Clinical Benefit, Price, and Uptake for Cancer Biosimilars vs Reference Drugs in China

This systematic review and meta-analysis examines clinical benefits, costs, and uptake rates of approved cancer biosimilars of bevacizumab, rituximab, and trastuzumab compared with their corresponding reference drugs in China vs other countries.

Key Points

Question

What are the clinical benefits, price, and uptake rates of approved cancer biosimilars compared with their reference drugs in China and other countries?

Findings

In this systematic review and meta-analysis of 39 randomized clinical trials and 10 cohort studies, clinical benefits of biosimilars of rituximab, bevacizumab, and trastuzumab were comparable to those of their reference drugs. In China in 2022, the biosimilar price was 69% to 90% of the reference drug cost, while uptake rates were 54% to 83%.

Meaning

This study found equivalent clinical outcomes and lower prices of cancer biosimilars vs reference drugs, suggesting that initiatives to increase uptake of biosimilars in China could benefit more patients.

Abstract

Importance

The high cost of biologics used to treat cancer has been an increasing burden in the world. In China, the recent approval of cancer biosimilar drugs to resolve this problem is promising, but evidence of clinical benefits, price, and uptake for these drugs is still lacking.

Objectives

To compare characteristics of pivotal clinical trials in China and other countries for biosimilars of bevacizumab, rituximab, and trastuzumab and investigate the efficacy or effectiveness, safety, and immunogenicity outcomes of cancer biosimilars compared with reference drugs by meta-analysis.

Data Sources

For this systematic review and meta-analysis, PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for published studies from database inception to February 1, 2023, using the search topics (cancers) AND (biosimilars).

Study Selection

Randomized clinical trials and cohort studies that included patients with cancer were included.

Data Extraction and Synthesis

Two authors independently extracted the outcome estimates and characteristics for each study. A random-effects meta-analysis was performed to summarize the relative estimates with 95% CIs. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline.

Main Outcomes and Measures

Clinical trial characteristics were collected for biosimilars of bevacizumab, rituximab, and trastuzumab. The relative estimates of efficacy or effectiveness (objective response rate, progression-free survival, and overall survival), safety, and immunogenicity outcomes were analyzed for biosimilars vs reference drugs. The weighted average price and uptake rate were evaluated for biosimilars relative to their reference drugs between 2015 and 2022.

Results

A total of 39 RCTs (involving 18 791 patients) and 10 cohort studies (involving 1998 patients) were included. The biosimilars of bevacizumab (16 RCTs; risk ratio [RR], 0.97; 95% CI, 0.93-1.01; P = .17), rituximab (12 RCTs; RR, 1.03; 95% CI, 0.98-1.08; P = .70), and trastuzumab (9 RCTs: RR, 1.04; 95% CI, 0.97-1.12; P = .29) met equivalence with reference biologics in regard to the objective response rate. The results summarized from cohort studies were consistent with those from RCTs. In 2022, cancer biosimilars were priced at 69% to 90% of the costs for the reference drugs, and their uptake reached 54% to 83% in China.

Conclusions and Relevance

This systematic review and meta-analysis indicated that cancer biosimilars provided comparable clinical benefits at lower prices compared with reference drugs. These findings suggest the potential feasibility of expediting the transition from reference drugs to biosimilars to benefit more patients with cancer.

Introduction

Biological agents are increasingly used in clinical practice for the treatment of cancer, immune-mediated inflammatory disorders, and infectious diseases, with substantial effects.^1,2,3 In 2019, biologics accounted for 27% of all novel cancer drugs approved by the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japan Pharmaceuticals and Medical Devices Agency (PMDA).⁴ However, the high prices of biologics impose a serious burden on limited health care expenditures even for high-income countries.⁵

To address the high expense of novel biologics, the EMA established the first internationally approved pathway for biosimilars and authorized the first biosimilar, somatropin, in 2006.⁶ Similarly, the US established the Biologics Price Competition and Innovation Act of 2009 to abbreviate the regulatory pathway for biosimilars.⁷ In promoting the development of biosimilars, the PMDA issued the Guideline for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics in 2009.⁸ As of December 2022, the EMA,⁹ FDA,¹⁰ and PMDA¹¹ had approved more than 90, 40, and 32 biosimilars, respectively. Several studies have shown that biosimilars are equivalent to reference drugs, with varying degrees of price reduction.^{7,12,13,14,15,16} However, it was reported that biosimilars are still confronted with serious challenges to their use, including patent litigation, exclusivity protection, anticompetitive behavior, and interchangeability requirements, which have limited the use of biosimilars⁴ (eTable 1 in Supplement 1).

China has approved more than 200 new molecular entities since 2015, substantially improving patient accessibility.^17,18,19,20 Of these, therapeutic biologics account for about one-third of all novel drugs. Like other low- and middle-income countries, China is also confronted with high costs for these novel biologic products despite their superior clinical benefits.²¹ Therefore, the Chinese government has placed a high priority on the development of biosimilars to improve affordability (eFigure 1 in Supplement 1). In 2015, China’s National Medical Products Administration (NMPA) issued technical guidelines for the development and evaluation of biosimilars to facilitate their development.²² Subsequently, the NMPA also issued guidelines for the development of individual biosimilars, such as rituximab,²³ trastuzumab,²⁴ and bevacizumab²⁵ (eTable 2 in Supplement 1). These policies provided substantial incentives for research and development of biosimilars. As of February 2023, China had approved more than 20 biosimilars developed by local companies,²⁶ trailing behind only the US, the European Union, and Japan; these approvals are expected to markedly increase accessibility of biosimilars for Chinese patients (eTables 3 and 4 in Supplement 1).

