What Is an Orphan Drug?

"Orphan drugs" are also called rare drugs. They are used to prevent, treat and diagnose rare diseases. Due to the small population of rare patients, low market demand, and high R & D costs, few pharmaceutical companies pay attention to the development of their therapeutic drugs. These drugs are therefore known as "orphan drugs". At present, the research and development of "orphan drugs" in China is still blank. The treatment of patients with rare diseases basically depends on foreign imports. As a result, many patients with rare diseases can only choose expensive imported drugs or no drugs are available.

Drug Name: Orphan drug

Alias: Rare medicine
Foreign name: Orphan drug

Orphan Drug Related Concepts

1.Orphan drugs

Due to the cost of drug development, the cost of research on rare diseases is too high, and the market demand is too small. Under normal circumstances, it is difficult to recover the cost of drug development. Therefore, no company is willing to develop and produce drugs for rare diseases, resulting in scarcity of drug types. It is expensive and the treatment for rare diseases is also known as Orphan drug. ^[1]

Rare diseases

According to the definition given by the World Health Organization (WHO), rare diseases refer to diseases with 0.65 -1 of the total population. Leukemia, hemophilia, phenylketonuria, albinism, and osteogenesis imperfecta are common. Disease, Gaucher disease, etc. Although there are some differences in the criteria for identifying rare diseases in different countries, and there is no clear definition in China, there are already nearly 7,000 rare diseases diagnosed in the world, and 80% of them are genetic diseases. ^[1]

3. The folk edition of China's Reference List of Rare Diseases

On September 23, 2016, at the Fifth China Rare Disease Summit Forum co-sponsored by the Rare Disease Development Center and Shulan Medical, a private edition of the China Rare Disease Reference List was released, defining a total of 147 rare diseases.

Huang Rufang, director of the Center for Rare Diseases Development, said: "There is no official definition of rare diseases in China so far, and the list released this time is a" civilian version ", hoping to provide reference for the launch of the official list. Relevant departments formulate policies for rare diseases to provide reference for all parties in the scientific research, diagnosis and treatment of rare diseases, drug development and market access, medical security and social assistance.

The establishment of the list is mainly based on the global incidence of rare diseases and the clinical detection rate of domestic genetic testing institutions. Collected the corresponding disease types of domestic rare patients with corresponding treatment programs at home and abroad, and referenced the rare disease lists in Taiwan and Shanghai. ^[2]

Folk version of China's Reference List of Rare Diseases

Development of Orphan Drugs in China

China currently does not have an official authoritative definition of rare diseases, and data on the types of disease and the population affected have not been accurately reported. According to the World Health Organization's definition of the incidence of rare diseases 0.065% ~ 0.1%, according to incomplete statistics, the total number of patients with rare diseases in China is about 16.8 million, of which 95% of the diseases have no treatment methods. "The research and development is still in a blank. The treatment drugs for patients with rare diseases basically rely on foreign imports. ^[1] China's work in the prevention and treatment of rare diseases is progressing slowly. Policy support has created a gap in the domestic rare drug development industry.

However, due to low profits, low market demand, and high R & D costs for domestic orphan drugs, domestic pharmaceutical companies are not profitable and do not produce. As a result, many patients with rare diseases can only choose expensive imported drugs or no drugs are available. At present, most of them are incurable without drugs, and only a few are curable. However, this part of the "orphan medicine" is very expensive, and ordinary families cannot bear huge economic pressure. Taking drugs for Gaucher disease as an example, the cost of a year's treatment is about 200,000 US dollars, and many patients can only give up treatment. At present, 134 patients with Gaucher disease in China have received free medicine through the charity donation project of the Rare Disease Relief Program.

In the Chinese pharmaceutical market, domestically known "orphan drugs" include long-acting diabetes insipidus for the treatment of diabetes insipidus, and the antidote for organophosphorus pesticides, chlorhexidine. During the planned economy period, China implemented a system of fixed-point production, specialized storage, unified distribution, and expired medicines. However, after the reform of the state-owned pharmaceutical enterprise system and the marketization of medicine production and distribution, the production of "orphan drugs" However, there is no set of compensation and incentive mechanism, so the production of such drugs cannot be guaranteed, and the enthusiasm of enterprises for producing "orphan drugs" is suppressed. At the same time, due to the uncertainty of the timing and number of populations of special and rare diseases, the use time and quantity of "orphan drugs" are also uncertain. Therefore, companies are also reluctant to bear the risk of expired medicines, resulting in "orphan drugs" "Shortage.

Fortunately, my government has begun to realize this problem. Recently, Wu Ritu, a member of the Standing Committee of the National People's Congress and a member of the Financial and Economic Committee of the National People's Congress, suggested adding "orphan drugs" for special diseases and rare diseases to the national drug reserve, and timely transferring such drugs through the reserve bank to ensure that the Supply of medicines.

