the use of rare disease drugs to encourage companies to develop orphan drugs[7].Since rare diseases have caused a heavy burden on patients,it is one of the areas that modern medicine needs to focus on[8].At present,rare diseases are mainly divided into the following 10 categories:(1) Metabolic diseases;(2) Digestive system diseases;(3) Urogenital system diseases;(4) Malignant tumors;(5) Musculoskeletal diseases;(6) Nervous system diseases;(7) Endocrine system diseases;(8) Blood and hematopoietic system diseases;(9) Cardiovascular system diseases;(10) AIDS and related diseases[9].

2 Policies and regulations related to rare diseases in China

2.1 Collection of policies and regulations related to rare diseases in China

A comprehensive collection of China’s national policies in the field of rare diseases is carried out in this research.The policy texts are derived from the National Health Commission,the National Medical Products Administration (NMPA),the State Council,and other government official websites.Besides,it is supplemented by the CNKI government document database.The collection time is from January 1st,1999 to January 1st,2021.A total of 39 documents related to the policy text are collected (Table 1).

The time span of policy publications related to rare diseases at the national level in China is between 2007 and 2020,and the publication of policy documents is concentrated after 2017,accounting for 69% of the total number of publications.There are a few special rare disease policies in China.Prior to 2018,issues such as the use of drugs for rare diseases are only individually mentioned in relevant medical policy documents.As early as 1999,rare diseases and orphan drugs are mentioned in China’s“Provisions for Drug Registration”,but they have not yet been clearly defined by law.With the continuous improvement of medical standards and improvement of laws and regulations,China has also obtained some developments in the research and policy legislation of rare diseases and orphan drugs.In September 2016,the Chinese Organization for Rare Disorders (CORD)published the “China Rare Disease Reference List”,which included a total of 147 types of diseases,and launched the domestic rare disease patient registration project.In October 2017,the General Office of the Central Committee of the Communist Party of China and the General Office of the State Council issued the“Opinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices”,proposing to support the research and development of drugs for the treatment of rare diseases (orphan drugs) and medical devices,allowing applicants to reduce the number of clinical trials or exempt from clinical trials for the registration of rare disease drugs and medical devices,and rare disease drugs and medical devices that have been approved for marketing overseas can be approved for listing in China with conditions.The “National Key Research and Development Program” of the Ministry of Science and Technology of the Thirteenth Five-Year Plan has successively carried out scientific research projects such as “Clinical Cohort Study of Rare Diseases” and “Research on Precision Diagnosis and Treatment Technology and Clinical Norms of Rare Diseases in China”.Then,the first nationwide rare disease registration study was launched.In May 2018,the “First List of Rare Diseases” jointly formulated by five ministries and commissions including the National Health Commission was officially released,containing a total of 121 rare diseases.Although the types of diseases listed in this catalog are limited,the definition of rare diseases that are not included still needs to refer to the standards of other developed countries.However,its introduction is still for the screening,diagnosis and prevention of rare diseases,as well as the research and development of related orphan drug,which provides reference for the formulation of social security,medical assistance and other policies.

2.2 Specific regulations on priority review

In the “Provisions for Drug Registration”(issued by Order No.27 of the State Administration for Market Regulation on January 22,2020),the characteristics of the drugs that meet the priority review and approval procedures are described.The NMPA established the registration system for drugs to accelerate and prioritize the listing.For clinically needed drugs,innovative drugs,improved new drugs for the prevention and treatment of major infectious diseases and rare diseases,and new varieties of drugs for children can be subject to priority review and approval or special approval procedure.Drug supervision and administration department and its professional technical institutions will also provide necessary policy and technical support.

Regarding orphan drugs,in recent years,relevant pharmaceutical departments have successively introduced some policies to encourage drug companies to develop and produce orphan drugs.Among them,the “Provisions for Drug Registration” stipulated that the NMPA could implement special approval for new drugs for rare diseases with obvious clinical advantages.Orphan drugs can apply for exemption from clinical trials when applying for clinical trials.The “Opinions on Deepening the Reform of Drug Review and Approval to Further Encourage Drug Innovation and the Announcement on Several Policies for Drug Registration Review and Approval”issued by NMPA also include priority approval for orphan drugs.The “Regulations on the Management of Special Approval for New Drug Registration”stipulates that the registration application of orphan drugs will be included in special approval,and they can enjoy special approval policies,such as having a separate channel for priority review and approval when applying for registration.The State Council’s“Twelfth Five-Year Plan for Drug Safety” also encourage the development of drugs for rare diseases and suitable formulations for children.In addition,in December 2015,the National Health and Family Planning Commission established the “National Expert Committee for the Diagnosis,Treatment and Guarantee of Rare Diseases” which could provide opinions and suggestions for the diagnosis and treatment of rare diseases.