The high morbidity and mortality rates of cancer in China have resulted in a substantial economic burden. The biosimilars of bevacizumab, rituximab, and trastuzumab approved in China are anticipated to alleviate the financial burden on patients with cancer. To our knowledge, there are 37 cancer biosimilars under development in China (eTable 5 in Supplement 1). As the number of cancer biosimilar approvals increases, their clinical benefit (efficacy or effectiveness, safety, and immunogenicity), price, and uptake are rarely reported in China. Therefore, this study conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) and cohort studies comparing the clinical benefit between cancer biosimilars and their respective reference drugs. Furthermore, the price and the uptake rate of biosimilars were also estimated relative to the reference drugs. This study may provide robust evidence for expanding the use of cancer biosimilars in China and elsewhere.

Methods

Data Sources

This systematic review and meta-analysis followed the related portions of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The approvals for cancer biosimilars and their pivotal trials (defined as a phase 3 clinical trial of a biosimilar vs a reference drug) through December 2022 were extracted using the publicly available listing databases of the China NMPA,²⁶ FDA,¹⁰ EMA,⁹ and PMDA.¹¹ The prices and uptake of biosimilars were collected from a centralized procurement platform and the Pharnexcloud database module.²⁷

Eligibility and Exclusion Criteria

We included RCTs and cohort studies that included patients with cancer. The intervention groups were patients receiving any of the rituximab, trastuzumab, or bevacizumab biosimilars. The comparators were patients receiving the respective reference drugs. We did not have any restrictions on dosage, lines of therapy, treatment regimen, or number of patients included. Noncomparative studies (eg, reviews, expert commentaries, editorials, and clinical guidelines) were excluded. A detailed description of the eligibility and exclusion criteria is shown in eAppendix 1 in Supplement 1.

Evidence Sources, Search Strategy, and Selection Process

We conducted a systematic search in Embase, PubMed, the Cochrane Library, and ClinicalTrials.gov from database inception to February 1, 2023, using the search topics (cancers) AND (biosimilars). The detailed evidence sources and search strategy are described in eAppendix 2 in Supplement 1. In addition, we manually searched publicly available review reports of cancer biosimilars from the NMPA,²⁶ FDA,¹⁰ EMA,⁹ and PMDA¹¹ and extracted their information on pivotal clinical trials. If the same study was published in multiple journals or posted in other sources (eg, ClinicalTrials.gov and review reports), we chose the report with the most informative data. Since some of the studies did not have publicly available full-text information, we extracted data based on abstracts. No restrictions were placed on the language. Two of us (X.L., X.D.) were responsible for screening documents independently for double-blind studies that met the inclusion criteria by title, abstract, and full text. If there was an inconsistency, it was resolved by a third reviewer (Z.L.).

Data Extraction

Two of us (X.L., X.D.) extracted the characteristics of cancer biosimilars from RCTs and cohort studies, including the number of patients, whether the study was sponsored by a manufacturer, study design, duration of study, lines of therapy, efficacy or effectiveness end points, safety, and immunogenicity. The efficacy end points included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The safety outcomes included adverse events of grade 3 or greater according to the Common Terminology Criteria for Adverse Events (version 4.0),²⁸ serious adverse events, death, neutropenia (grade ≥3), and thrombocytopenia (grade ≥3). Additionally, immunogenicity outcomes included incidence of neutralizing antibodies and antidrug antibodies during treatment. Prices and quarterly sale volumes of each cancer biosimilar and reference drug were extracted for 2015 to 2022 (a detailed description is shown in eAppendix 3 in Supplement 1).

Assessment of Risk of Bias

Two investigators (X.L., X.D.) assessed the risk of bias in the RCTs according to the Cochrane Collaboration’s tool,²⁹ including selection bias (sequence generation and allocation concealment), performance bias (blinding of participants, personnel, and outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and other bias. In addition, the Newcastle-Ottawa Scale was used to assess the risk of bias for the cohort studies.³⁰

Statistical Analysis

Medians (IQRs) were used for continuous variables, and counts and percentages were used for categorical variables. We determined the median of weighted average prices (WAPs) for drugs that had several approved biosimilars. For biosimilars or reference drugs with varying dose strengths, we unified the conversion to price per milligram (eg, trastuzumab is available in 440 mg per vial or 600 mg per vial in China) to better compare the price difference between them. Since the sales volume obtained was quarterly, the uptake rate of biosimilars was defined as the ratio between quarterly (3-month) sales volume of the biosimilar and total quarterly sales volume (quarterly sales volume of the biosimilar plus its reference product). The χ² test was used to compare the uptake rate of biosimilars for 3 cancer drugs (rituximab, bevacizumab, and trastuzumab) with the uptake rates of the respective reference drugs in the first and second years after the entry of biosimilars into the market.

We pooled the relative estimates (eg, relative risk and hazard ratio) of rituximab, bevacizumab, and trastuzumab biosimilars separately, as the indications and mechanisms of the tested drugs were substantially different. Also, the pooled relative estimates were calculated separately for the RCTs and cohort studies due to substantial differences in their designs. The efficacy or effectiveness, safety, and immunogenicity outcomes of cancer biosimilars were all pooled using meta-analysis with a random-effects model, similar to a previous study.⁷ Heterogeneity across studies was assessed using the Cochrane Q statistic and quantified by I² values.³¹ Subgroup analyses, including the type of indication, country of the sponsors, and sample size, were performed to assess the source of heterogeneity. To estimate potential publication biases, funnel plots, Begg tests, and Egger tests were conducted for primary efficacy end points. Relative estimates and 95% CIs were calculated based on the available data (number of cases and noncases by treatment group) if they were not reported in the trials. Sensitivity analyses were conducted for the primary efficacy end points by removing each study.

