【Tomorrow 10-11 o'clock】

Every Friday at 9:30 am, Wang Tingwen (pseudonym) takes his 4-year-old daughter Tingting to Zhejiang Children's Hospital for infusion.

It takes more than 4 hours to incorporate 35ml of liquid medicine into 65ml of normal saline. This innovative drug from the United States costs more than 50,000 yuan per time. The active enzyme ingredients can degrade the mucopolysaccharide accumulated in Tingting's body and prevent it from eroding Tingting's body.

But it does not cure Tingting. As a child with mucopolysaccharide storage, her genes have undergone mutations. Before more advanced gene therapy is released, she will have to use this enzyme replacement from the body for life.

The annual cost of medicine is more than 2 million yuan and requires lifelong use. For families of patients with mucopolysaccharide storage diseases, this is an endless battle.

Tingting is Wang Tingwen's second daughter.

After the Spring Festival in 2019, she found Tingting's sternum bulge, suspected to be "chicken breast", and took her to Zhejiang Provincial Children's Hospital for examination. After taking the chest radiograph, Wang Tingwen waited until the afternoon until the doctor told her in the clinic that Tingting was suspected to have mucopolysaccharide storage disease (mps).

In the "First Rare Disease Catalog" released by the state in 2018, mps ranked 73rd.

This is a rare genetic disease with a total incidence rate of about one in 25,000. Mucopolysaccharides that cannot be metabolized in the body will accumulate in cells, blood and connective tissue, causing gradual and permanent cell damage. The child's growth and development are delayed, and as the disease develops, it affects the heart, bones, joints, respiratory system and central nervous system, etc. until the whole body system is crushed.

At Shanghai Xinhua Hospital, Tingting was further diagnosed with mps     iv type. The incidence rate of this subtype is about one in 300,000, and the most significant feature is skeletal deformity.

Wang Tingwen has checked a lot of information, about 1 meter tall, sitting in a wheelchair, with a flat face, x-shaped legs, hunchback, chicken breasts... The pictures on the Internet constantly suggest their daughter's possible future fate, and Wang Tingwen even thought about dying.

"There is no cure at present." Dai Yangli, deputy chief physician of the Endocrinology Department of Zhejiang Children's Hospital, told the "medical community". "When the symptoms are mild, patients can treat conservatively by wearing some limb correction equipment. Once serious complications occur, they will be operated in the corresponding department, such as airway reconstruction surgery, spinal surgery, hip surgery, etc.... Wherever they are 'bad', they will be in harmony with the disease for life."

The impact of the disease has been revealed in Tingting. In 2019, she only grew two centimeters taller in her entire year, her wrists and spine were slightly deformed, and her physical and motor abilities were far inferior to those of children of the same age.

"For iv-type patients, one of the biggest risks on weekdays is that the atlantic joints of the neck are unstable. Once dislocation occurs, it can cause paralysis and even endanger life." Dai Yangli said, "And due to continuous cardiopulmonary function damage, bone deformities and spinal cord involvement, the patient's lifespan will also be severely affected. The lifespan of severe patients may not exceed 30 years.

The turning point comes from the launch of an enzyme-substituted drug with an active ingredient elosulfate α. In May 2019, it was approved by the China National Medical Products Administration and officially entered China for the treatment of mps     iv-type patients.

Wang Tingwen’s habit is neatly stacked in the transparent sealed bag at the end of the bed.

If it weren't for her daughter's illness, she would have an enviable life. She walked out of rural Shandong, struggled all the way until she graduated from a doctorate, and worked in a university. She bought a house and a car, and the family of four took root in the livable Hangzhou.

Now, the medicine in front of her is always stimulating her nerves. Like many rare diseases special drugs, the high R&D costs and narrow consumer market were doomed to have a sky-high fate, which brought a glimmer of vitality while also making Wang Tingwen feel desperate.

Hope was originally dependent on medical insurance. As early as the end of 2019, there was a news circulating among the patient group that the medicine is expected to enter Zhejiang Province's security policy in 2020, and patients only need to bear an additional 100,000 yuan in drug costs per year.

On April 30, 2020, the Zhejiang Provincial Medical Insurance Bureau and four other departments issued the "Notice on Establishing a Mechanism for Drugs for Rare Diseases in Zhejiang Province". Class 3 drugs: aracosidase α, agasase β, and elosulfate α were identified as the negotiators for special drugs for rare diseases. The first two were used for Pompeii and Fabre disease, and the costs were also more than one million a year.

