Using health technology assessment to inform insurance reimbursement of high technology medicines in China: an example of cancer immunotherapy
BMJ 2023; 381 doi: https://doi.org/10.1136/bmj-2022-069963 (Published 15 June 2023) Cite this as: BMJ 2023;381:e069963Read the full collection: Health Technology Assessment in China
- Yingyao Chen, professor1 2,
- Hengjin Dong, professor3,
- Yan Wei, associate professor1 2,
- Yi Yang, researcher1 2,
- Jian Ming, researcher1 2,
- Hao Yu, associate professor4
- 1School of Public Health, Fudan University, Shanghai 200032, China
- 2National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, China
- 3Center for Health Policy Studies, School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- 4Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
- Correspondence to: Y Chen yychen{at}shmu.edu.cn
High technology medicines (innovative medicines with potentially substantial clinical effectiveness and expensive price tags) have created a dilemma for health insurance programmes across the world. On one hand, they offer a great source of hope for patients, especially those who have severe health conditions such as late stage cancer. On the other hand, they are typically expensive, substantially contributing to rising healthcare costs. Maintaining a balance between cost control and meeting patients’ demand for high technology medicines has been a challenge for health insurance decision makers in many countries.
The challenge is particularly serious regarding public insurance coverage of cancer immunotherapies in China. The country had 3 002 899 cancer related deaths in 2020, accounting for 30.2% of the world’s cancer related deaths, although it had only 18.6% of the world’s population.1 To enhance cancer treatment, the Chinese government has recently promoted investment in oncology innovation and accelerated market approval of oncology products,2345 including immunotherapies such as inhibitors of programmed cell death protein 1(PD-1) and programmed cell death 1 ligand 1 (PD-L1). These have been in high demand since they first entered the Chinese market in 2018 as they increase survival rates and improve quality of life for patients.6789
The demand for cancer care, especially immunotherapies, has been boosted by China’s universal health insurance coverage, which has been successfully sustained since 2011 through three major public insurance programmes.9 However, this has led to a rapid growth of cancer care expenditures, which reached ¥304.8bn (£38bn; €44bn; $43bn) in 2017, accounting for 5.8% of total health expenditure.10
Chinese policy makers have used health technology assessment (HTA) to inform their decisions on insurance reimbursement of cancer immunotherapies in recent years. We summarise China’s experience in applying HTA for insurance reimbursement of cancer immunotherapies, identify challenges in the application, and draw lessons from China’s experience that other countries may find useful when dealing with the challenge of funding high technology medicines, given the World Health Organization’s advocacy of HTA to support universal health insurance coverage.11
Current national reimbursement coverage
As of 31 May 2022, 13 programmed cell death inhibitors had received market approvals in China: nine PD-1 inhibitors and four PD-L1 inhibitors12 (table 1). Since 2018, four of these immunotherapies (toripalimab, sintilimab, camrelizumab, tislelizumab) have been included in the national reimbursement drug list (NRDL), allowing them to be reimbursed by China’s public insurance programmes. All four are PD-1 inhibitors that are made by Chinese biopharmaceutical companies. None of the four immunotherapies produced by multinational corporations made it to the reimbursement list, partly because the corporations insisted on preserving the stability of their products’ global price system and could not reach an agreement with China’s National Healthcare Security Administration (NHSA) on price.13
Cancer immunotherapy market approval and national reimbursement status in China (as of 31 May 2022)
Assessment methods
To decide whether to include a cancer immunotherapy in the reimbursement list, NHSA uses a multistep approach that relies heavily on HTA methods and evidence. Clinical benefit is the primary focus in the first stage of the appraisal.
Manufacturers wishing to be included in the reimbursement list submit a dossier summarising the basic information (target population, disease condition, comparator, etc) and HTA evidence on clinical evaluation (including effectiveness and safety), cost effectiveness, budget impact, innovation, and fairness. Manufacturers are required to include the most up-to-date clinical evidence not only from randomised controlled trials and systematic reviews (meta-analysis and network meta-analysis are both acceptable) but also from real world evaluations to show comparative effectiveness. An NRDL expert panel with clinical, pharmacy, and HTA expertise then conducts a comprehensive review of the evidence to determine the immunotherapy’s clinical value and whether it qualifies for price negotiation.