Statistical analyses were performed and graphical representations generated using IBM SPSS, version 20 (IBM Corp) and R, version 4.1.0 (R Project for Statistical Computing). The R packages used in the analysis included meta (version 5.2.0), forestplot (version 1.10.1), and ggplot2 (version 3.4.0). Two-sided tests were conducted with a significance threshold of P < .05.

Results

Search Results

eFigure 2 in Supplement 1 shows the process of study screening. Of the 1195 records sourced from the database and manually searched, 49 studies met the inclusion criteria, including 39 RCTs^{32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70} and 10 cohort studies.^{71,72,73,74,75,76,77,78,79,80}

RCT and Cohort Study Characteristics

Table 1 and eTable 6 in Supplement 1 summarize the characteristics of the 39 RCTs, which included 18 791 patients with cancer.^{32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70} Of those, 37 RCTs were published in journals,^{32,33,34,35,37,38,39,40,41,42,43,44,45,46,47,48,49,50,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70} 1 was reported in ClinicalTrials.gov,⁵¹ and 1 was reported in an NMPA review.³⁶ Of the 39 RCTs, 18 studied bevacizumab biosimilars,^{32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49} 12 studied rituximab biosimilars,^{50,51,52,53,54,55,56,57,58,59,60,61} and 9 studied trastuzumab biosimilars.^{62,63,64,65,66,67,68,69,70}

Table 1. Characteristics of the Included RCTs and Cohort Studies.

Source	Country	Cancer type	Biosimilar drug	Reference drug	Patients, No. a	Females, No./males, No.	Primary end point	Study design
Bevacizumab biosimilar vs bevacizumab
Stroyakovskiy et al,34 2022	Russia	NSCLC	BCD-021	Bevacizumab	357	110/230	ORR	RCT
Thatcher et al,48 2019	UK	NSCLC	ABP215	Bevacizumab	642	NA	ORR	RCT
Reinmuth et al,49 2019	US	NSCLC	PF-06439535	Bevacizumab	719	252/467	ORR	RCT
Reck et al,46 2020	Korea	NSCLC	SB8	Bevacizumab	763	255/508	ORR	RCT
Yang et al,47 2019	China	NSCLC	IBI305	Bevacizumab	450	162/279	ORR	RCT
Trukhin et al,39 2021	Ukraine	NSCLC	MB02	Bevacizumab	627	244/383	ORR	RCT
Rezvani et al,45 2020	Iran	MCRC	BE1040V	Bevacizumab	126	35/91	PFS	RCT
Qin et al,43 2021	China	MCRC	HLX04	Bevacizumab	677	271/404	PFS	RCT
Shi et al,42 2021	China	NSCLC	LY01008	Bevacizumab	649	237/352	ORR	RCT
Chu et al,44 2021	China	NSCLC	QL1101	Bevacizumab	535	217/318	ORR	RCT
Hengrui (sponsor),36 2022	China	NSCLC	BP102	Bevacizumab	517	NA	ORR	RCT
Wan et al,38 2021	China	NSCLC	MIL60	Bevacizumab	517	183/325	ORR	RCT
Syrigos et al,40 2021	UK	NSCLC	FKB238	Bevacizumab	731	248/483	ORR	RCT
Kim et al,35 2021	US	NSCLC	BI695502	Bevacizumab	671	246/417	ORR	RCT
Socinski et al,41 2021	US	NSCLC	MYL-14020	Bevacizumab	671	247/424	ORR	RCT
Chen et al,37 2022	China	NSCLC	BAT1706	Bevacizumab	651	NA	ORR	RCT
Lu et al,32 2023	China	NSCLC	Table 008	Bevacizumab	549	194/457	ORR	RCT
Verschraegen et al,33 2022	US	NSCLC	CT-P16	Bevacizumab	689	149/397	ORR	RCT
Zhao et al,71 2023	China	DLBCL	QL1101	Bevacizumab	946	413/533	ORR	Cohort study
Rituximab biosimilar vs rituximab
Kaplanov et al,61 2014	Russia	FL	BCD-020	Rituximab	92	NA	ORR	RCT
Toogeh et al,57 2018	Iran	CLL	Zytux	Rituximab	70	13/57	ORR	RCT
Jurczak et al,60 2017	Poland	FL	GP2013	Rituximab	629	350/277	ORR	RCT
Kim et al,59 2017	Korea	FL	CT-P10	Rituximab	140	77/63	ORR	RCT
Ogura et al,58 2018	Japan	FL	CT-P10	Rituximab	258	145/123	ORR	RCT
Poddubnaya et al,54 2020	Russia	Indolent NHL	BCD-020	Rituximab	174	90/84	ORR	RCT
Candelaria et al,56 2019	Mexico	DLBCL	RTXM83	Rituximab	272	117/155	ORR	RCT
Sharman et al,53 2020	US	FL	PF-05280586	Rituximab	394	216/178	ORR	RCT
Niederwieser et al,55 2020	Germany	FL	ABP 798	Rituximab	256	126/130	ORR	RCT
Archigen (sponsor),51 2020	Korea	FL	SAIT101	Rituximab	315	174/141	ORR	RCT
Shi et al,52 2020	China	DLBCL	HLX01	Rituximab	407	182/220	ORR	RCT
Song et al,50 2021	China	DLBCL	IBI301	Rituximab	419	202/214	ORR	RCT
Roy et al,74 2013	India	DLBCL	Reditux	Rituximab	173	51/112	NA	Cohort study
Bankar et al,73 2020	India	DLBCL	Reditux	Rituximab	152	41/111	NA	Cohort study
Deng et al,72 2022	China	DLBCL	HLX-01	Rituximab	33	13/20	NA	Cohort study
Trastuzumab biosimilar vs trastuzumab
Stebbing et al,69 2017	UK	Early BC	CT-P6	Trastuzumab	549	549/0	PCR	RCT
Rugo et al,70 2017	US	MBC	MYL-14010	Trastuzumab	500	500/0	ORR	RCT
von Minckwitz et al,67 2018	Germany	Early BC	ABP 980	Trastuzumab	725	725/0	PCR	RCT
Pivot et al,68 2018	France	Early BC	SB3	Trastuzumab	875	875/0	PCR	RCT
Pegram et al,66 2019	US	MBC	PF-05280014	Trastuzumab	707	707/0	ORR	RCT
Pivot et al,62 2022	France	Early BC	HD201	Trastuzumab	502	502/0	PCR	RCT
Alexeev et al,65 2020	Russia	MBC	BCD-022	Trastuzumab	225	225/0	ORR	RCT
Xu et al,64 2021	China	MBC	HLX02	Trastuzumab	649	649/0	ORR	RCT
Nodehi et al,63 2022	Iran	Early BC	TA4415V	Trastuzumab	92	92/0	PCR	RCT
Bae et al,80 2021	Korea	Early and metastatic BC	CT-P6	Trastuzumab	254	NA	PCR and PFS	Cohort study
Park et al,77 2022	Korea	Advanced GC	CT-P6	Trastuzumab	102	14/88	NA	Cohort study
Yang et al,76 2022	Canada	Early BC	MYL-1401O	Trastuzumab	136	NA	PCR	Cohort study
Bernat-Peguera et al,79 2022	Spain	Early BC	CT-P6	Trastuzumab	44	NA	NA	Cohort study
Eser et al,75 2023	Turkey	Early and metastatic BC	MYL-1401O	Trastuzumab	53	NA	PCR and PFS	Cohort study
Liu et al,78 2022	China	Early BC	HLX02	Trastuzumab	105	105/0	NA	Cohort study

