Dozens of policy incentives make it difficult to support new pediatric medicines. Where is the difficulty?

In 1952, an 8-year-old boy was sent to the pediatrician Ogden Bruton due to repeated pneumonia infection and severe seps.

Forty years later, the immunodeficiency gene was first isolated and named "Bruton's tyrosine kinase, abbreviated as BT.

In 2022, BeiGene's BTK inhibitor zanubrutinib was approved by the FDA, becoming the first locally developed anticancer therapy, but its approved indication is only for "adult" mantle cell lymphoma (MCL) patien.

Numerous diseases that have been discovered in childhood patients, and innovative drugs that have emerged after decades, are often limited to "adults" when they are finally approved, which is embarrassi.

However, this is not the first time that the relevant state departments have issued an encouragement docume.

It can be said that the issue of children's drug use has been haunting the minds of relevant departments of the country, and its attention is also increasing day by d.

Why? How to do it? It has become the two most tangled issues for countless pharmaceutical compani.

The status of new pediatric drugs is not optimistic

When it comes to children's medicines, it is normal to rely on "breaking" and "guessing" within the scope of public percepti.

In the overall situation of pediatrics, the severe situation of children's oncology drugs is even wor.

And since 1995, of the more than 180 cancer drugs approved by the FDA, only 14 have been approved for pediatric patients, and another 26 have been used off-label (note: used in ways not described in the license) , only 3 drugs are approved exclusively for use in childr.

In China, only 3,061 (194 ingredients) approval numbers of all approved drugs involve pediatric use, accounting for less than

Whether it is pediatrics as a whole or the oncology field in key areas of innovative drugs, the situation is far more severe than we imagin.

Where is the difficulty in new pediatric drugs?

The main reason why children's medicine is so "lack" is mainly due to "difficulty", which is the long time-consuming research and development in the process, the high risk of clinical research, the high requirements for the selection of raw materials and excipients and the quality control, the difficulty in recruiting clinical trial subjects, and the lack of institutions involv.

Among them, the most important ones are clinical trials, market and project approv.

The research and development of children's medicines is difficult to recru.

Children's drug clinical trials refer to any drug research conducted in children to confirm or reveal the effects, adverse reactions and/or absorption, distribution, metabolism and excretion of the test drug in the human body, with the purpose of confirming the application of the test drug to the population of children safety and effica.

According to relevant regulations, children's drug clinical trials must follow the basic principle of "minimum harm and minimal risk", and will only be conducted when the benefits outweigh the har.

In addition, there are stricter rationale and scientific review in the trial process than ordinary clinical tria.

Unless it is a drug that has been on the market for many years with accurate clinical evaluation, or a drug that has been fully demonstrated to have no difference in metabolic properties between children and adults, it will be considered It is also difficult for powerful leading pharmaceutical companies to devel.

To give a simple example, in the process of new pediatric drug research and development, the “ reason ” alone is enough to discourage most dru.

Imagine if it were not for orphan diseases or some mortal diseases , how many parents would like their children to be clinical subjects? How many people give up the relatively conservative but safe past treatment methods and choose to embark on an unknown ro.

And even if some major diseases have successfully carried out clinical trials, a small problem of placebo use in the control group has become the fuse for terminating the entire clinical trial, and "children" cannot afford to be offend.

So, since "children" cannot be the subjects of clinical trials, is it feasible to directly substitute adult trial data?

The answer is "n.

The death of grey infant syndrome caused by chloramphenicol around 1956 is the best examp.

Because children's organs are immature compared to adults, and the PK PD in the body is different from that of adults, even the response to reduced doses of drugs may be different from that of adul.

Not doing clinical trials is tantamount to gamble with the lives of all "childre.

Therefore, under the combined effect of various difficult factors, there is such a "deformed" pediatric drug development sce.

According to the specific data of children's clinical trials, there are 129 clinical trials involving children in related drug clinical trials since 722, accounting for 8%; and a total of 33 new drug clinical trials conducted only in children are register.

, accounting for 2% of the total clinical trials of new dru.

As of 722, there have been no more than 100 clinical studies on children enrolled in the group, which is not even as much as the number of clinical trials of a new crown vaccine in a few yea.

In addition, in addition to the difficulties in conducting clinical trials, the results of clinical trials are biased due to problems such as the inability of children to express their physical symptoms and the inability to clearly quantify the perception of physical symptoms; Among the majors recognized by each clinical trial institution, there are 918 children's majors, accounting for about 2%) and other problems are further exacerbating the difficulty of clinical trials of children's dru.

The research and development of children's medicines is difficult to establi.

According to the current centralized procurement rules of the Medical Insurance Bureau, the clinical needs and classification of pediatric drugs are difficult to differentiate, which makes it difficult to obtain advantages in the process of establishing relevant drug projec.

It is also one of the proble.

For example, in the case of drug compliance that is generally concerned by family members of clinical children, the manufacturer has changed the taste, but the dosage form is no different from the original research, and it is difficult to obtain the approval of the medical insurance bure.

In the "Technical Guidelines for Clinical Trials of Improved New Drugs of Children's Chemical Drugs (Trial)" issued by CDE in 2021, it is also proposed: "It is usually difficult to change the taste, change the packaging specification, change the solvent or change the characteristics of some pharmaceutical preparations as a single improvement purpo.

However, due to its clear clinical value, enterprises are encouraged to pay attention to the research and development of improved new drugs for children, and to optimize the characteristics of preparations with multiple objectives at the same ti.