In the second stage of the appraisal, both cost effectiveness and budget impact analysis are used to determine whether those immunotherapies invited for price negotiation will ultimately be eligible for the reimbursement list. Once a cancer immunotherapy qualifies for price negotiation, the manufacturer will be required to submit a more detailed economic evaluation dossier. The evidence is required to be based on evaluations against an NHSA assigned comparator, which it selects from drugs on the reimbursement list that have been used for the same or similar patient population.14 NHSA will then convene a small HTA expert panel to appraise the submitted economic evidence, mainly validating the cost effectiveness analysis. An oncology immunotherapy will be randomly assigned to two experts for independent appraisal against a generic range of incremental cost effectiveness ratio thresholds. These thresholds are not yet publicly available, but in general the HTA appraisal experts have limited discretion to grant high technology drugs a higher threshold than other negotiated medicines.
The budget impact of the immunotherapy is assessed separately by the NHSA and the Insurance Funding Analysis Expert Group, which consists of insurance programme officials and insurance experts. The group uses its insurance data and the submitted budget impact data to analyse the potential budget impact of different reimbursement levels of a particular cancer immunotherapy and assess affordability for insurance programmes.
NHSA uses the information to conduct a price negotiation before deciding whether to include a drug in the national reimbursement list. The NHSA has been able to take advantage of the huge market and intense competition among many cancer immunotherapy manufacturers in China in its negotiations. Although most of the negotiated prices have remained confidential, the price of sintilimab was reduced by 64% during the 2019 negotiation.15 This may be an indication of the reductions received for other drugs. Three PD-1 drugs —toripalimab, camrelizumab, and tislelizumab—were included in the 2020 update of the national reimbursement drug list, after national drug price negotiation with an average price reduction of nearly 80%.16
Main challenges
Lack of long term outcomes and local utility data—Insufficient follow-up data for most cancer immunotherapies, particularly those from China’s domestic manufacturers, makes it difficult to understand the long term effect of these products (especially their “trailing effect”). This is a challenge common to many countries.17 Additionally, limited health utility data from China hampered the application of cost effectiveness evidence to the country’s reimbursement decisions on cancer immunotherapies. Almost all the published cost effectiveness analyses of cancer immunotherapies in China used health utility data from international literature.1819
Lack of head-to-head comparisons between oncology immunotherapies—Many HTA dossiers were not based on head-to-head clinical trials, and some of them even relied on single arm trials. For example, all the comparators in clinical trials for non-small cell lung cancer in China were traditional chemotherapy, serving the manufacturers’ purpose of generating superior outcomes to improve the chances of successful regulatory approval. Using conventional therapy as a comparison rather than other immunotherapies allowed the manufacturers to bring “me too” products to the market instead of true breakthrough therapies. Such products have led to frustration among payers in China and other countries.20
HTA appraisal methods—Compared with other countries (e.g., the UK, Australia, and South Korea), China’s HTA appraisal guidelines and decision making process have not yet been described in sufficient detail to the public. In the NHSA appraisal process, a manufacturer’s dossier is appraised separately by two independent reviewers selected from a dozen HTA experts in a few weeks (much shorter than other countries). The lack of coordinated deliberation contrasts with international experiences, which emphasise expert deliberations as part of scientific assessment to inform policy making.2122 Furthermore, although China’s HTA application is a multidisciplinary, wide ranging analysis, it has not incorporated patients’ perspective to meet the increasing emphasis of providing patient focused healthcare.23
Lack of risk sharing arrangements—Unlike countries such as the UK and Australia, China has not yet made risk sharing arrangements (eg, performance based payment or managed access arrangements) with manufacturers (table 2). These can mitigate the risks to payers from uncertainty about the long term effects of high technology medicines.
Comparison of use of health technology assessment (HTA) to inform insurance reimbursement of cancer immunotherapies in China, UK, Australia, and South Korea
Lessons from China’s experience
Clinical benefit is the primary consideration of China’s HTA appraisal of cancer immunotherapies. As the largest developing country, China’s HTA also emphasises cost effectiveness, acceptability, and budget affordability. By tapping the country's HTA expertise, using its bargaining power, and taking advantage of market competition (eg, 13 cancer immunotherapies), China’s price negotiation mechanism seems to have led to substantial price reductions for high technology oncology medicines and improved patient affordability. Like China, several European countries have successfully implemented price negotiation for cancer drugs,3233 showing that price negotiation is an effective tool for controlling cancer costs. This is a valuable lesson for other countries (eg, the US) where price negotiation has not yet been implemented.3435 The price reductions negotiated in China may also affect international markets as the drugs made by Chinese companies are being assessed for US Food and Drug Administration approval.
