In-depth | less than 6% of children's special drugs in the medical insurance catalog, who can solve the problem of children's drug research and development

On 25 February, the European Medicines Agency ("EMA") approved the US-based Modelna vaccine for children aged 6 years and older. That's just over a year or so since the EMA recommended that the EU authorize Modelna for COVID-19 vaccine approval.

Generally speaking, the research and development of children's drugs is based on adult drugs and expands to children's indications. Some vaccine developers told reporters that according to the situation abroad, the expansion of the new crown vaccine to children is 6 months, and ordinary drugs are more than 2 years more than normal. However, due to the different pathogenesis of children and adults, some tumor drugs can be extended from adults to pediatric indications and even take up to ten years.

Supported by national policies, in recent years, the enthusiasm of domestic innovative pharmaceutical companies for the introduction of children's drug projects has been higher than in previous years, and some pharmaceutical companies have also accelerated the layout of children's drugs. Zhaoke Ophthalmology, Weisheng Pharmaceutical, Puli Pharmaceutical, Jianfeng Pharmaceutical, etc. have recently released the research and development dynamics of children's drugs.

However, the current situation of the lack of medical treatment and drugs in children has not changed, how to give enterprises the motivation to devote themselves to the research and development of children's drugs, how to build a clinical trial team of children's drugs, will become the key to the sustainable operation of children's drug research and development.

Lack of medical treatment and medicine

"Some people ask, in recent years, so many innovative drugs, is there a children's medicine?" Wang Jinhu, deputy director of the Hematology and Oncology Center of the Children's Hospital affiliated to Zhejiang University School of Medicine, raised such a question in a public sharing.

Taking the field of children's tumors that Wang Jinhu is most familiar with, it is most appropriate to use "lack of medical treatment and less medicine" to summarize the current situation of children's tumor treatment. She explained that childhood tumors are not miniature adult tumors, each with its own characteristics. There are fewer relevant specialists than pandas in the country, and there are no domestic drugs, and there are only 26 in the world.

In fact, the situation of pediatric oncology drugs is extremely serious. Among the pediatric tumor patients diagnosed each year worldwide, leukemia is the most common, accounting for about 30% of all cases, brain and spinal cord tumors account for about 25%, and neuroblastoma, nephroblastoma and lymphoma account for about 6% respectively. According to relevant media reports, since 1995, of the more than 180 cancer drugs approved by the FDA, only 14 have been approved for use in pediatric patients, another 26 have been used off-label (Note: in a manner not described in the license), and only 3 drugs have been approved for exclusive use in children.

"Because the biological characteristics are completely different, it is necessary to develop drugs for children individually. For example, brain tumors and neuroblastomas are unique to children's tumors, and molecular mechanisms need to be studied separately. Li Zhizhong, secretary general of the Shiyu Children's Public Welfare Foundation, said that the overall survival rate of children's tumors is relatively high because the dose of chemotherapy and radiotherapy is much higher than that of adults, and many children have 50-60 years of survival after clinical cure. However, more than 90% of children have various levels of long-term side effects. If new drugs are combined with chemotherapy and radiation therapy, side effects can be reduced.

The first financial reporter combed through the 2021 medical insurance directory and found that children's special drugs are also pitiful, accounting for less than 6%, and are limited to antibiotics, cold medicines, analgesic and antipyretic tracks.

Among the proprietary Chinese medicines, 54 of the 1312 drugs clearly have the word "pediatric", accounting for 4.12%; 1273 Western medicines, 41 drugs with the words "pediatric" and "children", accounting for 3.22%; in the drug part negotiated during the agreement period, among the 213 Western medicines, there are 12 drugs with the words "pediatric" and "child", accounting for 5.63%; among the 62 proprietary Chinese medicines, there are 2 drugs with the words "pediatric" and "child", accounting for 3.23%.

At the enterprise level, the current number of children's pharmaceutical companies has also become a major obstacle to the development of the industry. According to data from the State Drug Administration (NMPA), among the more than 6,000 pharmaceutical factories in China, the number of enterprises with children's drug production departments is more than 30, while there are only more than 10 enterprises specializing in the production of children's drugs.

Smell the business opportunity?

Since August 2011, the state has successively issued more than 30 policies involving the research and development of children's drugs, and has issued three batches of lists to encourage the development and declaration of children's drugs. The "Healthy China 2030" planning outline also mentions that the under-5 mortality rate will be reduced from 9.5 ‰ in 2020 to 6.0 ‰ in 2030.

In addition to the general direction of national policies, in fact, the research and development of children's drugs in each disease field is not the same, such as preventive vaccines, respiratory, skin, ophthalmology, otology, infectious diseases, metabolism, psychiatric diseases and other fields, there are more layouts, while tumors, rare diseases and other difficulties are the most difficult, and only a few pharmaceutical companies are in research and development.

On February 17, Zhaoke Ophthalmology has launched a Phase 3 clinical trial of atropine sulfate eye drops (NVK-002) to delay the progression of myopia in children, with plans to enroll 526 patients in China. The eye drops were imported by Zhaoke Ophthalmology from Nevakar. Also strategically laid out in the form of foreign introduction is Weisheng Pharmaceutical, which mainly includes long-acting growth hormone and rare disease treatment drugs.

