Advancing rare disease clinical trials and orphan drug research: A focus on APAC and China

Rare diseases are notoriously difficult to study. There may be limited patient data and information about disease progression, small patient populations available to join a trial and a lack of clinically meaningful endpoints. Despite these challenges, drug development sponsors around the world have recognized the transformative potential of developing treatments that can address ongoing unmet medical needs and improve outcomes for people living with a rare disease.

To help build awareness around these challenges and promote Rare Disease Day 2024, this article provides a high-level overview of rare diseases and development efforts in the Asia Pacific (APAC) region with a specific focus on operational practices in China and a new regulatory framework from China’s National Medical Products Administration (NMPA).

Understanding rare disease from a global perspective

While global statistics about rare diseases can vary, researchers often say that “rare diseases are not so rare.” Rare diseases are estimated to affect at least 3.5–5.9% of the world’s population^1,2, which adds up to approximately 283-477 million people (if counting the world’s current population at 8.1 billion). It’s also important to know that:

• New rare diseases continue to be identified: As of 2022, one analysis has identified 10,867 distinct rare diseases, which was previously thought to be around 5000-8000.³
  
• Most rare diseases are genetic in origin: An estimated 87% of rare diseases have a known- or suspected-genetic basis.³
• Children represent around half of the people living with rare diseases: Given that genetic diseases are present at birth,⁴ children represent around 50% of the people living with a rare disease, however, symptoms may not be apparent at birth or early childhood.
• Unmet medical needs persist: Fewer than 500 treatments have been approved for rare diseases, meaning that less than 5% of rare diseases have approved therapies.⁵

Defining rare diseases in Asia-Pacific (APAC)

When it comes to labeling a disease as "rare," there is no universal standard. A rare disease may have inconsistent presentation, can widely vary in prevalence between populations, and may even lack diagnostic consensus.

In APAC, a rare disease is defined by its prevalence in the general population. However, each country has its own definition.⁶ For example, in:

• Australia: Any disease affecting fewer than 2,000 people or about 1-2 per 100,000 people
• China: Either affects fewer than 1 in 10,000 people, or a has a prevalence of fewer than 1 in 10,000 or an affected population of less than 140,000.⁷
• Japan: Affects fewer than 50,000 people or about 1 in 2,500 people
• Singapore: Affects fewer than 1 in 2,000 people
• South Korea: Affects fewer than 20,000 people or ~4-5 in 100,000 people

Rare disease definitions may be harmonized in the future since the Asia-Pacific Economic Cooperation (APEC) Life Sciences Innovation Forum established a Rare Disease Network with government, academia, and industry members in 2017. With an overarching goal of addressing barriers to healthcare and social welfare services by 2025, the APEC Rare Disease Network has been working to define rare diseases and orphan products with policies and processes and promote innovative research and development, among many other initiatives.⁸

Focusing on rare disease support in China

Further support for rare disease clinical trials was noted in September 2023 when The National Health Commission in China published its “Second List of Rare Diseases.” This list, called the Chinese Rare Diseases List (CRDL), now includes 207 rare diseases, up from 121 rare diseases in 2018 with the list’s first publication.⁹

By defining rare diseases in the form of this catalog, China is helping raise societal awareness and attracting the attention of people living with rare diseases. The Chinese government is also working on gradually establishing a multi-party cooperation system for rare diseases and integrating resources related to policy support and legal protections.

China's National Medical Products Administration (NMPA) has also been heavily involved in efforts to encourage rare disease drug development. At the 2023 DIA Asia Meeting, Dr. Zhimin Yang, Deputy Director of the Center for Drug Evaluation (CDE) at the NMPA, mentioned that the NMPA promotes rare disease treatment development through a program called CARE (Patient-Centered Action for Rare Disease Encouragement), which highlights the "care and concern for patients living with rare diseases."

As summarized in an article reporting on the 2023 DIA Asia Conference,¹⁰ Dr. Yang reported that the CDE will use rare diseases as a breakthrough to establish a "patient-centered rare disease drug research and development" framework. This framework spans the entire drug development workflow of a therapeutic, biologic or cell/gene therapy—from market research, drug discovery and development, to Pre-IND, IND, clinical trials and eventually the New Drug Application (NDA) to request NMPA approval. During the process development process, pharmaceutical and biotech sponsors can expect timely support and communications from regulatory affairs.

In the article, Dr. Yang said she hopes that rare disease drug development companies will actively sign up to participate in the program and implement patient-centered processes based on the awareness of the disease, the urgent need for treatment, the innovation of the product's mechanism, and the feasibility of patient participation methods during the development of the submitted drug. With the framework, Dr. Yang also hopes that patients can join clinical trials as early as possible to help advance precision medicine.

