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Industry Insights From the landing of rare disease "life-saving drugs" in China, the current situation and development of rare disease drugs are discussed

 Last Update: 2022-10-20
 Source: Internet
 Author: User

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Recently, with the efforts of the National Health Commission, the State Food and Drug Administration and other parties, as a temporary import of urgently needed clinical drugs, clobazam, which was also once known as a "life-saving drug", issued the first prescription in the country in Peking Union Medical College Hospital, which means that the temporary import policy of urgently needed clinical drugs has been implemented, and the problem of drug accessibility has been alleviated, benefiting patients and families
.

This paper analyzes and organizes the current status of drugs for rare diseases, the registration and application policies of drugs for rare diseases, and real-world research, and explores the value of
data intelligence technology in the registration of drugs for rare diseases.

The concept, characteristics and distribution status of rare diseases

Rare diseases are a class of diseases with the characteristics of low incidence of a single disease and complex pathogenesis, most of which are chronic diseases, and they occur in childhood, and such diseases are often life-threatening
.
Globally, the definition of rare diseases has not been completely unified, and the latest definition of rare diseases in China is: diseases with a neonatal incidence of less than 1/10,000, a prevalence rate of less than 1/10,000, and a number of patients less than 140,000 [1].

On June 27, 2022, the Comprehensive Department of the State Food and Drug Administration issued the Notice on Further Strengthening the Service of Foreign-funded Enterprises, and rare disease drugs/orphan drugs and pediatric drugs were mentioned
again.
Since the State Food and Drug Administration issued the Opinions on Deepening the Reform of Drug Review and Approval to Further Encourage Innovation in 2013, China's drug policies and regulations have continued to pay attention to the drug use of patients with rare diseases, and encouraged the introduction, marketing and research and development
of rare disease drugs.

According to the official website of the American Organization for Rare Diseases (NORD), there are currently more than 7,000 known rare diseases in the world
.
Although the number of patients with each disease is small, the overall number of people affected by rare diseases is very large
.
According to the official website of NORD, there are more than 300 million patients with rare diseases in the world, of which 50% are children
.
Referring to the "China Rare Disease Definition Research Report 2021", there are more than 20 million rare disease patients in China, due to the current lack of diagnosis and understanding of rare diseases in China, the average age of rare disease diagnosis is relatively long, and even many patients are not diagnosed
until adulthood.

According to data from The Silent Suffering: An Assessment of Cognition and Management of Rare Diseases in Asia and the Pacific, published by the Economist Intelligence Unit, it is understood that the average proportion of respondents who said patients received the best or suboptimal treatment in the Chinese mainland (see chart below).

Among them, only 23.
70% of the best evidence-based treatment was given, while 17.
4% were not given evidence-based treatment due to lack of approved marketing drugs and 22.
40% were not given evidence-based treatment due to lack of
clinical treatment guidelines.
With the gradual improvement of medical conditions in China, it is believed that more patients with rare diseases will be diagnosed
.

(Source: Silent Suffering: An Assessment of Cognition and Management of Rare Diseases in the Asia-Pacific Region)

In China, there are currently no effective drugs, effective drugs have not been listed in China, and the high price of drugs are the three main factors affecting the protection of rare disease groups [2], among which the price of rare disease drugs is the part that patients focus on
.
Although China's rare disease drug guarantee mechanism has been gradually established, and rare disease drugs are included in the medical insurance directory every year, there are still some rare disease drugs that are extremely expensive, which seriously affects the accessibility of
patients.

Throughout the world, the research and development of rare disease drugs is also trying to support a variety of policies, such as the "Orphan Drug Act" in the United States, and Japan's "Rare Disease Drug Management System" for rare disease drugs in terms of taxation, application fees, clinical research funding, drug registration and other preferential policies; China's newly revised Measures for the Administration of Drug Registration in 2020 and the recent Regulations for the Implementation of the Drug Administration Law (Draft Amendments for Solicitation of Comments) also have clear priority review and approval policies and market exclusivity policies for new drugs with rare diseases, which are conducive to reducing the economic burden of enterprises in R&D, clinical trials, etc.
, thereby promoting more new drugs for rare diseases to be listed
in China.

At this stage, in addition to gradually advancing the drug protection mechanism for rare diseases in terms of medical insurance policies, China is also actively exploring inclusive commercial insurance, charity assistance and other ways to explore the current situation
of alleviating the high cost of rare diseases.

Market size of rare disease drugs

According to statistics, as of November 2020, 75 of the 121 rare diseases in the First Rare Disease Catalogue have therapeutic drugs on sale
in the United States, the European Union and Japan.
Among these 75 rare diseases with therapeutic drugs, there are still 19 rare disease treatment drugs that are not listed in China, and there is a situation of
"there are drugs abroad, but there are no drugs in China".
As of May 18, 2022, of the three batches of the List of Overseas New Drugs with a total of 73 varieties officially released by the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China, 19 varieties have never been declared
in China.