Abbreviations: BC, breast cancer; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; GC, gastric cancer; MBC, metastatic breast cancer; MCRC, metastatic colorectal cancer; NA, not available; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; ORR, objective response rate; PCR, pathologic complete remission; PFS, progression-free survival; RCT, randomized clinical trial.

^a The number of patients was defined as the number of patients at randomization. The combined number of males and females of some studies does not equal the patient total because data on sex were missing for some patients.

Of the RCTs, 33 were prespecified as equivalence designs,^{32,33,34,35,36,37,38,39,40,41,42,43,44,46,47,48,49,50,51,52,53,54,55,58,60,62,64,65,66,67,68,69,70} while 6 were noninferiority designs^{45,56,57,59,61,63} (eTable 6 in Supplement 1). More than half of the RCTs (23 [59.0%]) were multiregional clinical trials.^{34,35,37,39,40,41,46,48,49,51,53,54,55,56,60,61,62,64,65,66,67,69,70} The median number of patients enrolled in the RCTs was 646 (IQR, 522-676) for bevacizumab biosimilars, 265 (IQR, 166-397) for rituximab biosimilars, and 549 (IQR, 500-707) for trastuzumab biosimilars. The median duration for assessing the primary efficacy end points was 18 weeks (IQR, 18-21 weeks) for bevacizumab biosimilars, 23 weeks (IQR, 23-24 weeks) for rituximab biosimilars, and 24 weeks (IQR, 23-24 weeks) for trastuzumab biosimilars. Thirty-four RCTs reported the incidence of antidrug antibodies,^{32,33,34,35,36,37,38,39,40,41,42,43,45,46,47,48,49,50,51,52,53,54,55,56,58,59,60,62,63,64,66,67,68,70} and 28 reported the incidence of neutralizing antibodies.^{32,33,34,35,36,37,38,39,40,41,42,43,47,48,49,50,51,52,53,54,55,58,62,63,64,65,66,67}

Table 1 and eTable 7 in Supplement 1 summarize the characteristics of the 10 cohort studies with a total of 1998 patients.^{71,72,73,74,75,76,77,78,79,80} Of the 10 cohort studies, 1 (10.0%) was of a bevacizumab biosimilar,⁷¹ 3 (30.0%) were of rituximab biosimilars,^72,73,74 and 6 (60.0%) were of trastuzumab biosimilars.^{75,76,77,78,79,80} All cohort study designs were retrospective.

