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648 days, the first in the country!

 Last Update: 2022-05-30
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Zhang Yan waited 26 months for this news

On April 6, 2022, Wang Jingjing, deputy chief physician of the Department of Nephrology, Children's Hospital Affiliated to Zhejiang University School of Medicine, told her that the first batch of drugs for the treatment of childhood progeria had arrived at Hangzhou Xiaoshan Airport.

Image source: Provided by the patient's family

Zhang Yanba had no choice but to give his son Kangkang wings, so he hurried to Hangzhou

From July 16, 2020, the Children's Hospital Affiliated to Zhejiang University School of Medicine (hereinafter referred to as Zhejiang University Children's Hospital) began to introduce drugs, and on April 25, 2022, the first Chinese child took lonafranil, which lasted 648 days

During this period, there have been various twists and turns: when the hospital first submitted an application for clinical medication to the Provincial Health and Health Commission, it was rejected because they had never applied for urgently needed clinical medicines by donation; After approval by the State Food and Drug Administration, drugs can enter China smoothly.

In order to enable Chinese children with progeria to use special medicines as soon as possible, in the past 26 months, the Children's Hospital Affiliated to Zhejiang University School of Medicine, Zhejiang Provincial Drug Administration, Zhejiang Provincial Health Commission, Zhejiang Provincial Women's Federation, Zhejiang Provincial Women's Great efforts have been made by UNICEF, Kod Rare Disease Center, and Hong Kong Weijian Pharmaceutical Group

The health community has learned that this time Lonafani will be given to Chinese children for free (before the drug is launched in China).

This is the first time in mainland China, led by medical institutions, to solve the problem of urgently needed clinical medicines for children with rare diseases in China through the temporary import route of urgently needed medicines

The dilemma of having medicine abroad and no medicine at home

So far, there are at least 7,000 rare diseases discovered in the world, of which less than 10% have effective treatment options

Since the research and development of rare disease drugs in China has just started, most drugs still rely on overseas imports

According to the data, as of December 2018, a total of 74 rare diseases have been approved for marketing globally with indications in the "First Batch of Rare Diseases List", involving 162 therapeutic drugs, of which only 51% (83) Listed in China, only 34% (55 kinds) of drugs with clear indications for rare diseases are registered

The time cost of drug access and the high price after access have troubled patients who are in urgent need of treatment options

Huang Rufang, director of the Center for Rare Diseases, hopes that through this cooperation, "it is not only necessary to find patients, but also to provide patients with therapeutic drugs

Children on the countdown to life

Previously, progeria faced a huge cognitive gap in China

Kangkang is one of the first seven children with progeria identified by this public welfare project
.
As a premature baby, Kangkang weighed less than 2.
5 kg at birth
.
There is no baby's chubby, soft skin, Kangkang has less fat and hard skin, and at first glance, there seems to be a problem with the joints, and when lying down, the thigh bones can't be spread out on the bed
.

In order to cure Kangkang, Zhang Yan took him everywhere to seek medical advice
.
From the county hospital to the city hospital to the Peking University First Hospital, Zhang Yan finally learned that Kangkang may be suffering from "progeria" at the Beijing Children's Hospital affiliated to the Capital Medical University
.

It was less than 90 days before Kangkang was born
.

At the beginning of the diagnosis, Zhang Yan thought that as long as she was actively treated, Kangkang would definitely get better
.
Later, she "the more I understand, the more disappointed"
.

Progeria in children is an extremely rare and fatal genetic disease, with an incidence rate of only 1 in 4 million to 8 million, and there are about 60-70 patients in China
.

Mao Jianhua, vice president of the Children's Hospital Affiliated to Zhejiang University School of Medicine and head of the hospital's children's progeria working group, introduced to the health community that the aging rate of children with progeria is more than 5 times that of ordinary people, and the early clinical manifestations of patients are crusty skin, Hair loss, loss of subcutaneous fat, skeletal abnormalities, joint dysplasia
.
With age, patients also suffer from atherosclerosis and cardiovascular and cerebrovascular diseases
.

"The biggest damage is affecting life expectancy
.
" Mao Jianhua told the health community that most children with progeria die from stroke, arteriosclerosis and other cardiovascular and cerebrovascular diseases at an early age
.
According to international data, the average lifespan of patients is only 14.
5 years
.

Due to the small number of cases and the fact that patients often die at a young age, there is insufficient research on childhood progeria, whether in academia or medicine
.
In 2014, when Kangkang was onset, there was no specific medicine for the disease
.

Kangkang's life seems to have entered a "countdown" at the moment of diagnosis
.
Zhang Yan could only take him back to his hometown in Shandong
.