Different from ophthalmic drugs and metabolic drugs that involve a large number of people, children's tumor drugs are rare diseases, and the choice to introduce or develop children's tumor drugs means that there is no economic benefit and requires great courage.

"There are 30,000-40,000 child cancer patients in China every year, and about 400,000 people in the world every year, and once the childhood tumor patients recur, the treatment plan will be very limited." Over the past 30 years, drugs that have targeted childhood tumors alone have been in the single digits. However, after 2017, the number of drugs that approve adult indications first, then children's indications, or both children's and adult indications, is also slowly increasing. Li Zhizhong sighed that ten years ago, the United States began to develop children's oncology drugs, and now China also pays attention to and attaches importance to it, the research and development of children's drugs is difficult and difficult, but China has the opportunity to achieve breakthroughs in this field, it can be said that the research and development of children's tumor drugs is opportune.

In recent years, more and more people have paid attention to children's drugs, and the industry situation is also improving, but the shortage of children's drugs still exists. Industry insiders who have paid attention to the children's drug market for many years told reporters that there are still not many domestic functional drugs and children's drugs with strong therapeutic properties. Some enterprises have also been affected by the purchase policy with quantity, and their profitability has decreased, and they have begun to turn to the blank market of children's medicine.

The online and offline exchanges of some industry organizations have also made the field of children's medicine more and more concerned. The China Children's Drug R&D and Industrialization Alliance (hereinafter referred to as the "Pediatric Drug Alliance"), an industry organization established in August 2020, has brought together a group of people concerned about children's drugs through a number of symposiums, promoting the overall development of the industry.

Conquer levels

The development process of children's drugs has a lot to do with the attributes of the patient population, which increases the difficulty of clinical trials to a certain extent. On November 10, 2021, the Drug Review Center of the State Food and Drug Administration released the "Annual Report on the Status of Registered Clinical Trials of New Drugs in China (2020)" (hereinafter referred to as the "Report"), which mentions that among the subject population, there are relatively few clinical trials carried out in specific populations, and 3 clinical trials carried out in the elderly population and the children population in 2020 are 3 and 33 respectively, accounting for only 1.4% of the total number of trial registrations in the whole year.

The results of the analysis such as the efficiency of clinical trials show that the proportion of pediatric drug clinical trials in mainland China is relatively low, and the geographical distribution of clinical trials is uneven. There are fewer clinical trials of pediatric drugs, mainly biological products and chemical drugs, and fewer traditional Chinese medicines, while the indications are mainly anti-tumor drugs and vaccines. The applicant's low enthusiasm for pediatric drug research and development may be related to factors such as the long cycle of pediatric drug clinical trials, the difficulty of recruiting subjects, and the high safety risk.

Specifically, the pediatric drug clinical trials section shows that there are 129 clinical trials including pediatric subjects, accounting for 8.8%; according to the classification and analysis of drugs, the number of biological products registered is the largest, 70, followed by chemical drugs and traditional Chinese medicines; according to indication analysis, the main indications are distributed as anti-tumor drugs, preventive vaccines, skin and five senses, etc., the main indications of biological products and chemical drugs are roughly the same, and chinese medicines are mainly respiratory drugs. A total of 33 clinical trials of new drugs were registered in the pediatric population alone, accounting for only 2.2% of the total number of clinical trials of new drugs.

The head of clinical trials of children's hospitals told the first financial reporter that the clinical trial cost of children's drugs is high, the operation is more difficult, and there are many details that are different from adult drugs. For example, some children cannot express themselves and cannot clearly quantify the perception of symptoms in the body. In addition, children's participation in clinical trials is mostly involved by parents, but some services are not doing well.

She mentioned that in the field of pediatric medicine, there are still too many clinical unmet needs. In addition to the effectiveness and safety of drugs, the way drugs are fed, the taste of drugs, the dosage of drugs, the frequency of drugs, etc. need to be more refined, and there is a lot of room for improvement, and each change and the acquisition of product numbers require the necessary research and corresponding registration approvals.

"Insufficient clinical resources, poor quality control, and lack of basic research teams are the main problems. From the perspective of medical research and enterprise collaboration, doctors should study together with researchers. Wang Jinhu said.

Based on the practical problems of clinical trials, policy support will become the most critical part of children's drug research and development. In order to let the people use new drugs faster, in the Hainan Boao Lecheng Pilot Zone, the state can collect foreign drugs that have been listed abroad and are not listed in China, through real-world data research, and then approve and list them in China. Such an idea will play a clear advantage in the field of children's medicine.

Li Zhizhong believes that this idea is particularly good, and even the treatment of certain rare diseases will be more ideal. "If the research and development of rare diseases is done according to the traditional model, the cost performance is too low. Real-world data will further reduce the difficulty of pharmaceutical companies and accelerate the availability of drugs. ”

While he was very supportive of such an exploration, he also mentioned the challenges to be faced. The biggest difficulty lies in the quality of real-world data. Clinical trial research will be carried out in a systematic and controllable manner, and in the real world, there will be more variables that affect the efficacy of the drug. How to collect data and how to judge the efficacy of the drug are very challenging.

