With the advent of gene therapy era, how can the most expensive therapy get medical insurance?

A series of signs indicate that the era of gene therapy in China has come
.

At the same time, the issue of medical insurance payment for gene therapy has aroused heated discussions in the industry

Starting in 2020, CDE has issued 5 guidelines (formal draft or draft for comments) related to gene therapy, namely, "Guiding Principles for Pharmaceutical Research and Evaluation of Gene Therapy Products (Draft for Comments)" and "Non-Genetic Therapy Products".
Technical Guidelines for Clinical Research and Evaluation (Draft for Comments), "Technical Guidelines for Non-clinical Research and Evaluation of Gene Modified Cell Therapy Products" (Trial), "Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products (Draft for Comments)" And ICH guiding principle "S12: Biodistribution Study of Gene Therapy Products"
.

This means that China has prepared for the relevant policies for the registration and application of gene therapy products

Gene therapy products usually consist of vectors or delivery systems containing engineered gene constructs, and their active ingredients can be DNA, RNA, genetically modified viruses, bacteria, or cells
.

According to the characteristics of gene carriers, gene therapy products can be divided into virus-based gene therapy products, plasmid DNA-based gene therapy products, RNA-based gene therapy products, and bacterial or microbe-based gene therapy products.

At present, several gene therapy products have been approved for marketing worldwide
.

For example, Luxturna is used to treat retinal dystrophy caused by RPE65 gene mutation, CAR-T cells are used to treat a variety of hematological malignancies, and Strimvelis is used to treat severe combined immunodeficiency caused by adenosine deaminase deficiency

In June 2021, Fosun Kate’s anti-human CD19 autologous CAR-T Akilensai injection (FKC876), China’s first cell therapy product, was approved by the State Food and Drug Administration for the treatment of adult relapsed and refractory large B cells Lymphoma
.

In September, WuXi Junuo's CAR-T cell therapy product, JWCAR029, was also officially approved.

What has attracted much attention is that Akirensai injection has entered the 2021 "National Medical Insurance Drug List Adjustment Passed the Preliminary Formal Review of the Drug List" on the grounds that it belongs to the national medical insurance industry during the period from January 1, 2016 to June 30, 2021.
New generic drugs approved by the drug regulatory authority for marketing
.

Guangdong Pharmaceutical Exchange Center recently announced the new products (the third batch) newly approved for listing on the third-party drug electronic trading platform of Guangdong Province and their proposed online prices.

1.
Gene therapy: the most expensive type of therapy in the world

1.
Gene therapy: the most expensive type of therapy in the world

In the United States, Novartis’s CAR-T cell therapy drug Kymriah (tisagenlecleucel) targets relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) indications, respectively Pricing is 475,000 US dollars and 373,000 US dollars
.

Kymriah's competitor, Gilead Yescarta, is priced at $373,000

In addition to the United States, countries such as the United Kingdom, Israel, Canada, Japan, and Italy have also included Kymriah or Yescarta in their medical insurance coverage
.

In May 2019, the Japan Central Social Insurance Medical Council approved the inclusion of CAR-T cell therapy product Kymriah in medical insurance, with a price of approximately 33.
5 million yen (approximately RMB 2.
1 million)
.

Japan became the first country to approve CAR-T cell immunotherapy in Asia

Novartis gene therapy Zolgensma, which is the most expensive gene therapy product in the world, for the intractable disease "spinal muscular atrophy" of general muscle weakness such as young children
.
The Japan Central Social Insurance and Medical Council will include Zolgensma in the medical insurance coverage in May 2020, and the price per use is 167 million yen (about 11.
07 million yuan)
.
The United Kingdom, Italy and other countries also include this therapy in the scope of medical insurance
.

2.
Two major obstacles and challenges for CAR-T to enter the medical insurance access

2.
Two major obstacles and challenges for CAR-T to enter the medical insurance access

Medical Insurance Problem 1

Medical Insurance Problem 1

Conditional listing, no phase III clinical data brings challenges

Conditional listing, no phase III clinical data brings challenges

The listing of CAR-T generally takes "conditional listing", and clinical observation is required after the listing
.

In 2018, Akirensai injection started an open clinical study on the safety and efficacy of the treatment of relapsed and refractory aggressive non-Hodgkin's lymphoma (NHL), with a target enrollment of 15 people
.
The non-interventional clinical study to evaluate the treatment of relapsed or refractory non-Hodgkin’s lymphoma with Akirensai injection will be launched on July 15, 2021, with a target enrollment of 200 people
.
There were fewer than 100 subjects in the key pre-market clinical trial of Akirensai injection
.