The day before Children's Day that year, Wang Tingwen, who was working in the office, called the Medical Insurance Bureau to consult the results as usual. This time, the other party clearly replied that MPS cannot be included in drug protection this year. After putting down the phone, his mood fell to the bottom. Wang Tingwen burst into tears. Two days later, the Zhejiang Provincial Medical Insurance Bureau officially issued a public announcement that only the three drugs were elosulfate α.

At this time, it was nearly one year since Tingting was diagnosed. From a medical point of view, this special medicine can only "pause" the progress of the disease, but cannot reverse the existing damage. The earlier the medication is used, the better the effect. The couple had to make a difficult choice and buy the medicine at their own expense.

They first posted the house online, applied for a credit loan, and with the support of relatives and friends, they barely collected half a year of medical expenses. In the next year, Wang Tingwen tried many times to communicate with the heads of pharmaceutical companies.

"Not borrowing money is our bottom line," said Wang Tingwen. "This medicine is a bottomless pit, and it will never be enough to borrow it, and we will definitely not be able to pay it back."

On August 12, 2020, at the Children's Hospital, Tingting became the first patient with mucopolysaccharide storage in Zhejiang Province to use special drugs.

Use vertical extraction to remove the medicine. After the first draw, it will be replaced with a thinner and softer needle, and it will be sucked and rotated around the inner edge of the cilin bottle. The nurse in the endocrinology department has never used such expensive medicine. The night before, he worked overtime to practice how to remove the medicine from the bottle without leaving a drop.

What made Wang Tingwen happy was that this medicine quickly showed a therapeutic effect that matched the "sky-high price". In the first three months of the medication, Tingting grew 1 cm taller every month, and then 0.5 cm taller every month, and her physical functions are also improving.

"When she was in the nursery class, she often bent her back and lay weakly on the table. Now the kindergarten organizes a spring outing to West Lake, and she can also walk the entire journey by herself," said Wang Tingwen.

"If there was no such medicine, the doctor told me that Tingting would have been paralyzed at around ten years old." According to the international mps treatment guidelines, after receiving long-term enzyme replacement treatment in the early stage, mps patients can get married, have children, study and work normally, and return to society.

"Can you tell the difference between her and a normal child now?" Wang Tingwen's mobile phone stores videos of Tingting performing in kindergarten this year's Children's Day. Wearing a white skirt, Tingting waved her hands on the stage in conjunction with the rhythm of the music, jumping with a smile on her face.

The hope of saving lives is now in front of Wang Tingwen.

On November 5, 2021, Wang Tingwen had the last round of medicine left in his hand, which was specially transferred from the inventory in Sichuan Province by a pharmaceutical company.

In the past year, Wang Tingwen has not remembered how many times he has looked for the provincial and municipal medical insurance bureaus. He hopes to promote the implementation of the drug in the Zhejiang Province Rare Disease Protection Directory, but all attempts have made no progress.

The medical insurance policy is so big. "What kind of social value can your child bring? You have to spend millions of dollars a year on her." A rare disease expert once responded without hesitation.

Now, the "old and broken" set of more than 50 square meters online has not been sold, and the drug costs that Wang Tingwen has pieced together have been exhausted. Another more cruel reality is that this drug has also been cut off in Zhejiang Province. Considering the lack of stable consumer payment capabilities, the American pharmaceutical company has lowered the amount of medicines supplied to the Chinese market.

On June 18 this year, on Wang Tingwen's lunar birthday, she received a reply from the Provincial Medical Insurance Bureau. The other party said that the country has issued a relevant notice that it is unlikely that similar high-value drugs will be included in the Zhejiang Province's protection scope in the future.

In fact, in recent years, the country has successively issued relevant policies requiring all regions not to formulate local catalogs on their own or use adaptable methods to increase the drugs in the medical insurance catalog. On September 15 this year, the "14th Five-Year Plan" National Medical Insurance Plan once again clarified that by 2022, the national basic medical insurance drug scope must be basically unified.

Previously, this drug, which had not passed the national medical insurance negotiations, appeared within the protection scope of some provinces. In a southwestern province, elosulfate α has almost been implemented, but it was temporarily terminated. "People from the company told me that this temporary change of mind forced the headquarters to re-examine the necessity of opening up the Chinese market." Wang Tingwen said.

