Why can't rare disease drug research and development feel the "chill" of the industry? First scene

In China, a scientific and advanced rare disease ecosystem is being established
.
China's rare disease drug market is growing faster than the global rate
.
Song Ruilin, who participated in the Rare Disease Summit Forum for the first time, said in his speech: "The development of drugs for rare diseases can promote the development of innovative drugs around the world and bring greater social effects
.
”

At the nucleic acid testing point near the Sheraton Hotel in Shanghai's Jiading District, Huang Rufang, director of the Cord Rare Disease Development Center, was doing nucleic acid while thinking about what
he wanted to say in his speech at the 11th China Rare Disease Summit Forum.
He came to Shanghai for the first time after three months of lockdown due to the epidemic
.

He decided to put forward some thoughts in his speech, such as whether there is still motivation for domestic innovative drug research and development, how overseas innovative drugs continue to enter China, whether national medical insurance should pay for innovation, etc.
, which led the participants to express their views
.

Cord Rare Disease Center founder Huang Rufang

China's rare disease drug market is growing faster than the world

The rare disease market is growing
rapidly under the huge clinical demand and the attention of governments.
Chen Jinhao, head of IQW's China management consulting business, gave the data that the global rare disease market size will be $135 billion in 2020 and $383 billion
by 2030.
Rare disease drugs account for more than half of the new molecular solid drugs listed globally (51% in 2017, 46% in 2018, 51% in 2019, 53% in 2020, and 56% in 2021).

Chen Jinhao believes that the success rate of rare disease drugs is high, which further stimulates innovation
.

Looking at China, the growth rate of the rare disease drug market is even faster than the global growth rate, and the proportion is expected to grow from 1% to 7% in 2030, and the market size will grow from US$500 million in 2016 to US$25.
9 billion
in 2030.
"Favorable factors such as patient demand, policies, funds and technology have created a favorable environment
for the rare disease industry to flourish.
" He believes that by adhering to the patient-centeredness, the rare disease market will become the next blue ocean
.

At present, the three therapies of cell therapy, gene therapy and nucleic acid drugs in the field of rare diseases are sought after, and the market size will be $6 billion in 2021, of which cell therapy drugs account for 29%, gene therapy drugs account for 26%, and RNA therapy accounts for 45%.

Group photo of the main guests of the 11th China Rare Disease Summit Forum

Song Ruilin, executive president of the China Pharmaceutical Innovation Promotion Association, participated in the Rare Disease Summit Forum for
the first time.
In his speech, he said: "The development of drugs for rare diseases can promote the development of innovative drugs around the world and bring greater social effects
.
”

He analyzed that countries give special incentive policies for rare disease drugs, and the success rate of clinical trials is significantly better than that of other drugs
.
Eight of the top 10 innovative drugs sold worldwide in 2021 have been designated orphan drugs
by the FDA.
From the perspective of new drugs approved from 1992 to 2017 around the world, their approved non-rare disease indications were 61.
4%, rare diseases were 38.
6%, and many new drugs initially listed rare diseases as a breakthrough
.

However, despite the growing popularity of rare disease research and development, there is still a huge unmet clinical need
.
Less than 10%
of the more than 7,000 rare diseases worldwide have treatment options.
In 2018, the first batch of rare disease catalogs in China included only 121 rare diseases, covering only 3 million of the 20 million Chinese rare disease patients; And 47 diseases in the catalogue still have no treatment worldwide
.
Many innovative drugs have yet to enter China
.

"We strongly call for the rare disease catalogue to be combined with the actual situation of rare patients as soon as possible, and at the same time introduce a new catalogue to update the types of
diseases.
" In addition, for the definition of rare diseases, the valuation should be determined according to the number of rare diseases, so that the definition of rare diseases can be truly implemented in the system
.
Song Ruilin said
.

