Introduction
Uveitis is a heterogeneous group of intraocular inflammatory diseases affecting the uvea, retina, retinal blood vessels, and vitreous body [
1]. The prevalence of uveitis in China is estimated to be 152 per 100,000 people [
2], higher than that in the United States of America (USA) [
3] and the European Union [
4]. Uveitis ranks as the second leading cause of blindness in China [
5] and commonly affects individuals in their working age [
6], which may force them to cease work or studies [
7]. Non-infectious uveitis (NIU) is the most common type of uveitis, accounting for about 41–55% [
8]. Non-infectious uveitis affecting the posterior segment of the eye (NIU-PS) encompasses both posterior and panuveitis [
9], which commonly manifests as a chronic relapsing condition persisting over several years [
10] and is associated with a higher risk of sight loss [
11], representing about 67.0% of NIU [
12].
The primary treatment goals for chronic NIU-PS are to induce disease quiescence, minimize involvement of adjacent structures, and preserve or improve vision [
1,
13]. Currently, there are no established national and international standard guidelines in place [
14,
15]. Clinic guides [
16,
17], expert consensuses [
18,
19], and recent therapeutic advancements [
1,
6,
20‐
22] indicated corticosteroids as the preferred clinical choice, which may be administered systemically (oral or parenteral) or locally via periocular or intravitreal injections, as well as intravitreal implants [
15]. Local corticosteroid treatments are generally favored, since prolonged high-dose systemic treatments often have treatment-limiting side effects, including hyperglycemia, hypertension, osteoporosis, depression, and weight gain [
1]. When systemic corticosteroid treatments are deemed inappropriate for patients, or proven insufficient in disease control, or likely to cause severe side effects upon prolonged use, immunosuppressive drugs are administered as an alternative [
13,
15,
17,
20]. Nevertheless, immunosuppressive drugs come with drawbacks such as hepatic and renal impairment, bone marrow suppression, and gastrointestinal intolerance [
20]. If the disease is still active or if these treatments are not tolerated, biologics may be used. Presently, the majority of conventional treatments (i.e., corticosteroids, immunosuppressive drugs, and biologics) being used for chronic NIU-PS are off-label [
16,
20,
22]. Local treatments, exemplified by peribulbar and intravitreal injections, offer only short-term disease control [
22], which makes repeated injections a necessity. Hence, long-acting intravitreal implantable drugs, offering the advantage of prolonged effective control of intraocular inflammation and reducing the need for frequent surgeries, have emerged as a welcoming new treatment.
The fluocinolone acetonide intravitreal (FAI) implant (YUTIQ
®; Ocumension Therapeutics) is the inaugural injectable 0.18-mg intravitreal implant accessible for precise management of chronic NIU-PS in China. It continuously releases a sub-microgram dose (0.25 mcg/day) of fluocinolone acetonide to the posterior segment over a period of 36 months [
10,
13]. Two phase 3, multi-national, multi-center, randomized, masked, sham-controlled studies (clinicaltrials.gov: NCT01694186 [
10] and NCT02746991 [
23]), have demonstrated that the FAI implant significantly reduces the recurrence rate of chronic NIU-PS. Additionally, a real-world study (RWS) for the Chinese population (Chictr.org, ChiCTR2300069849 [
24]) is currently under investigation. The first phase of the study, known as the Boao Injection Phase, has been completed. The sample size of the FAI implant arm and the external control arm (conventional treatments), based on propensity score matching (PSM), were both 74 patients. Results indicated that the 6-month uveitis recurrence rate in the FAI implant arm was significantly reduced, compared to pre-implantation (8.70 vs. 79.37%) and the external control arm (8.70 vs. 35.14%). Importantly, a low rate of severe adverse events (SAEs) was observed in the FAI implant arm at 2.70%, and there were no adverse events (AEs) resulting in withdrawal or death, of which the most common one was elevated intraocular pressure (IOP) (16.22%). Based on the effectiveness and safety of RWS, the FAI implant was approved for marketing by the National Medical Products Administration (NMPA) on June 16, 2022. Previously, it obtained approval in the USA on October 12, 2018, making it the latest long-acting corticosteroid implant approved by the Food and Drug Administration (FDA).
Despite its clinical benefits, the FAI implant may pose heavy economic burdens on patients with chronic NIU-PS, highlighting efficiency issues in a health resource-limited setting. Economic evaluation has become paramount in the last decades to help prioritize healthcare spending, that is, to spend healthcare budgets optimally to ensure the highest health gains for limited resources [
25]. However, there were no specific economic evaluations for the 0.18-mg FAI implant, and its cost-effectiveness in treating patients with chronic NIU-PS remained unclear. Therefore, this study aimed to assess the cost-effectiveness of the FAI implant for chronic NIU-PS from the perspective of the Chinese healthcare system.
