Orphan Drug Development in China
February 28, 2021
Since 2008, the last day of February is the international Rare Disease Day, which is aimed to raise awareness amongst the general public and decision makers. Depending on the exact definition of a rare disease, there are between 6000 and 7000 recognized rare diseases, and approximately 1 in 20 people will suffer from a rare disease at some point in their life. The diagnostic process for rare diseases is often difficult and lengthy, with frequent unrecognized or wrong diagnoses. Furthermore, adequate and affordable treatment does often not exist, inevitably leading to greater suffering, poor quality of life and shorter life expectancy.
In the traditional pharmaceutical markets of the USA, Europe and Japan, specific regulatory policies have long existed to stimulate drug development for rare diseases, also called orphan drugs. In China, this is a still developing field, but especially since 2018 the first national regulatory framework has been established, and further development and a growing market can be expected.
In this blog post, we will shortly outline the regulatory framework for orphan drug development in the USA and Europe, and then focus on recent developments and future prospects in China.
Orphan Drug Development in the USA and Europe
In the USA, the Orphan Drug Act was established in 1983. The FDA Office of Orphan Products Development (OOPD) is tasked with stimulating and evaluating orphan drug development. A pharmaceutical company can apply for orphan drug designation if its product is used to safely and effectively treat, diagnose or prevent a disease that affects fewer than 200 000 people in the USA. This designation can also be obtained if the disease affects more people, but the product would not be profitable due to the rare nature of the disease. Naturally, the drug cannot have been approved earlier and it needs to be superior over existing treatments. The FDA offers several benefits for orphan drug manufacturers, including fast-track regulatory review, financial benefits and assistance, and a 7-year market exclusivity as opposed to 5 for normal drugs.
In the EU, the EMA has very similar criteria for designating orphan status to a drug as the FDA, but a disease is considered rare when it affects fewer than 5 in 10 000 people. The Committee for Orphan Medicinal Products (COMP) is responsible for recommending orphan designation to the European Commission. The EMA stimulates the development of orphan drugs, among other things by offering protocol assistance, fee reductions, a faster centralized authorization procedure, and a 10-year market exclusivity for each drug indication. A two-year extension for market exclusivity is possible for pediatric drugs.
The orphan drug policies in the traditional pharmaceutical markets have been hugely successful, with an expected 20% of prescribed drugs in 2024 being for rare diseases, thereby greatly benefiting patients who would not be served under regular pharmaceutical market conditions.
Rare Diseases and Orphan Drug Development in China
The First National List of Rare Diseases
National policy for rare disease was lacking for a long time in China, but rare diseases were included in the 5-year plan on public healthcare (2016-2020) and in the Healthy China 2030 Planning Outline.
In China, the most common definition used for rare diseases is when it affects fewer than 1 in 500 000 people in China, or has a neonatal morbidity of less than 1 in 10 000. However, epidemiological data on disease prevalence in China is scarce, and therefore the inclusion of a disease on a list of rare disorders is largely determined by expert opinions. For instance, the NGO Chinese Organization for Rare Disorders (CORD) published a list with 147 rare diseases in 2016. In 2016, the Expert Committee on the Diagnosis, Treatment, and Care for Rare Diseases was formed by the National Health Committee (NHC). Together with other national health organizations, they published the First National List of Rare Diseases, known as the CRDL (Chinese Rare Diseases List) in 2018. The CRDL comprises 121 diseases, of which 88 were also on the CORD list.
For a disease to be included on the CRDL, the disease needs to have a low prevalence, have a severe impact on the patient and their family, be easily diagnosable, be treatable and economically affordable. This latter criterion means that an application should include pricing and insurance data from other countries. Professional health organizations and NGOs are permitted to request a disease to be added to the list, but pharmaceutical companies are not explicitly mentioned to have this option. Furthermore, the list cannot be amended more than once every two years, which obviously impacts the drug development process for disorders that are not yet included.
Foreign Drugs and Acceptance of Foreign Clinical Trial Data
In addition to the CRDL, a List of Overseas New Drugs Urgently Needed in Clinical Settings was published. To simplify the acceptance of orphan drugs available in foreign markets, the Drug Administration Law of China was reformed in 2019 to include the so-called green channel mechanism. This allows foreign clinical trial data to be used as evidence for the effectiveness of orphan drugs, depending on whether ICH GCP standards were followed, the safety and efficacy shown in those trials, and whether different racial groups were included. It is possible to obtain preliminary approval, with additional trials to show safety and efficacy in the Chinese population. Furthermore, the Chinese National Drug Administration (CNDA) committed to an accelerated approval process of 3 to 6 months.
These reforms greatly impact market opportunities for existing orphan drugs in other markets. If trials for these drugs have been conducted under ICH-GCP standards, a relatively straightforward and quick (preliminary) approval for the Chinese market is feasible. It has therefore already led to the approval of dozens of foreign orphan drugs by the Chinese National Medical Products Administration (NMPA).
Research and Patient Involvement
China is also increasing its research efforts for rare diseases, most notably in the form of the National Rare Diseases Registry System of China (NRDRS), the Rare Diseases Clinical Cohort Study, and the National Network of Rare Diseases (NNRD). Initiatives like this are intended to increase knowledge of the nature and prevalence of rare diseases in China, and to improve and standardize diagnosis and treatment. It is also coupled to a trend of greater recognition of patient associations. Bottom-up initiatives are not standard in China, but in the case of rare diseases the experiences of patients are of great benefit to improving care and obtaining knowledge, which is increasingly recognized by health authorities. Participation of China in Rare Disease Day (since 2009) is just one example of the growing recognition for patients suffering from rare diseases.
Future Prospects and Opportunities
It is important to realize the regulatory landscape for orphan drug development in China is still forming. The CNDA has proposed a ten-year market exclusivity for new orphan drugs, and a 3-year exclusivity improved orphan drugs in 2017, but this has not yet been adopted as law.
Looking at the CRDL, there is great room for expansion given the number of recognized rare diseases worldwide and for instance given the longer list established by CORD. Furthermore, the Chinese orphan drug market offers unique opportunities, since about a third of diseases on the CRDL do not have orphan designation in the USA. Another important difference to keep in mind is that in China the orphan drug designation is disease based, meaning that all safe and effective drugs developed for a particular disorder obtain this status, whereas in the USA and the EU, individual drugs obtain this designation. Overall, with increasing research efforts and recognition of patients with rare diseases, and with a developing regulatory landscape, the Chinese orphan drug market shows great potential for entry with existing drugs and development of new ones.