2.3 Special approval procedures for responding to public health emergencies

The “Provisions for Drug Registration” stipulates that for drug registration applications subject to special approval,the NMPA will organize the accelerated and simultaneous implementation of drug registration acceptance and review in accordance with the principles of unified command,early intervention,rapid,efficient and scientific approval.

2.4 The Central Committee of the Communist Party of China’s emergency guidelines and policies on major public health emergencies

At present,the novel coronavirus pneumonia has appeared in many countries,and the Central Committee of the Communist Party of China and the State Council attach great importance to it.On March 2,2020,Xi Jinping,General Secretary of the Central Committee of the Communist Party of China,President of the State,and Chairman of the Central Military Commission emphasized that it is the top priority to do our best to save more patients’ lives.It is necessary to strengthen the combination of drug and medical equipment research and development and clinical treatment.Besides,we should speed up the process of drug research and development and adhere to the combination of traditional Chinese and western medicine to explore new treatment methods.Xi Jinping pointed out that with the emergence of the novel coronavirus pneumonia,China should strengthen communication with the World Health Organization so as to contribute to the construction of a community with a shared future for mankind.

3 Summary and challenges

3.1 Status quo of rare diseases in China and the challenges in the treatment

3.1.1 Status quo of rare diseases

Although there is no official definition of rare diseases in China,the Medical Genetics Branch of the Chinese Medical Association reached a definition of rare diseases when organizing experts’ seminar.Diseases with the prevalence rate of less than one in half a million,or the neonatal incidence rate of less than ten thousand can be called rare diseases.According to this definition,the number of patients with rare diseases in China is as high as 16.8 million.75% of rare diseases involve children,and 30% of those with rare diseases die before the age of 5.In China,most rare diseases have no cure,and a few rare diseases that can be treated are expensive,which brings a huge burden to the families of patients.

The development of orphan drugs in China is still in its infancy,and the vast majority of rare disease drugs has to be dependent on imports.Because of the limited clinical dosage and small market,domestic pharmaceutical companies major multination are reluctant to develop and produce orphan drugs.Drugs for rare diseases are also vividly called“orphan drugs”.In the past 10 years,the research and development of orphan drugs became a key area of major multinational pharmaceutical companies.Domestic pharmaceutical companies start to focus on the research and development of rare disease diagnosis and orphan drugs,but the number is small.The factors associated with rare diseases that need to be considered during the research and development of drugs are many,including diseases,drug development,market prices,government support policies,etc.,which has to be taken into consideration.The living conditions of patients with rare diseases in China are worse than that of developed countries.Although China has regulations on special approval for new drug registration,it lacks corresponding implementation rules.For many years,domestic pharmaceutical companies have no motivation in the research and development of orphan drugs.In addition,if one company wants to make a difference in gene therapy of rare diseases,it must have a research institution.Currently,there are few research institutions carrying out related work.Secondly,research institutes in college and universities receive little support of major national funds in rare disease treatment.

In addition,there is a large gap in economic development and medical standards in various regions of China,and the epidemiological foundation is weak.Due to the late development of research on rare diseases and the lack of information dissemination platforms,China’s government is unable to timely and effectively prevent and find rare genetic diseases through genetic examination,prenatal screening,and newborn screening in all regions of the country.Therefore,once discovered in the later period,rare diseases will cause a huge economic burden to the patient’s family.

3.1.2 Challenges in the treatment of rare diseases

There are more than 7 000 rare diseases in the world,80% of which are genetic diseases,such as albinism and hemophilia,and 95% of rare diseases still have no specific medicine.