Discussion
The FAI implant, the sole long-acting intravitreal implant sanctioned in China for chronic NIU-PS, addresses an unmet need in the management of chronic NIU and represents a landmark significance for Chinese patients. This study, to the best of our knowledge, is the first to evaluate the cost-effectiveness of the FAI implant based on the Chinese RWS. The results from this study are more applicable than others, considering they were in better reflection of the traits of the Chinese population and provided a more accurate representation of real-world medication usage.
This study assessed the cost-effectiveness of the FAI implant vs. the LCP in treating Chinese patients with chronic NIU-PS. The base analysis yielded an incremental 0.43 QALYs under an additional cost of $7503.72 (¥50,575.05), which resulted in an ICER of $17,373.49 (¥117,097.33) per QALY gained. A variety of sensitivity analyses were conducted to explore uncertainty relating to all aspects of model assumptions. All ICERs in the DSA were under the Chinese threshold of three times GDP per capita ($38,145/QALY [¥257,094/QALY]). At a WTP threshold of $19,072 (¥128,547) (1.5 times the Chinese per capita GDP in 2022), the FAI implant had a 67.70% probability of being cost-effective. As demonstrated in the scenario analysis, if the FAI implant aligns its price reduction with the average rate from the 2023 negotiation of NRDL, it would result in lower costs and represent an absolute advantage. Therefore, the model results could be considered robust.
Currently, no CEAs of the 0.18-mg FAI implant were identified from our systematic review. CEAs conducted on other intravitreal implants sharing the same composition but varying in strength, such as the 0.19-mg ILUVIEN [
29] and 0.59-mg Retisert [
30], demonstrated that single implantation of fluocinolone acetonide intravitreal implant was cost-effective in the United Kingdom (UK) and the USA, while one implant in both eyes for a patient with bilateral disease was in the contrary. Due to inadequate evidence for subgroup analysis, this study encompassed a mixed population of patients with bilateral or unilateral disease and those with implants in one or both eyes, which made it distinct from prior studies. However, while the cost assumptions varied depending on whether patients had received implantation in one or both eyes or had a unilateral or bilateral condition, the effectiveness data in the model remained the same. The study design and assumptions may have certain limitations and are far from flawless, but under current circumstances, they have proved the cost-effectiveness of the 0.18-mg FAI implant in the mixed population in China. Additionally, the robustness of the results has been supported by extensive sensitivity analyses.
Moreover, this study did not account for re-implantation because of insufficient clinical data to support the efficacy evaluation of retreatment, aligning with the current CEA models. However, in clinical practice, patients without contraindications and expected benefits from retreatment would most likely receive retreatment after complete drug release. Several non-randomized studies of the dexamethasone implant [
53‐
55], which allow repeat implantation, suggested that patients could return to their state at baseline after complete drug release. The second and third implantation would produce outcomes similar to the first implantation. It also revealed that each successive implantation may have a correlation with an increased occurrence of AEs like IOP and cataracts. Squires et al. (2019) [
28] suggest that when the model is not sensitive to the cost of AEs and the cost of each implant is the same, the cost-effectiveness of up to three consecutive implants is expected to be similar to that of one implant. Therefore, the current study postulated that the fluctuations in cost-effectiveness stemming from multiple FAI implants could resemble the above scenario.
Given that the Chinese RWS did not collect any utility data of the FAI implant (0.18-mg), the utilities for the on-treatment of this model were derived from the MUST trial (0.59-mg Retisert) [
38]. Although the 0.59-mg Retisert shared the same composition as the 0.18-mg FAI implant, it had a higher dosage and release rate, which seemed to result in a lower recurrence rate [
10]. However, the 0.18-mg FAI implant provided lower AE incidence rates in treated eyes and significant improvements in vision compared with the 0.59-mg Retisert [
10]. These differences above may all influence the quality of life of patients, making it challenging to quantify the direction and magnitude of the bias. Further study about the utilities of the 0.18-mg FAI implant might offer data to enhance the accuracy of the findings.
Several challenges were encountered during this study. Firstly, this study focused on direct healthcare costs from the perspective of the Chinese healthcare system, omitting broader societal impacts like labor losses associated with blindness resulting from uveitis because of the lack of data. Notably, this could potentially lead to an underestimation of the cost-effectiveness of the FAI implant.
Secondly, experts have indicated that patients would probably achieve remission from disease after complete drug release, which means that patients would discontinue any treatment. However, this study did not incorporate the prospect of remission after 3 years due to lack of efficacy data, potentially resulting in conservative study outcomes.
Finally, while this study showcased the cost-effectiveness of the FAI implant via model analysis, the absence of long-term treatment effects and the utilities of local people, indeed introduce a level of uncertainty in this model. Further evidence is still warranted to accurately evaluate the benefits and cost of the FAI implant, and assist healthcare decision-makers in optimizing the allocation of our limited resources.