The "China Rare Disease Definition Research Report 2021" proposes that diseases with "neonatal incidence less than 10,000 people, prevalence less than 1/10,000 and fewer than 140,000 patients" should be included in rare diseases
.
Many people in the industry believe that this has implications
.

The regulatory review policy guides R&D in an orderly manner

In addition to the stimulation of market demand, another important driving factor is policy and regulation
.
In a significantly improved policy environment, rare disease drugs have made great progress
from research and development to supply security.

In August 2015, the State Council issued the Opinions on Reforming the Review and Approval System for Drugs and Medical Devices, proposing for the first time to accelerate the review and approval
of rare disease drugs.
Document No.
42 of the General Office of the CPC Central Committee and the General Office of the State Council once again confirmed the support
for the research and development of rare disease drugs.
Since then, the National Health Commission, the Ministry of Science and Technology, the Ministry of Industry and Information Technology and other relevant departments have issued a series of policies, and China's rare diseases have entered a stage of
rapid development.
From 2019 to 2021, the number of new rare disease drugs listed in China has increased year by year, and the number of clinical trials for rare disease drugs has also increased
significantly.

"The formulation and continuous breakthrough of one new policy after another has promoted the development of
the entire Chinese rare disease drug innovation ecology.
" Mao Ningying, deputy dean of the International Medical Business School of China Pharmaceutical University, said
.

She explained that policies to promote the development of the rare disease industry can be divided into three types
: supply-oriented, environmental-type and demand-oriented.
Supply-oriented policies focus on measures such as providing R&D funding or special funds, building information network sharing platforms, providing research recommendations, waiving/exempting clinical trials, and establishing special review channels, and their main role is to promote technological innovation
.
Those policies such as the construction of special laws and regulations on rare diseases, the formulation of standards and guidelines for the research and development of rare diseases, the protection of relevant intellectual property rights, and the granting of an exclusive period to the market are environmental policies, creating a better macro environment
for relevant entities in the rare disease industry.
Government procurement/price formulation, payment guarantees, etc.
are demand-oriented policies that help improve the payment ability of rare disease patients and ensure market demand
.

Among these three types of policies, the proportion of environment-based policies is relatively high, followed by supply-oriented policies, and the relevant policies for priority review and approval are more prominent; The current demand-oriented policy needs to be strengthened, of which the medical insurance payment policy has the greatest
impact.
"The use of policy tools should emphasize the balanced development of the three types of tools, and should also consider the interests of multiple parties in the protection of rare diseases to ensure the sustainable development
of this field.
" Professor Mao Ningying said
.

For enterprises doing new drug research and development, the "Technical Guidelines for Clinical R&D of Rare Disease Drugs" promulgated by the Drug Review Center (CDE) of the State Food and Drug Administration on January 10, 2022 is the most concerned, which directly guides the research and development direction and improves the R&D efficiency
.

For enterprises doing new drug research and development, the "Technical Guidelines for Clinical R&D of Rare Disease Drugs" promulgated by the Drug Review Center (CDE) of the State Food and Drug Administration on January 10, 2022 has attracted the most attention, which provides direct guidance on the clinical research and development strategy and specific design of rare disease drugs, aiming to improve the efficiency
of rare disease drug research and development.

Chen Xiaoyuan, a researcher at Tsinghua University School of Medicine and a former CDE reviewer, shared her understanding
of the guidelines.
The most important thing for new drug developers is to develop an overall clinical development plan
.
Rare disease drug development follows the general drug development rules, and also needs to go through the process
of dose exploration, proof of concept, and safety and effectiveness confirmation.
However, due to the limited number of participants in rare diseases, a multi-stage design can be employed in a study to achieve the corresponding goals
.
Some rare disease drugs can also be conditionally approved for marketing based on early data, and confirmatory clinical trials
can be conducted after marketing.
In the design of specific clinical trials, it is necessary to fully consider the characteristics of extremely low incidence/prevalence of rare diseases, and carry out reasonable planning and implementation
in combination with the mechanism of action of the drugs developed.