At the beginning of 2009, China's "Regulations for the Special Examination and Approval of New Drug Registration" was promulgated and implemented, and the approval of drugs for rare diseases was included in the special approval scope. However, there is still no rare disease drug developed and produced on our own market in China, and patients can only expect foreign drug companies to obtain registration for rare disease drugs in China as soon as possible. ^[3]

Development of Orphan Drugs in Foreign Countries

Based on the high-risk status of "orphan drugs", many countries have given them policy support.

Orphan Drug Europe and America

Laws and regulations on rare disease medicines in various countries around the world have stimulated biomedical companies' research and development of rare disease medicines, and have also greatly accelerated the market for rare disease medicines. Prior to the implementation of the Rare Diseases Act of 1983, there were fewer than 10 rare disease drugs on the market in the United States. By December 2008, there had been 1,951 rare disease drugs registered with the FDA, and 325 rare disease products had been approved for marketing. Before the implementation of the rare disease drug regulations in the European Union in 1999, only 8 orphan drugs were approved. As of February 2009, 619 rare disease products have been identified and 47 "orphan drugs" have been approved.

In 2014, the United States Food and Drug Administration (FDA) approved 19 new drugs for rare diseases, accounting for 38% of the total number of new drugs approved that year.

Orphan Drug Asian Countries

"" Orphan drugs "(orphan drugs) for treating special and rare diseases have huge potential demand in Asia. Asia currently has 4 billion people, accounting for two-thirds of the world's 6.4 billion people. Many Asian countries GDP is growing at a rate of 5%. In particular, more economically developed countries such as Japan and Singapore already have well-developed health care systems. Other countries such as China and Indonesia are also working hard to improve local health care as the economy develops. Situation. But because each country's health care system is different, the demand for "orphan medicines" also varies with regional economic and environmental differences, especially many Asian countries have truly recognized and understood the role of "orphan medicines". And status, the national health insurance policy has covered "orphan drugs." Unfortunately, many countries in Asia have only begun to focus on such drugs for rare diseases. " ^[4]

1. Japan ^[4]

Japan formally implemented the "Administrative System of Drugs for Rare Diseases" in 1993. The entire process of research can enjoy the benefits of funded funding, tax reduction, priority approval, extension of drug re-examination time, and payment of national health insurance. The US Food and Drug Administration (FDA) also provides fast-track procedures for the registration of "orphan drugs", which also enjoy tax reductions and 7-year market exclusivity.

Japan's health care is already at the highest level in the world. Japanese health care expenditures amount to $ 300 billion a year. Although this number is much less than the US $ 1.8 trillion of Americans, the demand for better and safer drugs is continuing to grow as the population ages, so the Ministry of Health, Labour and Welfare (MHLW) The more aware of the urgency of improving drug supervision and management and improving drug safety.

Japan's Ministry of Health, Labour and Welfare began implementing the "Orphan Drug Development Program" in 1993. The plan is to support the non-profit medicines that are necessary to sustain life. To date, Japan's Ministry of Health, Labour and Welfare has designated 182 "orphan drugs", of which 97 have been approved as new drugs.

The favorable conditions of the "orphan drug" development plan have attracted foreign "orphan drug" R & D companies. Of the 182 "orphan drugs" currently designated by Japan, more than half are developed by foreign companies. This further shows that foreign companies have made full use of Japan's "orphan drug" development plan. Most of the "orphan drugs" currently on the market in Japan are used to treat infectious diseases, hematological diseases, neuromuscular diseases, and more common pediatric diseases.

Only drugs that meet the following conditions can be designated as "orphan drugs" in Japan:

-Less than 50,000 patients in Japan and less than 200,000 in the United States;

Must be a disease that currently has no other treatment in Japan, or the drug is better than the current clinical medication;

A clear product development plan and scientific basis to support the marketing of this drug in Japan should be submitted when applying.

If a pharmaceutical company obtains an "orphan drug" status, it will receive the following benefits:

-Japan's Ministry of Health, Labour and Welfare will provide free consultation services for "orphan drug" applicants;

Applicants will receive funding from the Japanese government when collecting supporting data. These data include clinical trials and bridge research data. In particular, applicants will receive financial assistance equivalent to 50% of clinical costs. Levy a tax equal to 6% of development costs and a corporate tax of 10%;

Applicants will get fast approval. In theory, fast approval takes 10 months, and normal approval takes at least 12 months.

-Applicants will likely get a 10-year market exclusivity period;

-The update period for "orphan drugs" is 10 years, while other drugs are 6 years.

Japan's clinical trial data is the most valuable, and the Japanese data is decisive for product approval. Generally speaking, the data from abroad or Asia is only used as a reference by the Ministry of Health, Labour and Welfare.