Advancing rare disease clinical trials in China

Based on our experience at Fortrea, we have seen that running a rare disease study in China has a few advantages in terms of patient access:

• Larger population: China may have a relatively larger number of rare disease patients, depending on the disease, as compared to less populated APAC countries.  
• Patient interest: Many rare disease patients in China are interested in joining a clinical trial, especially if there is no approved standard of care or a “standard” treatment is cost prohibitive.
• Patient advocacy groups: Rare disease patients often form volunteer-based groups, which develop strong relationships with hospitals that are known for their work in rare diseases. Clinical trial participants can be identified or recommended by these patient groups.
• Existing patient pools: Doctors in hospitals often maintain their own patient pools, which can be used to support patient recruitment.

Site engagement has been another important facet of running a rare disease trial in China. Sponsors should understand the:

• Support of investigators: Most investigators in China are supportive of conducting rare disease clinical trials, which is related to the government’s overall encouragement of increasing the number of approved orphan drugs.
• Potential for site burden: It should be noted that enrolled patients may have low compliance during the study period, especially if they are living in economically disadvantaged areas. Therefore, investigators and sites must pay careful attention to informed consent as well as patient management. Knowing that fully informed consent of patients and routine patient maintenance can increase the site burden, drug development sponsors may choose to increase researcher fees or identify a Site Management Organization (SMO) vendor to support these processes.
• Special procedures and regulations: There are some special procedures for sites in China, such as HGRAC approval, GCP approval (should obtained ahead of ethics committee (EC) approval) and GCP QC (should be completed before database lock (DBL)).

As with any clinical trial in China, it is also critical to understand that human genetic biospecimen exportation is limited. Any exports and must be included on the applications with the Human Genetic Resources Administration of China (HGRAC) and go through the CIQ (China Inspection and Quarantine). Therefore, it is often more time- and cost-efficient to have samples analyzed within China.

To demonstrate our capabilities and experience working with local regulatory affairs in China, we are sharing our HGRAC and CIQ performance metrics across all therapeutic areas:

• Since 2019: Annually, we have been granted more than 100 import permits (for IMPs) and export permits (for biosamples) through the CIQ
• 2020: We submitted 400+ cases to the HGRAC; our first-time submission approval rate was around 90%, which was much higher than the industry rate of 78%.
• 2021 and 2022: We submitted 1000+ cases to the HGRAC with a first-time submission approval rate of 99.4%.
• 2023: We submitted 500+ cases to the HGRAC with a first-time submission approval rate of 100%.

Our role in supporting APAC drug development

Our team at Fortrea has been honored to serve several biotech and pharmaceutical sponsors, provide insightful guidance and support investigators with rare disease clinical trials in China and across APAC. Learn how we can apply our deep experience to help advance your product in its journey to market through our Rare Diseases, Advanced Therapies and Pediatrics Team (RAPT).

参照

1. Abozaid GM, Kerr K, McKnight A, Al-Omar HA. Criteria to define rare diseases and orphan drugs: a systematic review protocol. BMJ Open. 2022 Jul 29;12(7):e062126. DOI: 10.1136/bmjopen-2022-062126

2. Rare Diseases at FDA. Dec. 2022. https://www.fda.gov/patients/rare-diseases-fda Accessed 5 Feb. 2024

3. Lamoreauz, K, et al. The Power of Being Counted. RARE-X publication. https://rare-x.org/wp-content/uploads/2022/05/be-counted-052722-WEB.pdf

4. U.S. Government Accountability Office. GAO-22-104235. Oct. 2021. Rare Diseases: Although Limited, Available Evidence Suggests Medical and Other Costs Can Be Substantial. https://www.gao.gov/products/gao-22-104235 Accessed 6 Feb. 2024

5. Rare Diseases. National Institutes of Health. Nov. 2023. https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/promise-precision-medicine/rare-diseases Accessed 5 Feb. 2024

6. Schouten, A. KEI Briefing Note 2020:4 Selected Government Definitions of Orphan or Rare Diseases. 2020. https://www.keionline.org/wp-content/uploads/KEI-Briefing-Note-2020-4-Defining-Rare-Diseases.pdf Accessed 22 Feb. 2024

7. Lu Y, Han J. The definition of rare disease in China and its prospects. Intractable Rare Dis Res. 2022 Feb;11(1):29-30.

8. Asia-Pacific Economic Cooperation. Action Plan on Rare Diseases. https://www.apec.org/docs/default-source/satellite/Rare-Diseases/APEC_ActionPlan.pdf Accessed 6 Feb. 2024

9. Tang M, Yang Y, Ye Z, Song P, Jin C, Kang Q, He J. Release and impact of China's "Second List of Rare Diseases." Intractable Rare Dis Res. 2023 Nov;12(4):251-256.

10. Mao D. CDE will launch CARE plan. DIA Asia Conference 2023. https://mp.weixin.qq.com/s/pVcP1zy3-M4eOojFsf974w and English translation: https://mp-weixin-qq-com.translate.goog/s/pVcP1zy3-M4eOojFsf974w?_x_tr_sl=auto&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wappAccessed 14 Feb. 2024