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The incidence of rare diseases is extremely low. There are over 7,000 known rare diseases worldwide, but the number of patients for each single disease is usually only several thousand to tens of thousands. Taking China as an example, although the population is large, the distribution of patients with a single rare disease is extremely scattered, and there may only be several hundred cases meeting the criteria for clinical trial enrollment. This dispersion makes it difficult for traditional clinical trial centers to cover enough patients. For instance, in a clinical trial of an orphan drug, the target recruitment of 60 patients requires crossing multiple provinces and dozens of hospitals, while a clinical trial of a tumor drug may be completed with recruitment at a single hospital.

The low level of patient awareness further exacerbates the recruitment difficulties. Approximately 80% of rare diseases are genetic disorders, and 50% to 70% of them occur in childhood. However, patients' families have insufficient knowledge of the diseases, and some patients refuse genetic testing due to feelings of stigma, resulting in a low diagnosis rate. For instance, in a clinical trial for a certain neurofibromatosis, only 30% of potential patients were willing to undergo genetic testing to confirm the diagnosis, directly limiting the enrollment resources. Moreover, the problem of information asymmetry between doctors and patients is prominent. Some grassroots doctors have insufficient experience in diagnosing and treating rare diseases and are unable to effectively recommend patients to participate in the trials.

The pathogenic mechanisms of rare diseases are complex, with approximately 80% being genetic disorders. These disorders involve diverse types of gene mutations, necessitating the design of differentiated plans for clinical trials based on different subtypes. For instance, in the clinical trials of gene replacement therapy for X-linked myotubular myopathy, the efficacy needs to be analyzed hierarchically based on the patient's MTM1 gene mutation type, which increases the complexity and cost of the trial design. Additionally, the natural history of rare diseases is insufficiently studied, and some diseases lack clear efficacy endpoint indicators. For example, for certain neurodegenerative diseases, long-term follow-up is required to observe changes in motor function, which prolongs the trial period.

The strictness of ethical review is also a significant challenge. Clinical trials for rare diseases in children need to adhere to higher ethical standards. For instance, the participation of preschool children in the trials requires multiple ethical committees to review. Some trials have been forced to adjust their designs due to ethical controversies. In a spinal muscular atrophy drug trial, the initial plan was halted because it involved lumbar puncture sampling from infants. Later, an invasive-free detection method was adopted, and the trial was able to proceed.

Clinical trials for rare diseases are significantly more costly than those for common diseases. The recruitment of patients requires covering a wider geographical area, which leads to an increase in indirect costs such as travel and accommodation. A phase III clinical trial of a hemophilia drug showed that patient follow-up in different locations increased the cost per case by 40% compared to common disease trials. Moreover, most treatments for rare diseases are innovative therapies (such as gene therapy and cell therapy), and their production and quality control costs are extremely high, further increasing research and development expenditures.

The long duration of the trials is another major issue. Rare diseases progress slowly, and for some conditions, it takes several years of observation to assess the efficacy. For instance, in the drug trial for Duchenne muscular dystrophy, the primary endpoint was set as the change in the patient's 6-minute walking distance, and it required continuous follow-up for 48 months to obtain valid data. This long-term design increases the risk of patient dropout. In a muscular dystrophy trial, the data loss rate due to patient death or loss to follow-up reached 25%, which affected the reliability of the results.

In response to these challenges, the industry is exploring multiple innovative approaches. The decentralized clinical trial (DCT) model reduces the number of patient visits to the hospital and enhances participation convenience through technologies such as remote medical care and wearable devices. For instance, a trial for transthyretin amyloid cardiomyopathy increased patient retention by 30% through on-site sampling by a mobile medical team. Additionally, novel statistical methods such as adaptive trial design and basket trials can simultaneously evaluate the efficacy of drugs for multiple rare diseases, thereby improving the efficiency of research and development.

At the policy level, documents such as the "Technical Guidelines for Clinical Research on Drugs for Rare Diseases" issued by the China National Medical Products Administration provide guidance for optimizing trial design. For instance, it allows for the early approval of drug launches based on alternative endpoints, thereby shortening the waiting time for patients. Meanwhile, the medical insurance department has included more rare disease drugs in the negotiation list. In the 2025 adjustment of the national medical insurance directory, over 50 rare disease drugs passed the form review, reducing the economic burden on patients and indirectly increasing their willingness to participate in the trials.