The availability of rare disease drugs in China is poor.In 2018,121 diseases were included in the “First List of Rare Diseases” issued by China.According to the relevant catalogs,it can be seen that only 55 drugs are clearly registered for rare disease indications in China,involving 21 rare diseases,such as pulmonary arteries.hypertension,hemophilia,multiple sclerosis,gaucher disease,pulmonary cystic fibrosis,genetics bullous epidermochasis,sitosterolemia,myasthenia gravis,tuberous sclerosis,congenital suprarenal sexual dysplasia,paroxysmal nocturnal hemoglobinuria,systemic sclerosis,amyotrophic lateral sclerosis,phenylketonuria,retinoblast membrane,Parkinson’s disease (youth type,early onset),Leber genetic optic neuropathy,adult Osteopathy,idiopathic hypogonadotropic hypogonadism,lyron’s syndrome,and myotonic dystrophy.Among these 55 kinds of drugs,only 29 are included in the national basic medical insurance,work-related injury insurance and maternity insurance.

There are still many difficulties in the treatment of rare diseases.For instance,the rare disease is difficult to diagnose,and there is no medicine after the diagnosis of the disease.Besides,some drugs are not listed in China’s market or there is no indication for rare diseases.In addition,some drugs are already on the market but their prices are high,and these drugs are not covered by medical insurance.The inaccessibility and unaffordability of rare disease drugs is the biggest problems for patients.More than half of the patients fail to receive drug treatment in time.Hospital diagnosis and the quality of doctors and experts are important.Doctors have rich clinical experience,but when diagnosing rare diseases,they will have many difficulties.After all,in China,most patients are unable to afford the whole-genome sequencing.Since drugs for rare diseases are expensive,many families cannot afford them even if they are available.Poverty caused by illness is common in the past.The problem of poor access to drugs for patients with rare diseases requires medical coverage at the national level so that patients have a chance of treatment.

3.1.3 Thinking and strategy

Regarding challenges,they should be faced by the government and enterprises.First of all,the government can make good policies,which can help not only the patients but enterprises as well.Secondly,the government should reform the medical insurance payment system to control of drug prices.The policy supporting orphan drugs should also be implemented as early as possible.Companies should seize the opportunity and accelerate the development of project products for the patients with rare diseases.Regarding the cost-effectiveness of gene therapy,technology determines the quality of products.Therefore,the best viral vector system should be selected.In addition,the vertical integration of pharmaceutical companies to the downstream of the industrial chain is a stopgap measure.The binding and integration of pharmaceutical companies and hospitals is a general trend.Finally,it is also important to actively establish an industry patent pool.Increasing investment in original patented medicines,making good use of the intellectual property system,and forming strategic cooperation through industry alliances can build a larger industrial ecosystem.

In March 2020,the “Opinions of the Central Committee of the Communist Party of China” and“the State Council on Deepening the Reform of the Medical Security System” clearly stated that it is necessary to explore the protection mechanism for drugs for rare diseases,indicating that China took drug security for patients with rare diseases as an important reform goal.On September 29,2020,the Ministry of Science and Technology issued the“Notice on Approving the Construction of the State Key Laboratory of Rare Diseases”,stating that the key laboratory should be set up to strengthen the scientific research of rare diseases for people’s health.

In December 2020,the Customs Tariff Commission of the State Council issued an announcement that starting from January 1,2021,zero tariffs would be imposed on the second batch of anticancer drugs,raw materials for rare disease drugs,and food for some children patients.This measure could effectively reduce the R&D and production costs of rare disease drugs,promoting the development of the domestic rare disease-related pharmaceutical industry,broadening the domestic market,and reducing the economic burden of patients.

3.2 Challenges in the development of orphan drugs

Since most drugs for rare diseases in China are imported,the availability of orphan drugs is poor[10].Based on the characteristics of China’s population and region,joint efforts are required in multiple areas of rare disease research and prevention in the future.Firstly,research and development strategies should be formulated for orphan drugs.Then,international cooperation and exchanges should be encouraged.Traditional Chinese medicine should play a role in the field of rare diseases.The medical insurance screening system should be established for orphan drugs.Secondly,an epidemiological investigation of rare diseases must be carried out to combine prevention and screening.Then,the level of diagnosis and treatment improved.Thirdly,assistance and care for patients with rare diseases should be promoted.Besides,the coverage of rare diseases by medical insurance should be increased.The following recommendations are made.Firstly,policy design should strengthen the prevention and management of rare diseases,which can promote the development,marketing and use of rare disease drugs.Secondly,faced with the high price of orphan drugs,medical insurance,government pricing,social donations and corporate profits are needed to cut the price down.Moreover,the price of orphan drugs is high,which is difficult for ordinary patients to bear.There are two reasons for the high price of rare disease drugs: one is the high cost of research and development,and the other is the technological monopoly.Thirdly,we should apply traditional Chinese medicine to the treatment of rare diseases.When we attach importance to the role of traditional Chinese medicine theory in rare diseases,we can develop Chinese medicine preparations for rare diseases.Besides,we should increase the corresponding incentive mechanism to allow more capable pharmaceutical companies to carry out the research and development of new drugs,which can not only reduce the financial burden of patients,but also break through the international standardization of traditional Chinese medicine.

