Can the problem of pediatric drug research and development be solved by relying on the "data extrapolation" of adult drugs?

Written by Wu Xiaofei

On April 12, 2023, the Center for Drug Review (CDE) of the State Food and Drug Administration (NMPA) issued the Guidelines for Quantitative Methodology for Extrapolating Adult Drug Data to Pediatric Population (Trial) (hereinafter referred to as the "Quantitative Guidance"), which aims to improve the efficiency of pediatric drug research and development and guide the industry to rationally apply extrapolation methods.

The Center for Drug Review believes that due to the ethical and practical difficulties in clinical research and development of pediatric drugs, it is also a strategy and method for pediatric drug research and development to minimize the number and steps of pediatric test groups and optimize the R&D process by making full use of existing data.

It is worth noting that the Quantitative Guidance is only a guiding document, only for R&D reference, not a law or regulation, and is not mandatory. In fact, as early as 2016, the Drug Review Center widely solicited public opinions on the extrapolation of adult drug data to children, and in May 2017, the former State Food and Drug Administration issued the Technical Guidelines for the Extrapolation of Adult Drug Data to Pediatric Populations (hereinafter referred to as the "Guiding Principles"). The industry generally believes that the Quantitative Guidance in April this year is a supplement and improvement to the Guiding Principles at the operational level.

For the successive release of documents such as the "Guiding Principles" and "Quantitative Guidance", a number of industry insiders told the "medical community" that the official guidance of the drug review center is conducive to standardizing the data extrapolation method and helping the research and development of pediatric drugs, but in specific practice, it is necessary to specifically judge whether there are extrapolation conditions and the necessity of extrapolation according to different drug attributes.

"The method of data extrapolation should continue to advance and improve in the future, because based on the dilemma of pediatric drug research and development in the past, institutions interested in this will actively try new methods and explore new paths, and whether it can be promoted more widely by the industry needs to be observed, because business pays attention to profitability, and corporate behavior still depends on how high the rate of return can be." Shi Luwen, director of the Department of Pharmaceutical Affairs Management and Clinical Pharmacy of Peking University School of Pharmacy and member of the Pharmaceutical Affairs Management Professional Committee of the Chinese Pharmaceutical Association, said.

Source: Ruijing

The dilemma of pediatric drug research and development is difficult to solve

"The difficulty of developing pediatric drugs is a global problem that has lasted for a long time." Zhu Zonghan, honorary president of the Pediatrician Branch of the Chinese Medical Doctor Association and a senior pediatric expert, told the "medical community" that the resulting children's drugs generally exist in terms of variety, dosage, dosage, taste and other aspects, and it is difficult to meet the diverse drug needs of children.

A set of data widely cited by the media is: there are currently more than 6,000 pharmaceutical companies in China, and only more than 10 pharmaceutical companies specialize in the production of drugs for children; There are only more than 30 pharmaceutical companies whose products cover children's drugs; Less than 5% of the total volume of drugs produced specifically for children in China is produced, and 90% of drugs do not have a "children's version".

"Medication depends on breaking, dosage depends on guessing", this is the drug portrayal when there is a lack of special drugs for children in the past. In the real world, there are often alternatives to unmet needs. Zhu Zonghan introduced that clinically, if the drug label does not clearly write "prohibited for children" and there is no special drug for children, in line with the principle of treating patients and saving people, pediatricians will often convert drugs with fewer side effects and administer them according to the proportion of children.

The above medication is not completely risk-free. A number of pediatricians interviewed told the "medical community" that children are not a scaled-down version of adults, children of different ages have different tolerance and response to drugs, generally more fragile than adults, especially young children whose liver and kidney development are not perfect, the drug metabolism capacity is low, and the accumulation of metabolites may produce toxicity and affect health.