"The doctor said that there is no cure for this disease
.
You can only wait for the complications to occur, and then treat the symptoms
.
" Zhang Yan recalled to the health industry
.

A way of survival where risk and hope coexist

After joining the public welfare project to find children with progeria, Zhang Yan and the family members of 6 other children communicated with the American Progeria Research Foundation
.

The foundation said that there is a drug in clinical trials that can be introduced into China, and gave parents a detailed explanation of the development progress, effects and adverse reactions of lonafranil
.
In the end, among the seven families, only Zhang Yan decided to let the child receive treatment
.

In the end, among the seven families, only Zhang Yan decided to let the child receive treatment
.

"I don't know what other people think, but as long as there is medicine, I definitely want to give it to Kangkang, and I have to try it anyway
.
" Zhang Yan recalled
.

In mid-2020, under the guidance of Professor Liu Zhihong, Academician of the Chinese Academy of Engineering and Dean of Zhejiang University School of Medicine, the Children's Hospital Affiliated to Zhejiang University School of Medicine began to be responsible for the implementation of progeria in children.
group leader
.
The Children's Hospital of Zhejiang University led the introduction of Lonafani and assumed the examination fee for the patients
.

Because Lonafani has not been approved in China
.
Therefore, from the medical institutions that introduce the drugs to the families of the children, they all bear certain risks
.

Therefore, from the medical institutions that introduce the drugs to the families of the children, they all bear certain risks
.

According to the drug instructions, the incidence of adverse reactions of lonafanib is ≥25%, including vomiting, diarrhea, infection, nausea, abdominal pain,
etc.
Among them, gastrointestinal adverse reactions accounted for the highest proportion, and 48% of patients with vomiting required medical intervention
.

"Parents feel that the effect is small, but the side effects are large
.
" Recalling why many families of children did not receive treatment, Huang Juan, the head of the progeria program at the Kode Rare Disease Center, explained to the health community
.
According to data from a 2016 study of 37 volunteers with childhood progeria, lonafranil only extended patients' lives by an average of 1.
6 years
.

"But when we held a meeting with American experts, we learned that there are children who have been taking drugs for more than 10 years and have a good quality of life
.
" Huang Juan introduced
.

A set of experimental data based on 62 children with progeria showed that the average lifespan of those who received the treatment increased by 3 months in the first three years and by 2.
5 years during the 11-year follow-up
.

Image credit: Progeria Foundation of America

Xiao Li, vice president of Hong Kong Weijian Pharmaceutical Group and director of Boao Lecheng Rare Disease Clinical Medical Center, introduced to the health community that medical institutions need to undertake a lot of extra work to introduce unmarketed clinically urgently needed drugs in China, "for example, to develop specialized clinical technologies Standardization, clear clinical diagnosis and treatment uses of drugs, clear patient groups, and even the list of departments and doctors with prescribing rights need to be carefully evaluated
.
”

In addition, after the introduction of drugs, warehouse management, clinical management, etc.
also increased the cost of the hospital
.
"The monitoring of drug use should also have strict records, and medical institutions should monitor the safety, efficacy, and compliance of drugs throughout the entire process.
After serious adverse events occur, they must be reported in a timely manner
.
"

"Because of different races, patients need to bear the risk of differences in drug efficacy
.
" Mao Jianhua said that lonafranil is not a gene therapy drug and cannot cure progeria in children
.
In addition, since it has not yet been marketed in China, the efficacy of the drug on the Chinese population is unknown
.

However, as the only drug in the world that has a clear curative effect on children with progeria in children, patients can still benefit from it
.

"After evaluating the risks and benefits, we believe that this is necessary
.
Because the patient's life span is very short, there is an urgent need for a treatment plan to relieve the patient's pain and prolong life
.
" According to Mao Jianhua, Lonafani has been conducting clinical trials in the United States since 2007.
The trial follows a previous Chinese child with progeria who benefited from a clinical trial
.

"The results of clinical trials of the drug show that its efficacy is basically clear, and it can alleviate patients' symptoms, improve their quality of life and life expectancy
.
If there is no legal way to introduce it, the risk to patients will definitely be greater
.
" Mao Jianhua told the health community, although the introduction of drugs is not clear For a standardized process, hospitals need to explore from 0 to 1, but this is still "necessary"
.

The tortuous road of introduction

From July 16, 2020, Zhejiang University Children's Hospital began to introduce drugs, and until April 25, 2022, the first Chinese child took lonafranil, which lasted 648 days
.

"I don't know how difficult it is without experience" is Mao Jianhua's greatest feeling
.