The risk of bias assessment in RCTs and cohort studies is shown in eTables 8 and 9, respectively, in Supplement 1. Of the RCTs, 32 (82.1%) were low risk,^{32,33,34,35,36,38,39,40,42,43,45,46,47,48,49,50,51,53,54,55,57,58,59,60,63,64,65,66,67,68,69,70} 5 (12.8%) were uncertain risk,^{37,41,44,52,62} and 2 (5.1%) were high risk.^56,61 Of the cohort studies, 4 (40.0%) were high risk^72,76,77,79 and 6 (60.0%) were low risk.^{71,73,74,75,78,80}

Comparison With Pivotal Trials Among the 4 Agencies

As of February 2023, the FDA had approved 12 cancer biosimilars; the EMA, 16; the NMPA, 11; and the PMDA, 9 (Table 2 and eTable 10 in Supplement 1). The majority of biosimilars approved by the 4 regulatory agencies were evaluated in equivalence trial designs with low risk of bias (45 of 47 [95.7%]). In regard to the cancer types, RCTs of bevacizumab biosimilars enrolled primarily patients with non–small cell lung cancer (NSCLC). For rituximab biosimilars, the EMA, FDA, and PMDA included patients with follicular lymphoma, whereas the NMPA included patients with diffuse large B-cell lymphoma (DLBCL). Patients with early and metastatic breast cancer were included in pivotal clinical trials for biosimilars of trastuzumab (Table 2). Table 3 summarizes a pooled analysis of the primary efficacy end points in pivotal clinical trials of cancer biosimilars approved by the 4 regulatory agencies. With the exception of an EMA-approved rituximab biosimilar for patients with follicular lymphoma, the findings revealed no significant difference in primary efficacy end points between biosimilars and reference drugs.

Table 2. Comparison of Pivotal Clinical Trials Used to Support Approval of Cancer Biosimilars by the FDA, EMA, PMDA, and NMPA.

Characteristic	FDA	EMA	PMDA	NMPA
Bevacizumab biosimilar vs bevacizumab
Products, No.	4	7	4	8
Pivotal trials, No.	4	7	4	8
Sample size, median (IQR), No.	666 (638-696)	689 (657-725)	666 (638-696)	542 (517-650)
Equivalence, No.	4/4	7/7	4/4	8/8
Cancer type
NSCLC, No./total No.	4/4	7/7	4/4	7/8
MCRC, No./total No.	0/4	0/7	0/4	1/8
Rituximab biosimilar vs rituximab
Products, No.	3	3	2	2
Pivotal trials, No.	3	3	2	2
Sample size, median (IQR), No.	258 (257-326)	256 (198-325)	512 (452-570)	413 (410-416)
Equivalence, No.	2/3	2/3	2/2	2/2
Cancer type
FL, No./total No.	3/3	3/3	2/2	0/2
DLBCL, No./total No.	0/3	0/3	0/2	2/2
Trastuzumab biosimilar vs trastuzumab
Products, No.	5	6	3	1
Pivotal trials, No.	5	6	3	1
Sample size, median (IQR), No.	707 (549-725)	678 (574-721)	707 (628-716)	649 (649-649)
Equivalence, No.	5/5	6/6	3/3	1/1
Cancer type
Early BC, No./total No.	3/5	3/6	2/3	0/1
MBC, No./total No.	2/5	3/6	1/3	1/1

Abbreviations: BC, breast cancer; DLBCL, diffuse large B-cell lymphoma; EMA, European Medicines Agency; FDA, US Food and Drug Administration; FL, follicular lymphoma; MBC, metastatic breast cancer; MCRC, metastatic colorectal cancer; NMPA, National Medical Products Administration; NSCLC, non–small cell lung cancer; PMDA, Japanese Pharmaceuticals and Medical Devices Agency.

Table 3. Summary Results of Primary Efficacy End Points Used to Support Pivotal Trials for FDA, EMA, PMDA, and NMPA Approval of Cancer Biosimilars.

Outcome and cancer subgroup	RCTs, No.	Sample size, No.		Test of heterogeneity		RR (95% CI)a	P value
		Biosimilar	Reference drug	I2, %	P value
Bevacizumab biosimilar vs bevacizumab
NSCLC ORR
FDA	4	1343	1334	0	.78	0.97 (0.89-1.06)	.48
EMA	7	2423	2419	0	.65	0.99 (0.93-1.05)	.64
PMDA	4	1343	1334	0	.76	0.97 (0.89-1.06)	.48
NMPA	7	1938	1930	0	.60	0.99 (0.93-1.05)	.63
CRC PFS
NMPA	1	340	337	NA	NA	0.92 (0.78-1.06)	.27
Rituximab biosimilar vs rituximab
FL ORR
FDA	3	552	524	0	.66	1.06 (0.99-1.14)	.12
EMA	3	462	466	0	.70	1.06 (1.00-1.13)	.049
PMDA	2	510	513	17	.27	1.01 (0.95-1.08)	.69
DLBCL
NMPA	2	410	416	52	.15	0.99 (0.93-1.04)	.65
Trastuzumab biosimilar vs trastuzumab
Early BC PCR
FDA	3	1072	1077	68	.04	1.11 (0.94-1.32)	.21
EMA	3	1072	1077	68	.04	1.11 (0.94-1.32)	.21
PMDA	2	635	639	74	.05	1.05 (0.83-1.34)	.68
MBC ORR
FDA	2	602	605	64	.09	1.01 (0.87-1.16)	.93
EMA	3	926	930	28	.25	1.00 (0.93-1.08)	.99
PMDA	1	352	355	NA	NA	0.94 (0.84-1.05)	.27
NMPA	1	324	325	NA	NA	1.00 (0.91-1.11)	.98

Abbreviations: BC, breast cancer; CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; EMA, European Medicines Agency; FDA, US Food and Drug Administration; FL, follicular lymphoma; MBC, metastatic breast cancer; NA, not available; NMPA, National Medical Products Administration; NSCLC, non–small cell lung cancer; ORR, objective response rate; PCR, pathologic complete remission; PFS, progression-free survival; PMDA, Japan Pharmaceuticals and Medical Devices Agency; RCT, randomized clinical trial; RR, risk ratio.