The factors that make medication difficult for children are diverse. Zhu Zonghan said that the child population is much smaller than the adult group, and parents generally resist their children's participation in medical experiments, which makes it very difficult to recruit subjects for pediatric drug clinical trials. In addition, because of the vulnerability of children, the complexity and difficulty of clinical trials will be higher than that of adults, and "fully strictly executed randomized controlled trials are also unethical." ”

In reality, there are also types of diseases, and there is no gold standard for clinical drug trials using randomized controlled trials. Han Rui, head of the rare disease division of a leading multinational pharmaceutical company, told the "medical community" that the group of children is already smaller than that of adults, and there are even fewer children with rare diseases, and it is impossible to recruit enough subjects for trials.

Han Rui also said that rare diseases are generally major diseases for children, such diseases are similar to the type of diseases with a high fatality rate, double-blind trials cannot be conducted, and the control group using placebo is likely to be life-threatening because the drug is not taken in time.

In addition to the technical difficulties, fewer and more children's drugs on the market are also related to lower profits. According to a number of interviewees, compared with the adult drug market with a huge number, the children's drug market is small, the threshold is high, it is difficult for enterprises to obtain expected benefits, and the enthusiasm for research and development is not high.

How data is extrapolated

In order to solve the difficulties in the research and development of pediatric drugs, the concept of data extrapolation has been raised and widely accepted. The medical community generally believes that data extrapolation can simplify the development of pediatric drugs, solve problems such as difficulty in recruiting enough child subjects, improve the efficiency of pediatric drug development, and help increase the number of approved pediatric drugs.

The so-called data extrapolation refers to the extension of research information and conclusions of known populations to unknown populations through scientific research methods, thereby reducing unnecessary research in unknown populations.

The concept of data extrapolation was proposed by the U.S. Monetary and Food Administration (FDA) in 1992 when revising the Pediatric Drug Labeling Regulations in the Federal Drug Administration Act, and in 1994, it was officially written into the final revision of the Pediatric Drug Labeling Regulations. In the following decade, the European Medicines Agency (EMA) and the International Harmonization Committee on Technical Requirements for Registration of Medicinal Products for Human Use (ICH) participated in data extrapolation studies and incorporated this method into the relevant guidelines for clinical research of pediatric drugs. The extrapolation of the data referred to by the drug review center is basically consistent with the relevant definitions of FDA, EMA and ICH.

In practice, the extrapolation of broad concepts may have been practiced for many years. Zhu Zonghan pointed out that the research path of medical experiments ranges from animals to humans, from adults to pediatrics, from the advanced age to the young age of the pediatric population, and some experiments expand from foreign populations to domestic populations, all of which are extrapolated to a certain extent.

Zhu Zonghan believes that in recent years, because special drugs are less actual medicine for pediatric people, some people secretly buy drugs overseas in order to treat diseases, which is already a "data extrapolation" in the substantive sense, but in the past this concept was not used, but now it is more standardized and rigorous, requiring some scientific paths and methods.

The Guiding Principles divide the extrapolation of the Chinese pediatric population into three situations: 1. Chinese adult data are available and foreign indications for pediatric populations have been approved; 2. There are Chinese adult data and reference data of pediatric population at home and abroad; 3. Only Chinese adult data.

According to the above three cases, the extrapolation mode is divided into three types: "full extrapolation", "partial extrapolation" and "no extrapolation". In case 1, for example, this scenario is the easiest to implement. R&D institutions need to first evaluate whether there are differences in disease epidemiology, etiology, pathogenesis, prognosis, etc. in different regions. We then evaluated whether there were racial differences in the data from trials of adult patients at home and abroad. If there is sufficient evidence to show that there are no significant differences in the above aspects, then the drug clinical trial data of foreign pediatric populations can be used to the Chinese pediatric population for "complete extrapolation".

However, practitioners of medical institutions Zhang Huimin, Liu Aiming and others wrote that the current data extrapolation guidelines do not clearly describe some key concepts and algorithms, such as unclear methods for quantitative synthesis of qualitative data, unclear parameters to provide for similarity assessment between different groups, and unclear criteria for judging similarity.

The "Quantitative Guidance" issued by the Drug Review Center on April 12 mainly explains the specific extrapolation strategies, main quantitative methods and application scenarios such as data extrapolation, so as to provide R&D institutions with R&D reference and guide relevant institutions in drug registration.

Does it work? Is it safe?