Professor Chen introduced in particular how external controls (single-arm tests) should be applied rationally
.
The guidelines clearly state: "A single-arm trial design may also be considered when the incidence/prevalence of the target indication is very low, very few patients can be recruited who meet the criteria for inclusion, and are not eligible for a controlled study.
"
。 However, external controls (single-arm trials) do not eliminate systemic differences between non-concurrent treatment groups, the level of evidence is low, applicable only in specific contexts, usually only conditional approval of the drug is supported, and randomized controlled trials are required post-marketing as confirmatory studies; In the case of extremely rare diseases and the inability to conduct controlled studies, another independent one-arm study and real-world study can be considered as a confirmatory clinical trial
.
For details, please refer to the recently issued Technical Guidelines for the Applicability of One-Arm Clinical Trials to Support the Marketing Application of Antineoplastic Drugs (Draft for Comment
).

For effectiveness evaluation, in the selection of key clinical trial endpoints, it is necessary to pay attention to the high correlation with clinical benefits, objectivity, sensitivity, easy to quantify and reproducibility
.
Clinical endpoints remain the preferred measure of effectiveness, but the exploration and development of alternative endpoints that are relevant to clinical endpoints and have predictive value for clinical endpoints are encouraged in the development of rare disease drugs
.
Through sensitive alternative endpoints, the purpose of simplifying clinical trials and improving R&D efficiency is achieved
.

In the estimation of sample size, the same scientific principles are followed and the estimation based on statistical assumptions of the primary endpoint can reduce the sample size
by using more flexible experimental design, sensitive primary endpoint indicators, etc.
Rather than unprincipled reduction in sample size
because of low incidence.
In terms of safety assessment, adequate safety exposures are also required, and data from non-rare disease populations can be borrowed to support
the development of multiple indications.

Finally, Chen Xiaoyuan concluded that the design of rare disease drug clinical trials can be "streamlined" but does not mean that it can be simple, and the need to accelerate the development of rare disease drugs is not to lower the drug evaluation standards, let alone to compromise
on science.
It is necessary to closely combine the characteristics of rare diseases themselves and explore more scientific and sophisticated research methods to improve the efficiency
of research and development.
Throughout the R&D process, special attention should be paid to timely communication with regulatory authorities
.

Group photo of speakers at the Global Rare Disease Industry Development Forum

Overseas R&D cooperation and supply enterprises in action

Overseas new drugs and China's local rare disease drugs can currently enter the Chinese market
through the overseas new drug clinical trial exemption channel, the list of three batches of overseas new drugs urgently needed for clinical needs, and four rapid review channels.

Yi Yi, Vice President of Business Development of Weisheng Pharmaceutical, introduced the rapid growth of
rare disease drug licensing transfer and transfer in recent years.
Weisheng Pharmaceutical is an innovative biopharmaceutical company focusing on endocrine-related therapeutics, including endocrine rare diseases
.
According to Informa database statistics, the introduction and cooperation of rare disease products in China from 2015 to 2022 is growing, and 7 of the non-tumor rare disease products introduced in China in 2021 have been approved, 4 are applying for NDA/BLA, 12 are clinical Phase 1-3, and 2 are preclinical IND
.

The introduction and development of rare disease drugs requires companies to carefully assess the matching of
their capabilities with target products and markets.
"To fully assess the clinical real needs, market potential, transaction valuation, due diligence products and companies
of Chinese patients.
" Yi Yi said
.
He stressed that there are many other considerations for the introduction of product cooperation, for example, is there enough Chinese population in the existing foreign trials? Can a drug be exempt from clinical trials in China? Are drugs eligible for priority approval and orphan drug eligibility in the United States? Can drugs be prioritized for approval in China? Is it in the National Rare Disease Inventory? These are all factors
that influence the estimation of time to market and ultimately add points to the evaluation of the introduction of the collaboration.