^a Results of meta-analysis.

Clinical Benefit of Bevacizumab Biosimilars vs Bevacizumab

Meta-analysis of 16 RCTs^{32,33,34,35,36,37,38,39,40,41,42,44,46,47,48,49} showed that the primary efficacy end point (ORR) of bevacizumab biosimilars was comparable to that of the reference drugs in the treatment of NSCLC (risk ratio [RR], 0.97; 95% CI, 0.93-1.01; P = .17) (eFigure 3 in Supplement 1). No significant differences in the primary efficacy end point of PFS rate (RR, 0.92; 95% CI, 0.78-1.07; P = .27) or PFS (HR, 0.79; 95% CI, 0.46-1.35; P = .47) between bevacizumab biosimilars and the reference drugs were observed among patients with metastatic colorectal cancer. Subgroup analysis showed no significant differences in ORR between bevacizumab biosimilars and reference drugs across disease setting, country of sponsors, and sample size (eTable 11 in Supplement 1). Overall survival and PFS were not significantly different between biosimilars and their reference drugs. No significant differences were found in safety and immunogenicity outcomes between bevacizumab biosimilars and reference drugs (eTable 12 in Supplement 1).

A study from a clinical setting showed that the ORR of bevacizumab biosimilars was also comparable to that of the reference drug in patients with NSCLC.⁷⁶ No significant difference in safety outcomes was observed between bevacizumab biosimilars and reference groups (eTable 13 in Supplement 1).

Clinical Benefit of Rituximab Biosimilars vs Rituximab

The meta-analysis of 12 RCTs^{50,51,52,53,54,55,56,57,58,59,60,61} revealed no significant difference in the primary efficacy end point (ORR) between rituximab biosimilars and reference drugs in the treatment of lymphoma (RR, 1.03; 95% CI, 0.98-1.08; P = .70) (eFigure 4 in Supplement 1). Also, subgroup analyses indicated a comparable ORR between biosimilars and reference drugs (eTable 11 in Supplement 1). No significant difference was found in secondary efficacy end points (OS and PFS), safety outcomes, and immunogenicity outcomes between rituximab biosimilars and the reference drugs (eTable 12 in Supplement 1).

Three cohort studies of rituximab biosimilars were reported for the treatment of DLBCL.^72,73,74 The pooled ORR results showed comparable effectiveness of rituximab biosimilars and originator drugs. The occurrence of grade 3 or higher AEs, neutropenia (grade ≥3), and thrombocytopenia (grade ≥3) did not differ significantly between the rituximab biosimilar group and the reference groups (eTable 13 in Supplement 1).

Clinical Benefit of Trastuzumab Biosimilars vs Trastuzumab

The meta-analysis of 9 RCTs^{62,63,64,65,66,67,68,69,70} found no difference in the primary efficacy end points (ORR and pathologic remission) between trastuzumab biosimilars and reference drugs in the treatment of breast cancer (RR, 1.04; 95% CI, 0.97-1.12; P = .29) (eFigure 5 in Supplement 1). Subgroup analysis also suggested comparable efficacy outcomes between trastuzumab biosimilars and reference drugs (eTable 11 in Supplement 1). No significant differences were observed in secondary efficacy end points (OS and PFS), safety outcomes, and immunogenicity outcomes between trastuzumab biosimilars and the reference drugs (eTable 12 in Supplement 1).

Five cohort studies of trastuzumab biosimilars were for breast cancer,^{75,76,78,79,80} while 1 was for gastric cancer.⁷⁷ There were no significant differences in effectiveness and safety outcomes between the rituximab biosimilar group and the reference group (eTable 13 in Supplement 1).

Sensitivity Analysis and Publication Bias

Sensitivity analyses showed no significant change in the results of the primary efficacy end points after deleting each of the studies for the biosimilars of bevacizumab (eFigure 6 in Supplement 1), rituximab (eFigure 7 in Supplement 1), and trastuzumab (eFigure 8 in Supplement 1). No significant bias was observed in the primary efficacy end points for bevacizumab biosimilars (eFigure 9 in Supplement 1), rituximab biosimilars (eFigure 10 in Supplement 1), and trastuzumab biosimilars (eFigure 11 in Supplement 1), as suggested by the results of the Egger test, Begg test, and funnel plot.

Price and Uptake of Cancer Biosimilars vs Reference Drugs

The median WAP of cancer biosimilars vs reference drugs from 2015 to 2022 is shown in Figure 1 and eTable 14 in Supplement 1. Prices of cancer biosimilars showed a significant decline after 2017. In 2022, the estimated median WAP was 74% of the reference drug for bevacizumab biosimilars, 69% for rituximab biosimilars, and 90% for trastuzumab biosimilars. The uptake rate of cancer biosimilars showed an increasing trend over time (Figure 2 and eTable 15 in Supplement 1). eTable 16 in Supplement 1 shows the uptake rates of biosimilars for the 3 cancer drugs in the first and second year after launch and at the latest time (2022). The uptake rates of biosimilars for the 3 cancer drugs were significantly different in the first and second year after market entry. Bevacizumab biosimilars had the highest uptake rates in the first and second years after launch (26% and 68%, respectively), followed by trastuzumab biosimilars (20% and 47%) and rituximab biosimilars (6% and 44%). In 2022, the uptake rates for bevacizumab, rituximab, and trastuzumab biosimilars were 83%, 74%, and 54%, respectively.