Mo Wanqi, a researcher in the field of medical insurance, told the "medical community": "The considerations for inclusion in medical insurance mainly come from comprehensive clinical evaluation of drugs, pharmacoeconomics and other factors to ensure the maximum efficiency of input and output. However, the annual treatment costs of drugs that have not yet entered the catalog are very expensive, and they are considered by the academic community and the industry to be "reasonable pricing" are not optimistic."

Elosulfate α is prepared by cell expression using recombinant     DNA                                                                                                                 �

But the child's condition was there, and the medical insurance route was broken. She could only continue to try to communicate with American pharmaceutical companies to strive for opportunities for sustainable medication use.

"The concept of gene therapy has been in full swing in recent years. Maybe in a few years, this disease can be completely cured." Wang Tingwen said, "But there is no medicine now. By then, Tingting's bones are fixed, the organs are damaged, and completely disabled. What's the point of treatment?"

The person in charge of the pharmaceutical company tried to persuade Wang Tingwen to give up. In their opinion, even if he could continuously adjust the medicine for Tingting and provide certain discounts, Wang Tingwen was unable to continue to pay for the annual expenses of millions, and it would not take long for the whole family to spend all their savings.

"You have a healthy eldest daughter," the other party reminded her.

On Wang Tingwen's mobile phone, there are nearly 500 families of children with mucopolysaccharide storage diseases.

Unlike other stories that frequently appear in the public eye and "selling the pot" to cure children's illnesses, most of them do not even have the chance to struggle. As of now, among the multiple subtypes of mps, a total of 3 special drugs have been approved in China, with an average annual cost of over one million for the i, ii, and iv types.

Yangyang, 12 years old, is a type ii child. The corresponding special drug comes from a Korean pharmaceutical company. From 2017 to 2019, Yangyang went to South Korea with his family to join the overseas clinical trial project to take medicine for free. In September 2020, the drug was officially approved to enter China.

As the first domestic families to use this special medicine, after the project was over, they did not have the ability to pay for the medicine. The enlarged liver, spleen, abdomen, stiff bones and increasingly twisted facial expressions, Yang Yang's body was deteriorating after two years of discontinuation.

Ma Wanqi told the "medical community": "For high-value rare disease drugs that have not entered medical insurance, enterprises can try to carry out preferential policies, and then improve channels through charitable organizations or commercial insurance products. This is equivalent to filling the lack of medical insurance through market-oriented simulated co-payment and using corporate concessions to make up for the lack of medical insurance."

But for Yangyang's mother, she no longer cared about assistance measures. Her husband is a leukemia patient. She relied on doing micro-business to maintain her family's expenses. "Give medicine, commercial insurance? Our annual income is less than 100,000 yuan, and even if we report 90%, we can't afford it." Her only wish now is to let her children live every day as well as possible.

"No matter what method is used, the core is to ensure that the patient's family's own expenses are limited to a reasonable range." The head of a rare disease organization in China told the "medical community".

In May 2020, the special drug for spinal muscular atrophy with a drug price of about RMB 11 million was included in the applicable targets of Japanese public medical insurance, which caused heated discussions online.

As of July 2019, a total of 333 rare diseases in Japan were included in the protection scope, and the patient's own expenses accounted for about 20% of the total medical expenses. At the same time, according to the annual income of different families, the self-paid upper limit is implemented. If 20% of the medical expenses exceed the self-paid upper limit, the upper limit will be paid, and the rest will be paid by the government's rare disease budget fund.

At the end of last year, the National Health Insurance Administration pointed out in response to the "Suggestions on Innovating the Medical Insurance Payment Mechanism and the Multi-party Payment Mechanism for Rare Diseases" that for some expensive special rare diseases, drugs cannot be included in the basic medical insurance payment scope due to reasons such as far exceeding the fund and patient affordability.

The aforementioned person in charge does not think that the so-called "medical insurance market" is the core issue. "For mps      iv-type children, there are only about 10 known cases in the entire Zhejiang Province. Although many rare diseases have high prices, the number of patients determines that the total expenses will not exceed the limit of medical insurance coverage."

"The government must first take the lead and break the deadlock." The person in charge said, "Even if the reimbursement ratio is lower first and sends out a signal, enterprises and various private charitable organizations, commercial insurance institutions, etc. will actively intervene and work together to gradually improve multi-party payment channels."

Another expert who has been engaged in rare diseases for more than 30 years told the "medical community" that when the country has not planned a unified solution path, some wealthy provinces should be given certain authority to make guarantee policies that conform to the actual situation of the province on their own, and at least they can solve the problems of some patients first."
Chapter completed!