China's rare disease drug market[3] accounted for 0.
4% and 1.
0% of the global rare disease market in 2016 and 2020 respectively, and as China continues to reform to introduce more innovative drugs to the market and improve availability, the domestic orphan drug (rare disease drugs) market size is expected to be US$6.
4 billion in 2025 (as shown in the chart below), with a CAGR of 37%
from 2020 to 2025.
Compared with the more mature foreign rare disease market, China's rare disease market still has greater potential
.

(Source: Huajing Industry Research Institute)

Some large pharmaceutical R&D and manufacturers have already entered the market with excellent products, such as Fingolimod Hcl Ora Lcapsules, to treat recurrent multiple sclerosis; Elosulfase Alfa α injection, suitable for patients with type IVA mucopolysaccharidosis (MPS IV.
A), is very suitable for China's preferential strategy for rare disease drugs, and it took only three months
from registration to marketing.
Another example is the β of additive enzyme developed and produced by Sanofi, which was exempted from domestic clinical trials after being included in the priority review procedure, and directly applied for marketing based on overseas clinical trial data, and obtained marketing approval
after a natural year.

The current registration application policy for drugs for the treatment of rare diseases

Since 2015, in order to solve the problem of access to rare disease treatment drugs, the Chinese government has successively issued a number of specific policies and measures to encourage the introduction, R&D and production of rare disease treatment drugs and accelerate registration review and approval[4].

For products that have been marketed abroad and urgently needed for Chinese clinical practice, if they meet the following characteristics, they can apply for exemption from clinical trials and carry out real-world research after marketing:

There are safety and efficacy data abroad

There are no significant differences in clinical practice, disease and patient characteristics at home and abroad

There are no effective therapeutic drugs in China and there is an urgent clinical need

If the data of foreign studies are relatively sufficient, but there are racial differences, you need to apply for domestic clinical trials
.

The following figure shows the process of IND and NDA application for drugs for rare diseases in China, for drugs in the "List of Overseas New Drugs Urgently Needed for Clinical Needs", according to the "Working Procedures for Priority Review and Approval of Drug Marketing Authorization", the drug review center can be directly included in the priority review and approval procedure after acceptance, and the NDA review time limit is only 70 working days
.
When conducting registration inspection, within 2 working days after the issuance of the registration inspection notice, the applicant can send the materials and samples required for registration inspection to the drug testing agency
.

For rare disease drugs that are not on the list of urgent clinical needs, after communication and confirmation with CDE, an application for priority review and approval can be submitted to the Drug Evaluation Center, and the time limit for review and approval will also be greatly shortened, for example: the review time limit for drug marketing authorization applications is 130 days; Within 5 working days after the registration inspection notice, the materials and samples required for the registration inspection can be sent to the drug testing agency
.

(Flow chart of registration of drugs for the treatment of rare diseases at the time of IND and NDA application)

China's pharmaceutical industry is still in a period of development, the NMPA has frequently updated new regulations in recent years, and many domestic and foreign companies do not have a good understanding
of the relevant regulations in the field of rare disease drugs, costs and benefits.
Moreover, there are few research and production institutions for rare disease drugs, and the declaration strategy is not perfect enough, and sufficient experience
has not been accumulated.

As a well-known CRO in China, Happy Life Technology (HLT), a subsidiary of Yidu Technology, has advantages in the registration of drugs for rare diseases, including but not limited to:

Good communication and collaboration with regulators

He has experience in collaborative projects in real-world research in Boao, Hainan

He has rich experience in IND and NDA, and has also explored the registration strategy of rare disease drugs at home and abroad

Most patients with rare diseases are concentrated in childhood

According to the data provided by the international rare disease database Orphanet, about 72% of rare diseases are caused by structural changes or abnormal regulation of genetic material, that is, hereditary diseases
.
According to statistics, more than 50% of rare diseases occur in childhood
.
In the "First Batch of Rare Diseases List" jointly formulated by the Health Commission and other four departments, rare diseases that can occur in childhood account for a relatively large proportion and have a stronger
clinical urgent need.

Considering the actual needs of children's drug research and development and drug registration in China[5], and timely conveying the consideration of new research concepts and methods by drug regulatory agencies, CDE issued the "Technical Guidelines for Real-World Evidence to Support the Development and Evaluation of Pediatric Drugs (Draft for Comments)" on May 18, 2020, pointing out that real-world research can also be applied to rare diseases in children: drug research and development for rare diseases, or some pediatric critical, premature or neonatal diseases that lack effective treatment, There may be cases where traditional randomized controlled clinical trials cannot be conducted for scientific, ethical, or operational reasons, and real-world data can be used as historical or external controls
for one-arm studies.