Figure 1. Trends in Weighted Average Price (WAP) per Unit for Rituximab, Bevacizumab, and Trastuzumab Biosimilars Compared With Reference Drugs Between 2015 and 2022.

Orange dotted lines represent the year bevacizumab, rituximab, and trastuzumab were included on the National Reimbursement Drug List. B indicates biosimilar; R, reference.

Figure 2. Trends in the Uptake Rate of Rituximab, Bevacizumab, and Trastuzumab Biosimilars vs Reference Drugs After Market Entry.

The x-axis represents the time since the biosimilar was introduced to the market. The y-axis represents the uptake rates of biosimilars vs their reference drugs per quarter. Bevacizumab biosimilars and rituximab biosimilars were launched for sale in 2019, whereas trastuzumab biosimilar was launched for sale in 2020. The cutoff date for price uptake rates of biosimilars was December 31, 2022. The annual uptake rate for biosimilars is calculated by dividing the 1-year sales of biosimilars by the 1-year sales of their reference drugs. Orange dotted lines represent a 50% uptake rate of biosimilars vs reference drugs. B indicates biosimilar; R, reference.

Discussion

China initiated its biosimilar development at a later stage in comparison to the European Union, the US, and Japan. Nevertheless, with the initiation of China’s drug review reform in 2015, the research and development of biosimilars has garnered significant interest among domestic Chinese enterprises. The results showed that locally developed cancer biosimilars approved by the NMPA were comparable to those of the FDA, EMA, and PMDA in terms of the quantity and quality of clinical trial designs. All cancer biosimilars authorized by China were required to have a double-anonymized, equivalence, and low risk-of-bias design. Additionally, our study suggested that cancer biosimilars approved in China were shown to be equivalent to reference drugs in efficacy end points, safety outcomes, and immunogenicity outcomes. These findings indicated that China established rigorous and globally consistent review standards for cancer biosimilars.

The pooled analysis of 39 RCTs and 10 cohort studies revealed that bevacizumab biosimilars, rituximab biosimilars, and trastuzumab biosimilars did not differ significantly from the reference drugs with respect to efficacy, safety, and immunogenicity outcomes. Previous studies^7,13 also showed that the biosimilars of bevacizumab, rituximab, and trastuzumab had equally rigorous clinical trial designs and similar efficacy as the reference drugs, which was consistent with our findings. However, in most cases, studies included in our meta-analysis were exclusively premarket pivotal RCTs, which typically had more stringent patient inclusion and exclusion criteria, potentially differing to some extent from patients being treated in a clinical setting.⁸¹ Therefore, this study included cohort studies and suggested that the effectiveness and safety outcomes of these cancer biosimilars did not differ noticeably from those of the reference medications. These results from routine clinical practice add credence to the view that cancer biosimilars and reference medicines are clinically equivalent.

The price of cancer biosimilars is a worldwide issue since it directly affects affordability for patients and public health expenditures.⁴ Typically, biosimilars are priced between 70% and 85% of the reference product, while generics can be priced at only 20% of the originators.^82,83 Our results showed varying degrees of price reductions for cancer biosimilars compared with their reference drugs in China. In 2022, rituximab biosimilars accounted for the lowest price relative to the reference drugs (69%), followed by bevacizumab (74%) and trastuzumab (90%) biosimilars, similar to other countries.⁴ On a worldwide scale, biosimilars for the treatment of cancer are typically discounted by 30% in Europe, 10% to 33% in the US, and 30% in Japan.⁴ In the current circumstances, the reimbursement policy for biosimilars and their reference drugs is identical in China⁸⁴ (eTable 17 in Supplement 1). Interestingly, in 2022, trastuzumab biosimilars had a lesser price drop than the reference drug (90% of the reference drug price) compared with rituximab biosimilars (69% of the reference drug price) and bevacizumab biosimilars (74% of the reference drug price), possibly because only trastuzumab biosimilars were approved in China.

Indication extrapolation policies for biosimilars can play a crucial role in ensuring that patients have access to medications. A previous study reported that biosimilars in the US and Japan were under pressure from considerable patent litigation.⁴ Our findings also suggested that the NMPA and EMA appeared to have less stringent extrapolation requirements than the US and Japan (eTable 18 in Supplement 1). To our knowledge, bevacizumab, trastuzumab, or rituximab are not currently granted regulatory exclusivity or a patent term extension in China, which contributes to some extent to the development of cancer biosimilars. A previous study by some of us reported that China was strengthening intellectual property protection for novel drugs, including the establishment of patent term extension and regulatory exclusivity.¹⁷ Hence, it is anticipated that China will strive to achieve a harmonious balance in promoting research on biosimilars and reference medications in the forthcoming years.

The rapid shift from biologic reference drugs to biosimilars has been a worldwide challenge.^4,85,86 The uptake of cancer biosimilars also varies significantly between countries. A previous study showed that Denmark reached a 90% uptake rate in trastuzumab biosimilar entry after 3 months, while the lowest rate any country had was less than 10%.⁸⁷ In the US, a slow market uptake of cancer biosimilars was reported.^88,89 In China, bevacizumab biosimilars had the highest rate of uptake in the second year of marketing (68%), followed by trastuzumab biosimilars (47%) and rituximab biosimilars (44%). It should be admitted that the shift to cancer biosimilars in China has been relatively slow compared with Denmark. The success of the Danish model was largely attributed to its automated substitution system and the joint coordination among clinicians, administrators, patient organizations, and drug suppliers.⁹⁰ This strategy was similar to China’s national volume-based procurement (NVBP) for generic pharmaceuticals, which has also yielded favorable outcomes.⁹¹ Therefore, accelerating the uptake of cancer biosimilars through NVBP and multistakeholder consensus should be considered in China. Additionally, the uptake rate of biosimilars can be influenced by the preferences of both patients and clinicians.⁹² Further enhancement of understanding of biosimilars by physicians and patients is needed in China.