Cross validation to improve analysis accuracy
China uses cross validation for the acceptable prices in the HTA application, not only between two appraisal experts but also between two expert panels, with one conducting dossier reviews and the other analysing budget impact estimates. The coordination between them is likely to improve analysis accuracy. Such a coordinated approach could be useful in other countries.
Need for a high quality evidence ecosystem
China’s lack of long term outcomes, localised health utility data, and direct comparison clinical data underscore the challenge of applying HTA to inform reimbursement of high technology medication in developing countries. Like China, most developing countries have no prolonged follow-up outcomes or health utility data for their populations. These countries should conduct clinical trials with long term follow-up and accelerate the collection and disclosure of localised health utility and cost data as part of their efforts to establish a sound HTA evidence ecosystem. They will require extra support from international agencies to do this.
Risk sharing approaches worth piloting
Experiences from the UK, Australia, and South Korea show that risk sharing approaches can help cope with the uncertainty about the benefits of cancer immunotherapies and the related financial risk for the public insurance budget.36 China and other developing countries could pilot such approaches to reimbursing a cancer immunotherapy—for example, payers reimburse the drug’s cost despite uncertainties about its clinical or health economic value with the manufacturer agreeingto make a financial concession depending on the immunotherapy’s future performance.37
Using a third party HTA agency
China’s HTA appraisal relies on experts designated by NHSA, which is the largest payer for health services in the country, rather than a separate HTA agency. As experts in many countries have agreed on the importance of an independent HTA agency,3839 we recommended using an independent third party HTA agency in China to ensure objective analysis, avoid conflict of interests, and strengthen the separate roles of an HTA agency and a payer. Studies from other countries indicate that a positive HTA evaluation from a trusted third party source increased the speed of pharmaceutical adoption.40
Involving patients in the HTA appraisal and dissemination
Patient involvement in HTA is more established in other countries and has been shown to reduce the waste of resources and facilitate the implementation of patient-centred care by reflecting patient preferences, values, and priorities.41 42 China has not yet included patients in its HTA process, and we recommended that the manufacturer submitted dossiers and the appraisal results should be released in a way that helps providers and patients with their decisions. Furthermore, their feedback should be incorporated into the HTA process.
Balancing costs and clinical needs for high technology medicines is a challenge across the world. China’s HTA application has led to more affordable public insurance coverage of oncology immunotherapies, but application can be improved by addressing the challenges identified above. The lessons drawn from China’s experience in using HTA to inform insurance reimbursement of cancer immunology may prove useful to other counties considering insurance reimbursement for high technology medicines.
Key messages
Health technology assessment (HTA) has been applied to assist health insurance reimbursement decisions on expensive cancer immunotherapies in China
Drugs are evaluated for clinical benefit, cost effectiveness, and budget impact analyses, and their price negotiated in light of evidence and budget constraints
China has ensured accessibility and affordability of cancer immunotherapies, but HTA could be improved by better data on long term outcomes, local utility, and comparative effectiveness
HTA guidelines are not publicly available and appraisal times are insufficient
Costs might be further reduced by a risk sharing approach for reimbursing oncology immunotherapies
Acknowledgments
We thank Shimeng Liu and Hui Sun (Fudan University) for literature and data preparation.
Footnotes
Contributors and sources: YC’s research focuses on health technology assessment, health economic evaluation, hospital management, and health policy. HD’s research area includes health economic evaluation and health policy. YW, YY, and JM have focused on health technology assessment. HY has rich experience in health service research, population medicine and health economic evaluation. YC, HD, YW, and HY conceived the paper and drafted the manuscript, YW, YY, and JM collected data and undertook data analysis work. HY revised and edited the manuscript. YC is the guarantor.
Competing interests: We have read and understood BMJ policies on declaration of interests and have no interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.
This article is part of a series proposed by China Medical Board and commissioned by The BMJ. The BMJ retained full editorial control over external peer review, editing, and publication of these articles. Article handling fees (including printing, distribution, and open access fees) are funded by China Medical Board.
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