3.3 The concept of intractable diseases in traditional Chinese medicine

Traditional Chinese medicine is unique to China,which is also one of ethnic medicine with a long history.The intractable diseases are characterized by personalized diagnosis and treatment,and they are defined by the theory and difficulty of treatment.The study of intractable diseases was recorded in the“Huangdi Neijing” in ancient time[11].Suspicious syndrome refers to the syndrome of doubt[12],which means the cause,pathology,and diagnosis are unclear,and the medication is not effective.Difficult syndrome refers to the cause,pathology,and diagnosis are clear,but there is no corresponding treatment method and medicine.The miscellaneous syndromes include many symptomatic diseases,which may have one symptom,or a group of symptoms,but they lack obvious internal connections.

3.4 Similarities and differences between intractable diseases and rare diseases

The concept of intractable diseases is different from that of rare diseases.Rare disease patients are characterized by a small number of patients.Therefore,orphan drugs have the characteristics of low market demand,high cost for research and development costs,and high prices.Intractable diseases are defined by the degree of difficulty of treatment theory and methods[13].Although the concept of intractable diseases and rare diseases are different,they have similarities,such as unknown etiology,unclear pathogenesis,lack of treatment or inadequacy of drugs.However,the treatment schemes of the two are the same.Both of them are characterized by personalized medicine.Traditional Chinese medicines for intractable diseases generally use herbal medicines as therapeutic substances.Because the herbal medicines are relatively cheap,they increase the opportunity of treating these intractable diseases.

4 Discussion

4.1 Adopting incentive strategies to promote the development of traditional Chinese medicine

The materials used in traditional Chinese medicine to treat rare diseases are mainly derived from animals and plants.Therefore,the cost is much lower than the research and development costs of orphan drugs.The pricing policy of intractable drugs will affect the R&D efficiency of enterprises.The government can implement guiding policies such as designated procurement,capital investment,and tax incentives to increase the enthusiasm of domestic enterprises in R&D and production.The inclusion of medical insurance can not only increase the availability of drugs for rare diseases,but also increase the research and development power of traditional Chinese medicine companies.

4.2 Exploring domestic folk prescriptions as theoretical basis

Folk prescriptions are effective to prevent and treat diseases,which are the crystallization of folk medical practice experience[14].In the Eastern Jin Dynasty,the folk prescriptions and proven prescriptions were compiled into “Cuhou prescription” by Ge Hong[15].“Pujifang” of the Ming Dynasty is a famous prescription in Chinese history[16].Many prescriptions in this book are originated from the folk.Among them,the treatment of some intractable diseases is recorded,which can provide a basis for modern diagnosis and treatment.Therefore,the discovery of proven prescriptions for intractable diseases in traditional Chinese medicine will play an important role in the treatment of some rare diseases.

4.3 Adopting a registration review strategy of giving priority to curative effect

For some intractable drugs that have significant clinical effects,the government and relevant regulatory authorities can adopt a registration review strategy for them.In addition,including traditional drugs for intractable diseases with lower treatment costs into China’s medical insurance system can reduce medical insurance costs and effectively achieve the policy goals of China’s medical and health protection.

4.4 Giving full play to the role of hospital preparations

For special varieties such as rare disease drugs containing active ingredients that have not been approved by NMPA[17].For example,those that have been approved for marketing in developed countries like European Union,the United States,and Japan can be allowed to declare hospital preparations and be exempted from clinical trials[18].Special traditional Chinese medicines that are urgently needed and have clinical advantages but are not suitable for mass production as marketed drugs can be declared as hospital preparations.They can play an effective and convenient role in the treatment of rare diseases.

In short,traditional Chinese medicine is an important part in China’s medical system.Adopting the drug policy for rare diseases to encourage the development of traditional Chinese medicine for intractable diseases is conducive to enhancing the position of traditional Chinese medicine in the international drug market.