In Japan, as in other Asian countries, it is important to identify whether doctors are interested in "orphan drugs." In order to get strong support for the product, the best way is to carry out drug research and development for specific diseases that doctors care about. In addition, it is also important to get support from relevant Japanese associations. In most cases, applicants must obtain "orphan drug" status before the drug is approved for marketing. As long as the Ministry of Health, Labour and Welfare feels that the information is sufficient and complete, they will accept the application. After the drug is granted "orphan drug" status, applicants can consult and discuss Japanese clinical trial plans with the Ministry of Health, Labour and Welfare. After the clinical trial is completed, a new drug application will be submitted. Although Japan has an "orphan drug" bill, the final interpretation of the bill rests with the Japanese government.

Recently approved orphan drugs in Japan include GlaxoSmithKline's AIDS drug Lexiva, Genzyme's Fabrazyme drug and Novartis's macular degeneration Visudyen.

2. South Korea ^[4]

South Korea's current pharmaceutical market is worth $ 6.5 billion, making it the third largest pharmaceutical market after Japan and China. The Korean pharmaceutical market has grown steadily at a rate of 7% to 9% in recent years. The Korea Food and Drug Administration is in line with international standards to improve domestic drug management regulations. In May 2005, the Korean government and the World Health Organization signed an international memorandum on chemical safety of medicines and other medical products.

The organization that supplies "orphan drugs" in South Korea is a pharmaceutical company or a Korean "orphan drug center". In October 2002, South Korea approved the marketing of more than 130 "orphan drugs".

For a drug to be granted "orphan drug" status in Korea, the following conditions must be met:

Diseases with fewer than 20,000 people, and currently there is no suitable method to treat the disease;

For domestically produced drugs, the total output value must be less than 5 million US dollars. In the case of imported drugs manufactured abroad, the total import volume should also be less than US $ 5 million.

The approval of "orphan drugs" takes 6-9 months. According to Korean government regulations, approved "orphan drugs" have a 6-year market exclusivity period. In general, South Korea compensates for 1/2 to 1/3 of the cost of "orphan drugs" and medical expenses. Currently, many patient groups in South Korea have successfully lobbyed the government to provide similar funding. Recently, "orphan drugs" approved in South Korea include Abbott's anti-Moxa drug Kaletra, Schering-Plough's drug clodronate (Bonefos) for osteoporosis and malignant tumor-induced hypercalcemia.

3. Singapore ^[4]

Singapore has a small population, a developed economy, and a highly developed healthcare system. Singapore is considered by many pharmaceutical companies to be the center of Asia. Many large pharmaceutical companies such as Pfizer and GlaxoSmithKline have established branches in Singapore and have begun to expand their manufacturing bases and R & D institutions.

In January 2004, the Singapore Pharmaceutical Authority was established. The Medicines Administration Bureau is a combination of the former Drug Administration Center and Drug Evaluation Center. Its mission is to further simplify and rationalize the registration and evaluation process of drugs. However, Singapore's regulations on the orphan drug section have not been activated. There is no 100% clear definition of "orphan drug" in Singapore. As a result, rare drugs face many difficulties in gaining "orphan drug" status in Singapore.

To support a drug as an "orphan drug" in Singapore, the following conditions must be met:

-Drugs must be used to treat life-threatening diseases and play a decisive role in the treatment;

-The disease can affect only a very small number of people;

-A preliminary estimate of the incidence must be provided.

If the drug meets all the above conditions, the Singapore Ministry of Health will give the drug an "orphan drug" status and will receive the highest priority when it is approved. "Orphan drugs" can obtain a 10-year market exclusivity period. But so far, compensation mechanisms for "orphan drugs" remain a challenge for the Singapore government.

4. Hong Kong, China ^[4]

Hong Kong, China has a small population but a relatively rich economy. The health care level in Hong Kong is the best in Asia. The size of the Hong Kong pharmaceutical market is $ 1.6 billion. However, although Hong Kong also has local pharmaceutical factories, its most advanced drugs are basically imported from abroad.

The Hong Kong Department of Health (DOH) is responsible for the development of health-related laws and policies in the region. DOH is composed of many small departments such as medical device control center, health prevention center, dentistry and medicine. The drug service department is mainly responsible for drug registration, drug import / export control, etc.

In Hong Kong, applicants for orphan drugs can register for orphan drugs through the new chemical entity registration process. Such chemical entities must be new and essential to life. The drug will enter the process immediately and will be granted rapid approval by the Drug Registration Board. The committee meets four times a year, so applicants must submit application materials within a few weeks before the committee meets, which can shorten the approval time. The second type of application is applicable to those who do not meet the requirements for the application of a new chemical entity. It takes 6-9 months to follow the normal registration procedure.