The literature shows that between 1998 and 2008, of the 166 pediatric varieties declared to the FDA, 137 were extrapolated, accounting for 82.5%, and 84 were finally approved. Another study showed that from 2009 to 2014, 157 data extrapolated varieties were declared to the FDA, 34% of them used complete data extrapolation, and 29% of them were partially extrapolated, and the proportion of fully extrapolated varieties increased compared with the results of the 2011 research results.

In China, Geng Ying, an assessor of the Center for Drug Review, mentioned in the literature published that since the issuance of the Guiding Principles in May 2017, more and more research institutions have adopted the data extrapolation strategy to declare drugs, among which the existing Chinese adult data with a low threshold and the indications approved for pediatric populations abroad are mainly used, and the declared varieties are mainly imported original drugs and domestic generic drugs that have been marketed to expand to the Chinese pediatric population.

If data extrapolation is more efficient and convenient in pediatric drug development centers, does this mean that traditional randomized controlled trials can be exempted, and are extrapolated approved drugs equally safe and effective compared to the latter?

Both Chinese and foreign drug review institutions emphasize the premise of data extrapolation: it must be based on the same pathophysiology, the same drug metabolism process and similar dose-response between adult and pediatric populations. The proof and falsification of this similarity can be completed by certain models, referring to existing literature, real-world data, pharmacokinetic tests, bridging tests, etc.

"It is wrong to unilaterally understand data extrapolation as a 'simplification' of the reporting process or reporting requirements." Geng Ying et al. emphasized that data extrapolation cannot be simply equated with exemption from clinical trials in children, and when using data extrapolation strategies to declare drugs, the clinical data to be prepared also needs to be comprehensive and sufficient, and true, effective and sufficient evidence is needed to prove the effectiveness and safety of extrapolation.

When it comes to security, industry insiders don't agree completely. "Data extrapolation is generally safer than clinical trials, which have been fully tested in humans and have extensive real-world data, and what is missing may be some children's clinical data, which is completely new." He Shuwang, general manager of the R&D center of Shandong Dyne Marine Biopharmaceutical Co., Ltd., said that Dyne Biotech is a domestic manufacturer of special drugs for children.

Han Rui believes that children are not a scaled-down version of adults, and data extrapolation still requires a strong theoretical basis, qualifications and parameter indicators. Because children are vulnerable groups and pay more attention to the safety of medication, adults have some data, or adults prove to be safe, may not be safe in children, "I think we should be more cautious in this exploration, and clinical needs to be more cautious and comprehensive evaluation." ”

However, regarding Han Rui's concerns, Zhu Zonghan said, "Data extrapolation generally considers those that are less sensitive to age and weight and have fewer side effects, such as antibiotics and antivirals." Widely used examples include the non-steroidal antipyretic analgesic ibuprofen and fluticasone propionate inhaled aerosol for asthma.

The consensus in the industry is that randomized controlled trials are still widely accepted gold standards in drug clinical trials, and adult drug data is the basis for data extrapolation.

"Different research methods have their own research methods and applicable conditions, can not simply compare the advantages and disadvantages, can only say whether in a specific situation, which is more suitable, the two are not either/or relationship, 'black cat white cat, catch a mouse is a good cat'." Shi Luwen said.

In addition, for drugs declared by data extrapolation strategy, CDE also stressed that any extrapolated conclusions have limitations and need to be scientifically validated through clinical research and/or clinical practice, and R&D institutions should propose strategies to reduce uncertainty and risk. For uncertainties and risks that are difficult to know before listing, it is necessary to develop a post-marketing research plan, long-term follow-up, and post-market monitoring.

Challenges beyond technology

It is understood that the industry generally believes that the "Guiding Principles" and "Quantitative Guidance" are a kind of positive information for pediatric drug research and development, which helps enterprises to solve problems such as insufficient subjects and cannot conduct clinical trials, but in specific practice, they will not blindly declare due to the broadening of research and development methods, but choose according to the difficulty of existing product research and development and the expected market capacity.