Limitations

There are some limitations to this study. First, due to the unavailability of comprehensive publications for some of the trials, our analysis was solely based on abstracts, thereby restricting our full understanding of the investigations, similar to a previous study.⁷ Second, this study did not conduct research on influencing patient and physician preferences for biosimilars, which would be more conducive to expansion of biosimilar use in China. Furthermore, this study rarely retrieved cancer biosimilars with quality problems or rejection of biologics license applications, likely because this information was not readily available to the public.⁹³ Finally, this study focused on a pooled analysis of the primary efficacy end point. Other secondary efficacy end points, such as duration of response, were not analyzed due to the limited information available.

Conclusions

This systematic review and meta-analysis found that the clinical benefits of cancer biosimilars were comparable to those of the reference biologics according to the evidence of the included RCTs and cohort studies. Furthermore, these biosimilars were considerably less expensive, which could have substantial implications for expanding access to treatment for patients with cancer. Our findings suggest that China should speed up its efforts to promote the use of biosimilars to benefit more patients with cancer.

Supplement 1.

eAppendix 1. Detailed Description of the Eligibility and Exclusion Criteria

eAppendix 2. Evidence Sources and Search Strategy

eAppendix 3. Price and Uptake of Biosimilar and Reference Drugs

eTable 1. Comparison of Regulatory Factors for Biosimilar Oncology Drugs in the NMPA, FDA, EMA, and PMDA

eTable 2. Individual Biosimilar Guidelines Issued by the NMPA in China

eTable 3. Cancer Biosimilars Approved by the FDA, EMA, PMDA, and NMPA as of February 1, 2023

eTable 4. Biosimilar Products Approved in China

eTable 5. Approved and In-Development Oncology Biosimilar Products in China as of February 1, 2023

eTable 6. Demographic and Clinical Characteristics of the Included RCTs

eTable 7. Demographic and Clinical Characteristics of the Included Cohort Studies

eTable 8. Results of the Risk of Bias Assessment of the RCTs Based on the Cochrane Collaboration’s Tools

eTable 9. Results of the Risk of Bias Assessment of the Cohort Studies Based on the Newcastle-Ottawa Risk of Bias Assessment Tool

eTable 10. Characteristics of Pivotal Clinical Trials Used to Support Approval of Cancer Biosimilars by the NMPA, FDA, EMA, and PMDA

eTable 11. Subgroup Analysis of Cancer Biosimilars Compared With Reference Drugs Derived From Randomized Clinical Trials

eTable 12. Pooled Analysis of Efficacy, Safety, and Immunogenicity of Cancer Biosimilars Derived From Randomized Clinical Trials

eTable 13. Pooled Analysis of Efficacy, Safety, and Immunogenicity of Cancer Biosimilars Derived From Cohort Studies

eTable 14. Weighted Mean Price per Unit of Rituximab, Bevacizumab, Trastuzumab, and Their Biosimilars Between 2015 and 2022

eTable 15. Trends in the Uptake Rate of Rituximab, Bevacizumab, and Trastuzumab Biosimilars vs Reference Drugs After Market Entry as of December 2022

eTable 16. Uptake Rates of Cancer Biosimilars vs Reference Drugs in the First Year, Second Year, and Latest Time on the Market

eTable 17. Reimbursable Cancer Indications for the Biosimilars and Reference Drugs of Bevacizumab, Rituximab, and Trastuzumab in the National Reimbursement Drug List in China as of July 1, 2023

eTable 18. Comparison of the Approved Indications of Cancer Biosimilars vs Reference Drugs by the NMPA, FDA, EMA, and PMDA as of July 2023

eFigure 1. Development History of Biosimilars in China

eFigure 2. Flowchart of Included Studies for the Systematic Review and Meta-analysis

eFigure 3. Meta-analysis of the Primary Efficacy End Points Between Bevacizumab Biosimilars and the Originator Derived from RCTs

eFigure 4. Meta-analysis of the Primary Efficacy End Points Between Rituximab Biosimilars and the Originator Stratified by Cancer Type Derived From RCTs

eFigure 5. Meta-analysis of the Primary Efficacy End Points Between Trastuzumab Biosimilars and the Originator Stratified by Cancer Type Derived From RCTs

eFigure 6. Sensitivity Analysis of Primary Efficacy End Points for Bevacizumab Derived From RCTs

eFigure 7. Sensitivity Analysis of Primary Efficacy End Points for Rituximab Derived From RCTs

eFigure 8. Sensitivity Analysis of Primary Efficacy End Points for Trastuzumab Derived From RCTs

eFigure 9. Publication Bias Assessment of Primary Efficacy End Points for Bevacizumab Derived From RCTs

eFigure 10. Publication Bias Assessment of Primary Efficacy End Points for Rituximab Derived From RCTs

eFigure 11. Publication Bias Assessment of Primary Efficacy End Points for Trastuzumab Derived From RCTs

eReferences

Supplement 2.

Data Sharing Statement