In December last year, under the entrustment of Union Hospital and patient organizations, Sinopharm Group and Sanofi successfully negotiated a cooperation with
Chlorbachan, a rare and refractory epilepsy treatment drug.
Yang Wenzhe, director of business development of Sinopharm China Pharmaceutical Foreign Trade Co.
, Ltd.
, said that chlorbazhan has a certain degree of addictiveness and belongs to the second class of psychotropic drugs in China, which has not been approved for listing
in China before.
"We received a request from Union Hospital and were very anxious
.
As large state-owned enterprises, it is our responsibility to find these drugs and deliver them to patients
.
Yang Wenzhe said
.

In January this year, the State Food and Drug Administration approved the import and use of the urgently needed clinical drug chlorbachan; In June, the National Health Commission and the State Food and Drug Administration jointly formulated and issued the "Temporary Import Work Plan for Urgently Clinical Drugs" and the "Temporary Import Work Plan for Chlorbajan", which made it clear that in the 50 tertiary hospitals across the country led by Peking Union Medical College Hospital, imported Chlorbachan will be successively landed, and children and their families can purchase Chlorbachan
after being prescribed by qualified doctors.

"We just did what we had to do
.
" Yang Wenzhe told the developer that in the future, Sinopharm Group will rationally use national policies and internal and external resources of Sinopharm Group to actively change the status quo
of overseas drugs and domestic drugs.

In fact, 90% of rare diseases worldwide lack effective therapeutic drugs, and it is not enough to introduce overseas drugs and wait for other countries to develop them
.
Wang Hanbo, head of business development and innovation at Shanghai Langyu Health Technology Co.
, Ltd.
, said: "China's independent innovation should rise, and through independent innovation and cooperative development, bring more affordable treatment options
to patients.
The relatively high success rate of rare disease indications can achieve the verification of technologies and targets, so it can be used as the first field of innovative technologies and drugs, and rare diseases should play a pioneering role
in the process of innovative drug research and development.
”

"Improvements to existing drugs and expansion of new indications can reduce R&D costs and risks, save time, and quickly bring effective solutions
to patients with rare diseases.
" For example, by the first quarter of 2022, 50% of global approvals are modified new drugs
.
Wang Hanbo said
.

Patient organization forerunner and enabler

There are 20 million rare disease patients in China, and behind it are 20 million families
.
In China, a scientific and advanced rare disease ecosystem is being established
.

"We are not fighting for family property from enterprises, society, and the government for food and debts, but on the contrary, we are here to strengthen the
family business.
" Li Yangyang, chief commercial officer of Shanghai Langyu Health Technology Company, said, "More than 60% of patients with rare diseases are children, and if they receive timely and effective treatment, they can grow up to work for the motherland for 40 years, make due contributions to the country and society, and build a better future
.
" ”

Li Yangyang's views have been actively practiced
by patients and patient organizations.
Cai Lei, the founder of Gradual Healing Mutual Aid Home, is one such forerunner and promoter, comparing himself to the protester
of ALS (amyotrophic lateral sclerosis).
He and his team established the ALS big data platform, linking major ALS patient groups around the world, while investing in funds, charitable funds and charitable trusts, and assisting scientists and biotechnology companies in financing and promoting drug research and development; The company founded by Cai Lei has also built a number of ALS drug pipelines, launched an hourly rapid clinical recruitment and efficacy evaluation system platform, etc.
, and he also hopes to use his own resources or build a business model to raise funds
.

Cai Lei

"As patients, we should not always be demanding charity from others, but strive to strengthen ourselves, let others invest in patients, and let patients create value
.
" Cai Lei said
.

"Don't forget the faint light
of life of every rare disease patient.
" Huang Rufang said, "Whenever the cold hits, the first thing that freezes to death is the weak grass
.
The weakest groups of rare diseases are the most easily overlooked
.
Therefore, we must fight for and appeal
for the rights and interests of rare disease patients.
”