At the end of 2022, Hanrui's company expanded the target population of a rare disease drug from 8 years old to 2 years old and above. Han Rui learned that the application for the drug's expanded indications in China is part of its global initiative, "We were approved by the FDA and the European Union first, and then the Chinese market. ”

Han Rui said that when the drug applied for expanded indications in China, it held several rounds of consultations with the drug review center, and the topics exchanged between the two sides included whether it was necessary to expand the indications in China and whether it was necessary to carry out post-marketing studies, and "the whole process was relatively smooth."

Han Rui believes that the company's strong patient data is inseparable from the success of drug declarations. According to him, the company has established a global patient registry system, which covers patient data worldwide, "Before the drug declaration expansion, we already had real-world data on patients aged 2 to 7 years outside of China. ”

"There are no conditions for randomized double-blind trials for rare diseases, and data extrapolation is a way that companies will actively try, and favorable policies pay more attention to unmet drug needs, such as rare diseases, pediatric emergencies or major diseases." Han Rui said.

He Shuwang said that at present, Dyne Pharmaceutical does not have a drug that adopts a data extrapolation strategy. It is understood that the company's products include common children's vitamin supplements, anti-allergic drugs, fever-reducing pain drugs and children's health care drugs.

The reason, He Shuwang explained, is that at present, their product line and short-term market layout do not need to use data extrapolation strategies to declare new drugs or expand indications, "If there is a need in the future, we will consider extrapolation strategies."

For the above market behavior, Shi Luwen analyzes that because most of the rare diseases cannot be cured, there are few treatment methods, and the urgency of practical needs makes enterprises more enthusiastic about new methods. For common pediatric diseases, although many do not have special drugs, but there are many clinical alternatives, enterprises to invest energy to develop new drugs may not be superior to existing treatment options, but also need to invest a lot of manpower and material resources, facing some risks and pressures in research and development, "thankless, or investment reporting rate is relatively low, enterprises are not motivated."

"In recent years, China has had a lot of favorable policies for children's drug research and development, and the staff of the approval department have worked very hard, but the drug needs of the pediatric population are still not fully met, and the crux of the problem is not whether it is technically difficult or whether the approval is convenient, but whether the enterprise can make a profit." Han Rui said.

Han Rui hopes that for the unmet drug demand, especially in the niche drug market, functional departments should allow enterprises to link volume and price from an economic point of view, and give pharmaceutical companies a certain profit margin to stimulate their enthusiasm for research and development. "If the higher pricing of niche drugs is either not allowed to enter the medical insurance catalog, or the low-priced bidders are bidding, and the R&D costs and economic benefits of the enterprise are not considered, it is difficult for the company to have sustained enthusiasm in this field."

(At the request of the interviewee, Han Rui is a pseudonym)

Mentor experts

Shi Luwen, director of the Department of Pharmaceutical Affairs Management and Clinical Pharmacy of Peking University School of Pharmacy, and member of the Pharmaceutical Affairs Management Professional Committee of the Chinese Pharmaceutical Association

Zhu Zonghan is the honorary president of the Pediatrician Branch of the Chinese Medical Doctor Association

He Shuwang: General Manager of R&D Center of Shandong Dayin Marine Biopharmaceutical Co., Ltd

Bibliography:

1. Guidelines for quantitative methodology for extrapolating adult medication data to pediatric populations (for trial implementation);

2. Circular of the General Administration on Issuing Technical Guidelines for the Extrapolation of Adult Drug Data to the Pediatric Population (No. 79 of 2017);

3. Extrapolation of adult data to pediatric population_Liu Lu;

4. Analysis of scientific decision-making process and regulatory basis of extrapolation of adult medication data to pediatric population_Zhang Huimin;

5. Technical requirements and review consideration of extrapolation of adult medication data to pediatric population_Sun Yanzhe;

6. Comparative research on the technical requirements for extrapolation of biosimilar indications in various countries and improvement of mainland biopharmaceutical indications

7. Suggestions for pushing technical requirements_Wu Qiwei;

8. Data extrapolation strategies and general considerations for pediatric population varieties approved overseas_Geng Ying

Source: Medical community

Responsible editor: Qian Wei

Editor: Zhao Jing