5. Taiwan, China ^[4]

The scale of China's Taiwan pharmaceutical market has reached 2.75 billion US dollars. In order to attract more foreign companies and investors, Taiwan is improving its drug management regulations and management standards. According to data released by the Taiwan Ministry of Economic Affairs, at the beginning of 2005, Taiwan's western medicine imports reached US $ 440 million, an increase of more than 100% over 2004.

Taiwan is one of the regions with the best health care in Asia. There are already more than 2,000 health care centers with more than 50 beds per 10,000 residents. The ratio of patients to doctors reached 750: 1 in 2004. The Taiwan Department of Health (DOH) is primarily responsible for providing available and effective healthcare services to the people of Taiwan. The department monitors medical insurance, the quality of hospital operations and regional health care facilities. The Ministry of Drug Affairs and the Drug Control Center are responsible for formulating laws and regulations related to drugs.

On February 9, 2000, Taiwan's Legislative Yuan began implementing the "Orphan Drugs" Act. The bill is mainly aimed at improving the diagnosis, treatment and prevention of rare diseases and making it easier for patients to obtain medicines for rare diseases. The bill promotes the supply, production, and development of "orphan drugs." To implement the bill, Taiwan has set up a committee to review "orphan drugs." If an "orphan drug" has been approved by the US FDA, it can be exempted from clinical trials in Taiwan. However, the organization submitting the "orphan drug" application must be a subsidiary established by the company in Taiwan. Sellers, offices, or independent third-party organizations in Taiwan can also submit "orphan drug" applications.

The organization must be a Taiwanese subsidiary's sales office or an independent third party organization in Taiwan to submit an orphan drug application. It takes about 6 to 10 months to complete the review of the "orphan drug". In Taiwan, approved "orphan drugs" can enjoy a 10-year market exclusivity period. During this period, Taiwan's health department will no longer accept applications for similar drugs. However, patients can only receive full compensation if they are defined as "orphan drugs" by the Taiwan's rare disease prevention and medical legal department. Because "orphan medicines" are expensive, hospitals often do not provide medicines to patients without receiving advance compensation from medical insurance agencies.

Generally speaking, Taiwan can provide compensation for many rare diseases, and the level of compensation is relatively reasonable. The compensation includes the cost of treatment and the cost of seeing a doctor. Many patient groups have successfully lobbyed the government to provide similar compensation funds.

Examples of orphan drugs

OS2966: An experimental monoclonal antibody drug developed by OncoSynergy, which is effective against a variety of solid tumors, including relapsed and curative resistant glioblastoma.

ABT-414: Evaluating the treatment of glioblastoma multiforme, developed by AbbVie.

mocetinostat: is an experimental drug developed by Mirati Therapeutics for the treatment of diffuse large B-cell lymphoma.

ALN-AT3: Developed using Alnylam's proprietary Galactosamine Conjugated Delivery Platform (GalNAc-siRNA platform), which can be administered by subcutaneous injection for the treatment of hemophilia A and hemophilia B

Translarna: Developed by PTC Pharmaceuticals for the treatment of ambulatory patients with nonsense mutant Duchenne muscular dystrophy (nmDMD) aged 5 years and over.

Soliris ( Eculizumab ): A first-in-class terminal complement inhibitor developed by Alexion Pharmaceuticals for the treatment of myasthenia gravis.

Ryanodex (Dantrolene Sodium): Eagle Pharmaceuticals develops an injectable suspension for the treatment of malignant hyperthermia. Previously, the FDA had granted Ryanodex orphan drug status in August 2013.

necuparanib (M402): A new anticancer drug candidate developed by Momenta Pharmaceuticals for the treatment of pancreatic cancer is a heparan sulfate analog.

IMMU-132 (antibody-drug conjugate, ADC) : ADCs are a class of drugs that conjugate anticancer agents to antibodies. Compared with traditional treatment drugs, ADCs can kill tumor cells and have fewer side effects. The drug received a second orphan drug status, developed by Immunomedics.

vatiquinone: This medicine is an oral bioavailable small molecule drug, which belongs to benzoquinones. It is currently in the clinical development stage and mainly focuses on the treatment of hereditary mitochondrial diseases. Developed by Edison Pharmaceuticals.

Humira: used to treat non-infectious middle, posterior, or pan-uveitis or chronic non-infective pre- uveitis. Humira is AbbVie's flagship product prescription drug. It is the world's first approved tumor necrosis factor (TNF) - fully humanized monoclonal antibody drug, with as many as 7 indications approved.

Volasertib: This drug is an experimental polo-like kinase (Plk) inhibitor for the treatment of acute myeloid leukemia (AML). Developed by Boehringer Ingelheim (BI).

Ciprofloxacin dry powder inhaler: developed by Bayer for the treatment of cystic fibrosis bronchiectasis (NCFB).

marizomib: a new drug from Triphase Accelerator, used in the treatment of multiple myeloma.

amatuximab: Eisai's monoclonal antibody for the treatment of malignant mesothelioma. ^[5]