For a long time, only sporadic cases of childhood progeria have been reported in China, and there is still a huge gap in the systematic research and treatment of the disease
.
"Few people pay attention
.
" Mao Jianhua introduced, including drug research and development, pathogenesis, clinical basic research, treatment plans,
etc.

Beginning in August 2020, as the leader of the hospital's children's progeria working group, he began to communicate with the American Progeria Foundation online once a month
.
On the one hand, it is to exchange the systematic research and treatment experience of childhood progeria, and on the other hand, it is to gain the trust of the Progeria Foundation, so as to better promote the free drug donation of the foundation
.

"As one of the sponsors of a free drug donation project that has not been approved in China, the foundation also bears certain risks
.
In addition, it consumes a lot of human and material resources, not to mention the commercial value of the drug itself
.
During the step-by-step negotiation, We strengthened mutual trust and finally reached the cooperation of the foundation to donate medicines for free
.
" Mao Jianhua explained
.

There are two main ways for an overseas specific drug to enter China
.

"The most important way is to apply for registration and listing in the Chinese market
.
" Xiao Li said, according to the method of application by pharmaceutical companies, the quality of application materials, and the degree of clinical urgency of the drug, a drug that has been marketed overseas will be approved in China.
Usually a few months to a few years later
.

For a drug that has already been marketed overseas, the approval time in China is usually a few months to several years later
.

However, due to various reasons, overseas manufacturers of some products may not have plans to enter the Chinese market at all; or because overseas drug application materials do not meet the requirements of the Chinese drug regulatory authorities, and even need to supplement a large amount of clinical research data, resulting in a short period of time for drugs.
cannot be listed in China
.
"In this case, it is necessary to use controlled medication (MAP) to improve the accessibility of these drugs in the domestic market
.
" Xiao Li told the health community
.

In many countries and regions around the world, Managed Use of Medicines (MAP) is a mechanism established to meet the availability of medicines for patients with urgent clinical needs.
Methods such as the Early Access Medicines Program (EAMS), which provide conditional access to treatment options not approved in the country
.

Huang Juan introduced that at the beginning of the project, Lonafani had not yet been approved
.
After many exchanges with Zhejiang University Children's Hospital, it is planned to try to promote drugs into China in the form of compassionate use
.

Compassionate medication means that when a patient suffers from a life-threatening disease and cannot participate in a clinical trial after exhausting the existing treatment methods, with the informed consent of the patient or his or her family members, a doctor applies for the use of an unmarketed drug for the patient.
Compassionate medication is implemented after review and approval by the relevant subject
.

However, due to the fact that the relevant laws and regulations are true, there are still many difficulties in the practice of compassionate medication
.

In 2017, after the former Center for Drug Evaluation of China Food and Drug Administration organized the drafting of the "Administrative Measures for Expanded Compassionate Use of Drugs for Clinical Trials" (draft for comments), the official document has not been issued
.
Although Article 23 of the newly revised Drug Administration Law in 2019 provides principles for the compassionate drug use system, it does not clarify and refine the follow-up issues related to the compassionate system
.

It was not until June 2021 that Peking Union Medical College Hospital achieved the first ice-breaking of compassionate medicine for rare diseases in China
.
At this time, Lonafanib has been approved and does not meet the principle of compassionate use
.
In the end, Zhejiang University Children's Hospital realized the introduction of Lonafani through the path of "temporary import approval"
.

Can the imported experience be replicated?

Thanks to policy guidance, the "Boao Lecheng Pioneer Area" and the "Guangdong-Hong Kong-Macao Greater Bay Area" have relatively mature experience in the approval of temporary drug imports
.

Xiao Li analyzed that according to the differences in regional policies, the Boao model will be more accessible after special approval.
"After a new drug is launched overseas, it can be used in Boao at the fastest about a month
.
"

The conditions for the use of the Greater Bay Area model are clinically urgently needed drugs that have been marketed in Hong Kong and Macau
.
"However, many rare disease drugs may or may not be listed in Hong Kong and Macau
.
" Xiao Li explained
.

Initially, Weide also considered the introduction of Lonafani through the above method, but it did not materialize
.
After consulting various opinions, Zhejiang University Children's Hospital adopted the one-time import of clinically urgently needed drugs with medical institutions as the main body of application, and Zhejiang University Children's Hospital took the initiative to submit the drug import application to the local health and health commission and drug regulatory department
.

In 2019, Peking Union Medical College Hospital introduced the special drug "Mitotan Tablets" for the treatment of adrenocortical cancer in this way
.
The drug has not yet been listed in China, but patients with adrenocortical carcinoma and Cushing's syndrome can achieve standardized treatment
.