In 2018, Ruiji Orensai injection started a phase I study for the treatment of relapsed and refractory B-cell non-Hodgkin’s lymphoma and a phase I/II open study for the treatment of relapsed and refractory B-cell non-Hodgkin’s lymphoma.
Goals The number of participants was 30 and 76 respectively
.
In 2020, a phase Ⅰ open-ended, single-arm, multi-center study for the treatment of primary drug-resistant diffuse large B-cell lymphoma and a phase Ⅱ open-ended single-arm multi-center study for the treatment of relapsed and refractory mantle cell lymphoma will be initiated, with the target number of participants in the group There are 12 and 59 people respectively
.
There were more than 100 subjects in the key pre-market clinical trial of Ruiji Orensai injection
.

It can be seen from the clinical trials of two drugs that have been marketed in China that, as an innovative technology, CAR-T therapy can provide treatment benefits for relapsed or refractory non-Hodgkin’s lymphoma, which has been difficult to treat in the past.
Therefore, the drug regulatory authority provides a priority approval channel for the registration, application and marketing of CAR-T therapy
.

Although the two domestically marketed CAR-T therapies have followed up patients for more than 2 years, there is no phase III clinical trial data
.
This is challenging for medical insurance administrators: the efficacy and safety of CAR-T therapy are still uncertain, so it is difficult to judge-how many patients are suitable for this therapy, how many patients will have a positive therapeutic response, and the efficacy How long can it last, and the medical value that can eventually be realized
.

Medical Insurance Problem 2

Medical Insurance Problem 2

High cost is incurred at one time, and long-term safety is unknown

High cost is incurred at one time, and long-term safety is unknown

In terms of long-term safety, CDE’s "Technical Guidelines for Long-term Follow-up Clinical Research of Gene Therapy Products (Draft for Comment)" also requires gene therapy to ensure that it is sufficient to observe the subject's product characteristics and exposure (biodistribution and route of administration).
), etc.
, should not be shorter than the expected occurrence time of delayed adverse reactions
.
For the duration of long-term follow-up, the recommendations for different types of gene therapy products are as follows: vectors with genome integration activity (such as γ-retrovirus and lentiviral vectors) and transposon elements are recommended to be observed for no less than 15 years; can produce Bacteria or viral vectors with persistent infection or latent reactivation risk (such as herpes simplex virus) are recommended to be observed for 15 years or until the data shows that there is no longer any risk (infection or reactivation); gene editing products are recommended to be observed for 15 years or until the data Indicates that there is no longer any risk; Adeno-associated virus vectors are recommended to be observed for 5 years or until the data shows that there is no longer any risk
.
This reflects from the side that gene therapy, as an emerging therapy, its long-term safety is still unknown
.

The main cost of CAR-T therapy is a one-time occurrence, but the curative effect can only be determined by long-term observation
.
At present, China's medical insurance is paid according to the service item, and it is compensated according to the actual cost after the medical service behavior occurs
.
The high one-time medical expenses have not yet established a medical insurance payment mechanism in China.
In addition to bringing greater current financial pressure and risks to local medical insurance, if the outcome risk sharing model is adopted for refractory indications, the statistical management cost is high and implementation is difficult.

.

3.
What about the patient? Current status of CAR-T therapy payment in my country?

3.
What about the patient? Current status of CAR-T therapy payment in my country?

Medical insurance payment limit for a certain indication within a certain range and within a certain period of time

Medical insurance payment limit for a certain indication within a certain range and within a certain period of time

At present, the most recommended method in the industry is to adopt the method of paying by disease: CAR-T manufacturers and medical insurance jointly discuss the medical insurance payment limit for a certain indication of the treatment within a certain range and within a certain period of time, such as installment according to the annual treatment cost Payment
.
If the cost of a single patient or the total cost of all patients exceeds the indication limit in actual application, the medical insurance may no longer pay the excess cost, thereby alleviating the burden and risk caused by CAR-T therapy to the medical insurance fund
.

The hope of cancer patients: major insurance companies are intensively included in commercial insurance

The hope of cancer patients: major insurance companies are intensively included in commercial insurance

It is reported that a lymphoma patient in Zhejiang Province successfully obtained insurance direct payment for the use of CAR-T treatment
.
At present, major insurance companies are intensively incorporating CAR-T into the coverage of commercial insurance: Fosun United Health Insurance's two medical insurance products "Beyond Insurance 2020 Medical Insurance" and "Yaoshen No.
1 2021" Both have updated the "Malignant Tumor Special Drug List" and joined the CAR-T Therapy Achilles Race.
There is no need to pay, and old customers will automatically enjoy the update; in July 2021, Ping An Health Insurance Company announced that the i-medicine insurance (upgraded version) is in the basic Based on the original list of 18 drugs in the drug list, CAR-T therapy Achilles is added free of charge.
Consumers who have purchased Ping An e Health Insurance, Ping An e Health Insurance and long-term medical insurance can also purchase i-Medicine Insurance (upgraded version); 2021 In September 2008, Taiping Property Insurance Company's "Taiping Medical Insurance Worry-Free 2021 Million Medical" added two newly-listed CAR-T therapeutic drugs in China to the list of special drugs
.

In the short term, supplementation of commercial insurance will be the hope of cancer patients who need to use gene therapy
.