”

That is to say, for pediatric drug project approval, it is not feasible to improve by changing the taste and packaging specifications, perhaps because the advantages are not obvious, not to mention that it is not easy to meet the clinical advantages of CDE, and it is necessary to meet the requirements at the same ti.

The differentiation of the medical insurance bureau has also largely dampened the enthusiasm of manufacturers in the iterative upgrade of clinical pediatric drugs, resulting in a serious shortage of pediatric drug projects compared with adult dru.

The research and development of children's medicines is difficult in the market

Maybe someone told you that the pediatric drug market will be a new blue ocean market in the future, but the fact is that the pediatric drug market has always been a niche mark.

First of all, it is necessary to understand that the current pediatric medicines, whether outside or inside the hospital, except for rare diseases and major diseases, most of the drug types are covered by Chinese patent medicines, and then remove the respiratory system, digestive system and other common diseas.

The drug market developed by the people is actually not lar.

Throughout the world's leading multinational pharmaceutical companies, let alone specializing in paediatric drugs, there are very few paediatric drugs involved in the R&D pipeli.

Even Johnson & Johnson, which involves more pediatric drugs, will not exceed 7% of its field revenue in 2021 (drugs whose indications cannot be expanded to pediatric drug.

Secondly, due to the characteristics of pediatrics that is separate from internal medicine and surgery, the field of pediatrics is more like a brand new field for most pharmaceutical companies, and many factors such as sales and market cultivation are bla.

It looks lively, but there are many onlooke.

Finally, in addition to individual products such as growth hormone, even if the large variety of single products in the field of pediatric medicine with innovative attributes have scientific and clinical significance, it seems that it is not so easy to get ahead in the mark.

In terms of cost performance, it is far less than the field of adult medici.

However, the main object of appeals that have been constantly emphasized that "lack of doctors and medicines" is still focused on the research and development of rare diseases such as leukemia and children's tumo.

For new drug research in this blank area, not every company has the strength to get involv.

What's more, even if the product is launched, the market's resistance to advancement will be greater than that of other fiel.

First, the characteristics of pediatrics are different from internal medicine and surgery, which also makes the field of pediatrics more like a brand new field for most pharmaceutical compani.

Sales, market cultivation and many other aspects are basically started from scrat.

Except for individual products such as growth hormone in the pediatric field of the two, the probability of breaking out a large single product is not large, and the cost performance is obviously insufficie.

Real data, data extrapolation, or hope for 'pediatric' clinical trials

◆ Real world data

Based on the practical difficulties of clinical trials, some voices in the industry pointed out that for some drugs that are marketed abroad but not marketed in China, through real-world data research as case collection, speeding up the progress of domestic listing may to a certain extent strengthen the advantages of new pediatric drug developme.

After all, it is obviously unrealistic to want to produce multiple original innovative drugs in the field of pediatric medicine in a short period of time, and new pediatric medicines are likely to be equivalent to new drugs for rare diseas.

too l.

If the quality of real data can be effectively controlled and the many variables that affect drug efficacy can be reasonably analyzed, there is no doubt that there will be great hope that the popularity of new pediatric drugs in China will be greatly increas.

◆ Data extrapolation

Data extrapolation usually refers to extending the research information and conclusions of known populations to unknown populations (target populations) through scientific research methods, thereby reducing unnecessary research in unknown populatio.

The data extrapolation involved in CDE is to extend the known research information and conclusions of Chinese adults to the pediatric populati.

Image source: Screenshot of the Evaluation Center of the Food and Drug Administration

Of course, the "Guiding Principles" also point out that, as a form of clinical research, data extrapolation also needs to follow the general principles of clinical research and the special considerations of children's clinical research in the implementation process to support drug registration and regulatory decisio.

12 new pediatric drugs show promise for the future

With the approval of the first domestic child-specific expectorant spray last year and the suspension of the clinical trial of BC0335 granules for children's respiratory syncytial virus infection, in recent years, both the approval and the development of clinical trials in the field of pediatric medicine have been subject to frequent policy chang.

maintained a good growth moment.

According to incomplete statistics from the People's Daily Health Client, there are currently more than 40 new pediatric drugs in China that are in the clinical stage of approval and above, of which 12 are Category 1 new dru.

Among them, the first category of new drugs has entered Phase III clinical trials except Hengrui's Haitrombopag ethanolamine tablets, Tianjing Bio's TJ101 injection and Shanghai Aikebaifa's AK0529 enteric-coated capsul.

The products are still in the early clinical stage, and from the perspective of indications, chemical drugs mainly cover the fields of anti-tumor, anti-infection, nervous system, e.

, focusing on acute and serious diseases; biological drugs are still concentrated in growth hormone deficiency, treatment of children's production Slow; Chinese patent medicine is more used in common diseases, mainly in the field of respiratory syst.

At least for now, with all kinds of innovative drugs seriously infiltrated, the large clinical demand for pediatric drugs is still attractive to large pharmaceutical compani.

Compared with "insured" improved children's new drugs or generic drugs In today's general environment where volume procurement is not yet known, taking the lead in cooperating with national policies to develop new pediatric drugs can also enable pharmaceutical companies to gain a certain dominant position in the later competition proce.

It is expected that there will continue to be leading companies in the later sta.

"This difficult and relatively blank market is both a trend and a helpless situati.

Experts said, "Instead of competing for speed and funding on the same target, if pharmaceutical companies can explore the world's first drug with new indications in rare childhood tumors, such pharmaceutical companies will have more commercial val.

" For today 's It is a necessary stage for leading pharmaceutical companies to cross the river by feeling the ston.

Only after they have explored a set of templates, the rest can keep up, and the field can prosp.