However, the special thing that Zhejiang University Children's Hospital faces is that medicines enter China in the form of donated medicines, not for sale
.
This has never been seen before in the introduction of urgently needed clinical medicines in China.
It is an "ice-breaking journey" between medical institutions and charities
.

Medicines are brought into China in the form of donated medicines, not sold
.
This has never been seen before in the introduction of urgently needed clinical medicines in China.
It is an "ice-breaking journey" between medical institutions and charities
.

Mao Jianhua recalled that the biggest difficulty in drug introduction was the lack of a mature and proven introduction path
.

The biggest difficulty in drug introduction is the lack of a mature and proven introduction path
.

"When we first submitted an application for clinical drug use to the Provincial Health and Health Commission, it was rejected
.
Because they have never encountered a case of applying for urgently needed drugs by donation
.
The Provincial Health and Health Commission approved the application for urgently needed drugs after multiple demonstrations by experts from the Rare Disease Branch of the Medical Association
.
”

After receiving the letter of approval from the Zhejiang Provincial Health and Health Commission, the Zhejiang University Children's Hospital applied to the State Food and Drug Administration for the import of lonafanib through the Zhejiang Provincial Food and Drug Administration
.
Finally, on June 18, 2021, the official approval from the State Food and Drug Administration was obtained
.

I thought that after getting the approval from the Food and Drug Administration, the drug could enter China smoothly
.
Unexpectedly, overseas pharmaceutical companies have no experience in docking with the Chinese market, and Zhejiang University Children's Hospital has to start all over the drug access process
.

Unexpectedly, overseas pharmaceutical companies have no experience in docking with the Chinese market, and Zhejiang University Children's Hospital has to start all over the drug access process
.

In February 2022, substantial progress was made in the communication.
The British company CLINIGEN HEALTHCARE LIMITED signed a product agreement with Zhejiang Medical Technology Development Co.
, Ltd.
(a subsidiary of Hong Kong Weijian Pharmaceutical Group), and the latter handled the clinical trials of lonafanib on its behalf.
Import urgently
.

Although it is a donated medicine, if the overseas market price is as high as 1 million US dollars and is imported in the form of general trade, according to customs regulations, the medicine needs to pay up to 13% of taxes and fees, which is 130,000 US dollars
.
"Every patient had to continue treatment, and the annual treatment cost was as high as 1 million US dollars, and we had no funds to pay for it
.
" Mao Jianhua recalled
.

At that time, Zhejiang Medical Science and Technology Development Co.
, Ltd.
learned through the customs that the state has preferential tax policies for charitable donations of imported materials
.
And after the customs confirmed that it can be imported tax-free in this way, the company specially contacted the Zhejiang Women and Children's Foundation as a charity organization to receive and donate this batch of Lonafani worth 1,118,512 US dollars, which is limited to Zhejiang University Children's Hospital Progeria Continued treatment of children with the disease
.

The body is getting worse and worse, and the special medicine has finally arrived

Progeria in children is a disease that gradually develops serious complications as the patient ages
.

As he grew up, Kangkang's symptoms became more and more prominent
.
His bones were poorly developed, and he couldn't stretch his knees and elbows, so he couldn't walk
.
The knuckles were bent and could not be stretched, and the little hands were curled up
.
During the exam, Kangkang never finished the exam questions that the classmates wrote easily
.

What worries Zhang Yan even more is that due to the lack of development of the mandible, Kangkang's teeth are crowded together in a mess, which affects his breathing
.
The older you get, the easier it is to hold your breath when you sleep, just hold back
.

"I have to wake up several times every night
.
" Zhang Yan said distressedly
.

Every day of waiting for medicine, the child is in a race with death
.

"We definitely hope that the sooner the drug is launched, the better
.
" In the interview, Huang Juan expressed similar thoughts more than once
.

In March 2022, a month before the arrival of the drug, a 21-year-old father of a progeria patient sent a message to Huang Juan: "The child is gone forever, but thank you anyway
.
"

According to Huang Juan, this is the oldest patient with progeria in children found so far
.
After the patient's father learned about the drug donation plan, he had repeatedly inquired about the progress of drug access
.

"If the medicine can arrive a little earlier, I think it can help more patients
.
" Huang Juan said
.

As Lonafani entered China, the good news began to keep coming
.
Shu Qiang, secretary of the Party Committee of the Children's Hospital Affiliated to Zhejiang University School of Medicine, introduced that the hospital has formulated an integrated rescue service process for children with progeria, and formulated regulations and plans for drug sources, clinical use, risk control, and scientific research.
More children with progeria are expected to be Hope for better treatment in the future
.