How to motivate businesses?

The progress of each link is touching the core of the problem step by step, that is, who is really willing to develop children's drugs?

In January 2020, after BeiGene and Amgen reached a global oncology strategic cooperation, the new immunotherapy drug BLINCYTO (belintoumab for injection) became the first blood tumor product authorized by Amgen and approved by BeiGene in China. On August 31, 2021, the drug was officially commercialized. It is reported that at present, the marketing application of Belito for the new indications for children's relapsed or refractory precursor B-cell ALL has been accepted by the State Food and Drug Administration and included in the priority review.

In addition, On August 17, 2021, BeiGene and EUSA Pharma jointly announced that the State Drug Administration of China (NMPA) has approved Kaiser's Bai (datuximab β) for the treatment of high-risk neuroblastoma patients aged 12 months and older.

According to people familiar with the matter, after the successful application of this drug, BeiGene has discussed many rounds within BeiGene, and the conclusion of each round is that the drug will lose money, but in the end they decided to introduce it.

Compared with the number of adult tumor patients, the number of pediatric tumor patients is small. Therefore, due to economic considerations, very few companies are willing to develop drugs for children's tumors and rare diseases alone. Li Zhizhong told the first financial reporter that more opportunities are that there are some anti-tumor drugs or drugs used for the treatment of other diseases, if found to be beneficial in children, they will be quickly tested.

But this does not mean that the drug can be approved quickly, and the cycle of adult drugs to expand to children's indications is generally very long. In January 2021, the FDA approved a New Supplemental Drug Application (sNDA) for the treatment of children and young adults with anaplastic lymphoma kinase (ALK)-positive, relapsed, or refractory systemic anaplastic large cell lymphoma (ALCL) that targets the anticancer drug Xalkori (crizotinib). ALCL is a rare non-Hodgkin lymphoma (NHL) that accounts for about 30% of NHL cases in young people. About 90% of ALCL cases in the young population are ALK positive.

This ALK inhibitor was actually used in the treatment of lung cancer a decade ago, that is, in 2011. According to Li Zhizhong, it was not long before that, it was actually known that this drug may be effective for such children's tumors. But it took a long decade for approval. There may be a variety of factors such as slow project start-up, lack of motivation, insufficient funding, and difficulty in recruiting patients. "Expect better mechanisms in the future, not necessarily fully synchronized, but at least not a decade off."

Data show that between 2007 and 2017, the FDA approved 78 new adult cancer drugs, but none of them completed studies aimed at determining their efficacy against pediatric cancers.

2017 seems like a turning point. In May of that year, the state issued the Technical Guidelines for Extrapolating Adult Medication Data to the Pediatric Population. That same year, the FDA introduced the Research to Accelerate Cures and Equity (RACE) for Children Act, which came into effect on August 18, 2020. The act requires pediatric evaluation of new drugs and biologics used to treat adult cancer whose molecular targets are closely related to the growth or development of pediatric tumors.

If you count the economic benefits alone, this is not enough to give companies an incentive to develop children's oncology drugs, so there are guidelines after the bill is introduced, in addition to a special incentive, that is, to prioritize the review of preferential coupons. With this coupon, the new drug approval process can be shortened by several months, and more importantly, the coupon can also be traded, and large pharmaceutical companies are willing to spend hundreds of millions of dollars to buy it to help the products with large indications go to market in advance. Such a small business will be very motivated.

The staff of multinational pharmaceutical companies responsible for pediatric indications projects told reporters that due to the clinical needs of pediatric drugs, patients' willingness to pay and the relatively high degree of support for access policies, foreign pediatric drugs and pediatric indications of drugs will be actively introduced into the domestic market for clinical and follow-up registration declarations.

The above-mentioned industry insiders said that the research and development of children's drugs should take into account the commercial and social nature, the registration and approval of children's drugs, more importantly, follow-up market access, medical insurance, commercial insurance payment, social assistance and other links, the policy should be inclined and effectively supported, focusing on children. Give more market opportunities and channels to enterprises willing to develop and produce children's drugs, as well as give more policy support. The general direction of national policies has been guided, but specific incentive mechanisms have not yet emerged.

"Instead of competing for speed and money at the same target, develop new targets and become a true fierinclass." If pharmaceutical companies can explore the world's first drug to discover new indications on rare childhood tumors, such pharmaceutical companies will have more commercial value. As a doctor of cancer biology, Li Zhizhong has many years of experience in the development of new cancer drugs, and he hopes that the research and development of children's tumor drugs can eventually form a complete closed loop. In this way, once a set of templates is explored, it can provide references for other segments.

Many links are not yet mature, such as the statistical scientific problems of incidence and the training of pediatricians. "It's a slow job, and it's going to push a little bit." Li Zhizhong said.