Rare disease drug exploration delves into real-world research

China still lacks enough varieties of rare disease drugs, in addition to the introduction of foreign drugs that have been marketed, some domestic companies are also actively developing and exploring
.
Under normal circumstances, imported drugs also need to undergo randomized controlled clinical trials in China before they can be approved for marketing
.
For rare disease drug clinical trials, the target population is very small, and it is extremely difficult to conduct randomized controlled clinical trials, it is difficult to meet the requirements of randomized control double-blind, and even faces ethical problems, which is bound to greatly extend the time of orphan drugs for clinical treatment [6].

In order to further guide and standardize the use of real-world evidence in supporting drug R&D and review, on January 7, 2020, the NMPA officially issued the Guidelines for Real-World Evidence to Support Drug R&D and Review (Trial).

The guiding principles point out real-world applications to support drug regulatory decisions, covering pre-market clinical research and development to post-market re-evaluation
.

At present, we can use single-arm clinical trials based on real-world evidence as external controls to provide evidence of efficacy and safety for new drug registration and marketing for some rare diseases and life-threatening major diseases that lack effective treatment measures.
In clinical trials for some rare diseases, where recruitment is difficult due to the scarcity of cases, real-world data from natural disease cohorts can also be considered as the basis for
external controls.

Advantages of HLT in the registration process of rare disease drugs

HLT is a life science solution provided by Yidu Technology (2158.
HK), based on the Group's own medical data integration and intelligent data processing technology, HLT has obvious advantages
in real-world research on rare diseases.

First of all, HLT relies on medical intelligence technology, under the premise of obtaining full authorization from the hospital, and understands the disease distribution and diagnosis and treatment mode of specific rare diseases through data analysis intelligence, providing pharmaceutical companies with a sound R&D path and program design to promote patient recruitment
.

Secondly, HLT has advanced research data processing technology and perfect test software, as well as proven electronic data compliance extraction, text structuring, data standardization and other technologies to generate project data through efficient and high-quality data
governance.
At the same time, HLT has established a sound SOP and a rigorous quality control system
in accordance with the regulatory guidelines of regulatory authorities.

Under strict SOP specifications, HLT has developed and used trial software with completely independent property rights, such as EDC, ePRO, random drug dispensing system, eTMF and other tools, especially the remote intelligent clinical trial platform (DCT) developed by HLT, which is innovative patient-centered, can be visited online with researchers, no longer limited by geographical conditions, providing superior conditions
for recruiting and managing precious rare disease subjects.

Over the years, HLT has been deeply engaged in real-world research and has accumulated rich project experience in real-world research fields of rare diseases in China, with multiple advantages
.
HLT uses artificial intelligence to drive medical innovation solutions, provide enterprises with high-quality evidence-based medicine, pharmacoeconomics and other evidence-based decision-making, give scientific evaluation of drug introduction, optimize clinical development paths, reduce development risks, and seek a more reasonable combination between different indications to help enterprises accelerate new drug approval, expand product indications, and further improve the accessibility of drugs
.

brief summary

This article discusses the current status of drug research and development for the treatment of rare diseases, and looks forward
to the future real-world research using medical intelligence technology.
HLT assists companies in carrying out real-world research before and after drug launch, helping companies form a complete evidence chain related to clinical and registration from pre-market to post-market access, and deeply explore the value of
products.

It is believed that with the rapid development of real-world research, more products with clinical value and suitable for clinical urgent needs in the field of rare diseases will be listed
in China in the future.

(This article refers to many articles and data on rare disease drugs, if there is anything not clearly indicated, please contact the author to apostille
.
) At the same time, special thanks to Professor Rong Xiaohui of HLT Real World Research Group for providing valuable information
.
）

References:

References: References:

[1] Research Report on the Definition of Rare Diseases in China (2021)

[2] An Pu, Some Suggestions on Drug Protection for Rare Diseases in China, China Medical Insurance, July 6, 2022

3.
Source: Huajing Industry Research Institute

[4] Wang Xue, Zhao Cong, Analysis of the current situation of drug accessibility for rare diseases in China, Chinese Journal of Clinical Pharmacology, Vol.
37, No.
8, April 2021 (Issue 334)

[5] CDE "Technical Guidelines for Real-World Evidence to Support the Development and Review of Pediatric Drugs (Draft for Comments)," May 18, 2020

[6] Chen Shuobing, Yu Feng, Development Recommendations for Real-World Research on the Use of Rare Diseases and Orphan Drugs, International Journal of Pharmaceutical Research, Vol.
46, No.
9, September 2019

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