Mao Jianhua shared that the hospital will continue the rescue plan for children with progeria
.
On the one hand, we continue to communicate with the Progeria Foundation of America to ensure that medicines can be continuously supplied to Chinese patients; on the other hand, under the leadership of Academician Liu Zhihong, Zhejiang University School of Medicine has also started to study the gene therapy of progeria in children, and has purchased An animal model of progeria has been developed, and corresponding preparations are being made
.

On April 25, after the pre-medication evaluation, Kangkang took lonafranil
.
Twice a day, two capsules at a time, after taking the medicine, Kangkang has no obvious adverse reactions for the time being
.

Zhang Yan knows that lonafranil is a drug for patients with cardiovascular and cerebrovascular-related diseases, and may have no effect on Kangkang's bone improvement
.
But she still hopes that after taking the medicine, Kangkang can sleep well
.
She is most worried about the side effects of Kangkang after taking the medicine, "I don't want the child to suffer too much
.
"

However, the story of the introduction of drugs urgently needed in clinical practice in China is far from over
.

Qiang Xiangyin, secretary general of the Medical, Health and Health Professional Committee of Zhejiang Lawyers Association and director of Zhejiang Shengyin Law Firm, told the health community: There are few regulations related to the introduction of drugs that are urgently needed for clinical use in China.
In Article 37 of the Implementation Regulations of the Drug Administration Law, there are no specific provisions on the scope of urgently needed drugs, the procedures for applying for import, the use and management of drugs, and the rights and responsibilities of relevant subjects
.

On March 29, 2020, the National Health and Medical Commission announced the "Work Plan for the Temporary Import of Drugs Urgently Needed in Clinical" (draft for comments), and Qiang Xiangyin believes that "this should take a certain amount of time before the official implementation, and it cannot be regarded as a drug that is urgently needed clinically.
Corresponding basis for importation
.
”

Mao Jianhua expects that in the future, the state can provide more supplementary rules from the perspective of law and policy, so that the policy of benefiting the people can be further implemented
.

In Xiao Li's view, with the gradual implementation of supporting policies, the introduction of urgently needed clinical medicines led by medical institutions like Zhejiang University Children's Hospital will become more and more common, and the efficiency will become higher and higher
.
"In the future, it is very likely that the introduction of drugs urgently needed in clinical practice will be realized in a short period of time
.
"

(Note: In order to protect the privacy of patients, Zhang Yan and Kangkang are pseudonyms in the text)

References:

1.
Progeria Research Foundation: Finding 60 Chinese Children with Progeria, PR Newswire, https:// Progeria Research Foundation: Finding 60 Chinese Children with Progeria, PR Newswire, https:// 2.
After two and a half years, progeria patients finally took medicine! The first time in the country! New exploration of drugs urgently needed in clinical, Rare Disease Information Network, https://mp.
weixin.
qq.
com/s/WZ3haLuBpeobUUlN3vZhrg

2.
After two and a half years, progeria patients finally took medicine! The first time in the country! New exploration of drugs urgently needed in clinical, Rare Disease Information Network, https://mp.
weixin.
qq.
com/s/WZ3haLuBpeobUUlN3vZhrg

3.
In order to save her terminally ill son, this doctor and mother published 50 SCI articles in a row, raising 240 million yuan to change her life, Lilac Academic, https://mp.
weixin.
qq.
com/s/LX6Sal1T1Yu_j4howNL9CA

4.
Reply of the State Council on Approving the Establishment of Hainan Boao Lecheng International Medical Tourism Pilot Zone, Qionghai Municipal People's Government website, http://qionghai.
hainan.
gov.
cn/rdzt/bmxxxc/zcfg/201511/t20151104_1110861.
html

5.
Notice of the State Administration for Market Regulation and Other Departments on Printing and Distributing the Work Plan for the Innovation and Development of Drug and Medical Device Supervision in the Guangdong-Hong Kong-Macao Greater Bay Area, State Drug Administration, https:// /gzwjzh/20201020145834142.
html

6.
Exploring new ways to access drugs for rare disease patients in my country: Compassionate medication system under the epidemic, China Journal of New Drugs, https:// Exploring new ways to access drugs for rare disease patients in my country: Compassionate medication system under the epidemic, China Journal of New Drugs, https:// 7.
"The Legal Dilemma of my country's Compassionate Medication System and Its Countermeasures", Chen Ying, Medicine and Society, April 2022

7.
"The Legal Dilemma of my country's Compassionate Medication System and Its Countermeasures", Chen Ying, Medicine and Society, April 2022

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