he official “First List of Rare Diseases” was released jointly by five government agencies in May 2018. One hundred and twenty-one rare diseases are included in this list. It is a huge milestone in the developing history of China’s rare diseases, signifying the government’s determination to address the accessibility of drugs for rare diseases.

Looking back over the past two years, China has made significant progress unveiling various rare disease policies and regulations on research, diagnosis and treatment, drug access, and social medical coverage. As the largest and the most influential and professional rare diseases patient organization, the Chinese Organization for Rare Disorders (CORD) is obliged to embark upon a comprehensive review of the status quo of orphan drug access and social medical coverage at home and abroad. Based on our deep understanding of the practical needs of patients and their families, we share these thoughts as China begins to systematically tackle the issue of orphan drug access.

Currently, more than three million patients suffering from these 121 rare diseases in China still face mounting challenges: difficulty to obtain clear diagnoses; lack of treatment options; and a limited number of available orphan drugs in China. Even for those drugs available in China, sourcing could still be a problem, and many carry high prices that are not included in the national drug reimbursement list. Inaccessibility and unaffordability are the two biggest obstacles for patients; as a result, more than 50 percent of rare disease patients in China do not receive timely and adequate treatments.

As of December 2018, 74 rare diseases in the “First List of Rare Diseases” are considered “curable.” As many as 162 drugs for these 74 rare diseases have been approved in the US, EU, or Japan; in China, 83 drugs for 53 of these diseases have been approved. However, only 55 drugs for 31 rare diseases have a definite indication registration in China, and only 29 drugs for 18 rare diseases are covered under the National Medical Insurance, Employment Injury Insurance, and Maternity Insurance.

21 rare diseases have drugs available in other markets that are not approved in China: Arginase Deficiency, Citrullinemia, Fabry Disease, Huntington Disease, Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome, Hypophosphatasia, Hypophosphatemic Rickets, Isovaleric Acidemia, Laron Syndrome, Lysine Urinary Protein Intolerance, Lysosomal Acid Lipase Deficiency, Mucopolysaccharidosis, NAGS Deficiency, Ornithine Transcarbamylase Deficiency, Phenylketonuria Spinal Muscular Atrophy, Porphyria, Retinitis Pigmentosa, Severe Myoclonic Epilepsy in Infancy / Dravet Syndrome, Sickle Cell Disease, and Tyrosinemia.

There are tremendous obstacles to bringing rare disease drugs to China. Drug companies often resort to inaction in an uncertain market. Uncertainties on obtaining market approvals (regulatory hurdles) and subsequent drug sales (income uncertainties due to small patient population and lack of social medical coverage), and potential moral and ethical scrutiny cause further dilemmas. As a result, most companies choose to “wait and see.”

Although some rare diseases have treatment drugs available in China, these drugs are not specifically designated for such diseases. Compared to rare disease drugs approved in other markets, drugs used in China are secondary or tertiary treatment options with lesser efficacy, leading to less desirable outcomes for patients and their quality of life.

An Invisible Wall

Responding to this need, the Chinese regulatory agency has taken important steps to expedite review and approval of drugs for rare diseases. Priority review status is commonly designated to rare disease product applications. A conditional approval pathway is readily available to qualified rare disease product development programs. Most recently, the National Medical Products Administration (NMPA) and National Health Commission (NHC) jointly announced a special approval procedure for certain drugs for “urgent medical need” that have been approved in US, EU, or Japan during the past ten years but are not yet approved in China. Drugs treating rare diseases qualify for this special approval procedure. Eligible products are selected by NMPA and NHC for consultation with experts and public comment. Manufacturers of these drugs are encouraged to submit a marketing authorization application to the agency, based on overseas clinical trial data, to support their approval in China. The CDE timeline for technical review of rare disease products under this procedure is three months.

In October 2018, these agencies released the first list of 40 drugs selected for this procedure, 20 of which are indicated for rare diseases. In March 2019, the second list was released for public comment. Fifteen of the 30 drugs on the list are for rare diseases.

Off-Label Use

Drugs Not Covered by Social Medical Insurance

The Chinese government has made good progress on social medical coverage for rare diseases. Among the 55 orphan drugs approved in China, 29 for 18 rare diseases are on the National Health Insurance List; nine of these, indicated for eleven rare diseases, fall into the Category I Reimbursement scheme, which means no out-of-pocket costs for patients.

26 drugs for 21 rare diseases are not covered by social medical insurance, and thirteen of these 21 diseases have no drugs at all under coverage. This means that the patient must bear all the cost. There are approximately 230,000 patients with these thirteen diseases, most of whom will require lifelong treatment, in China. Eleven drugs indicated for one of these thirteen diseases each cost more than 80,000 yuan (approximately $12,000 US) annually. Without medical insurance, it is difficult for patients to afford the full treatment they need year after year.

“The Final Mile” Challenge

After a rare disease drug is approved and listed on the national social insurance list, many obstacles remain between patients and these drugs.

1. Hospital procurement restrictions: Because rare disease drugs carry high costs but low demand compared to other drugs, they pose great challenges to hospital pharmacy management.
2. Physician prescription restrictions: Pressure to maintain the desired ratio of drug costs to total insurance costs constrains doctors’ ability to prescribe orphan drugs, making reimbursement nearly irrelevant.
3. Restrictions on outpatient reimbursement: There are vast regional differences in reimbursement policies on outpatient costs for chronic and severe diseases, with many different regional rules and regulations in terms of deductible, co-pay ratio, and max-out amount.
4. Less than ideal referral system: It is difficult for patients in non-provincial capitals to maintain long-term treatment. Often, they can only choose low-dose treatment, self-medication, or even giving up treatment. Treatment compliance is difficult to enforce.
5. Drug shortages: There are often inadequate supplies of low-cost drugs. Manufacturers sometimes cease manufacturing because the commercial markets of low-cost drugs are too unattractive for their sustained investment, which leaves patients with no treatment options.

Underlying all the above problems is insufficient social medical insurance coverage for rare diseases, and the high price of orphan drugs.

Opportunity Meets Challenge