Balancing Access and Value in Multi-Indication Medicines: Implications of PD-(L)1 Broad Listings in Australia

Abstract

Multi-indication medicines challenge health technology assessment processes as health technology assessment relies on repeated indication-based assessments to determine cost-effective pricing and reimbursement. The reimbursement of programmed death-(ligand) 1 inhibitors is an international example of this. In 2025, Australia’s Pharmaceutical Benefits Advisory Committee adopted a novel broad cancer listing on the Pharmaceutical Benefits Schedule for nivolumab, ipilimumab and pembrolizumab. This agreement consolidates all advanced and metastatic cancer indications under a single broad listing per medicine, using a single weighted-average price and utilisation-based rebate caps. This article analyses the economic, policy and clinical practice implications of such an agreement. The broad listing agreement features several characteristics identified in the literature as desirable for a multi-indication reimbursement framework, including facilitating timeliness of access, potentially reducing the health technology assessment workload, mitigation of arbitrage risk and the partial preservation of indication-based pricing principles. However, the agreement also includes some contestable trade-offs and introduces unresolved challenges, such as weakening indication-level value signalling, constraining routine utilisation monitoring and distorting comparator pricing in future economic evaluations. Further, the agreement may alter evidence generation and shift decision-making responsibilities to other actors within the health system. We suggest that while a broad listing represents a pragmatic response to the growing prevalence of multi-indication medicines, it entails important trade-offs between access, transparency and value alignment. These design considerations are likely to be relevant for other jurisdictions considering similar reimbursement reforms.

Key Points

This paper examines a new policy approach in Australia that allows cancer medicines to be funded across multiple indications under a single listing.

While this approach can improve patient access and reduce delays, it may also weaken value-based pricing signals and have downstream implications for evidence generation and clinical practice.

These trade-offs are important for policymakers considering similar approaches.

Introduction

The evaluation of multi-indication medicines poses significant challenges for health technology assessment (HTA). These medicines require multiple time- and resource-intensive evaluations across different patient indications and the establishment of often complex multi-indication pricing arrangements. This can lead to delays in patient access to these medicines and persistent gaps in access for rare conditions or otherwise commercially unattractive indications [1]. Programmed death-(ligand) 1 (PD-(L)1) inhibitors are among the most prominent and mature examples of how a multi-indication medicine class can disrupt HTA processes globally. In response, several jurisdictions have implemented abbreviated or pragmatic reimbursement approaches to ensure timely subsidised access to these medicines. Example approaches include coverage with evidence development or price-volume agreements, which bypass the need for indication-based assessments [1–5].

In Australia, after more than a decade of repeated submissions and re-submissions across different indications, the Pharmaceutical Benefits Advisory Committee (PBAC) has accepted a broad listing agreement for the PD-(L)1 inhibitors: nivolumab (Opdivo^®) and ipilimumab (Yervoy^®) [6]. Prior to the implementation of this agreement, nivolumab (as monotherapy or in combination with ipilimumab) had already been reimbursed across approximately eight advanced and metastatic cancer indications, spanning tumour types and lines of therapy [6]. Under this agreement, all of these current indications, plus future advanced and metastatic cancer indications, would receive subsidised treatment with these PD-(L)1 inhibitors through listing on the Pharmaceutical Benefits Scheme (PBS). The price for each medicine was consolidated into a single weighted average price, calculated from existing PBS-listed indications and weighted by observed utilisation. Financial risk is then managed by two utilisation-based caps. Utilisation up to the first cap reflects use in indications already listed on the PBS, while utilisation beyond this level is assumed to be associated with additional indications estimated by the sponsor (the submitting pharmaceutical company) and is subject to a confidential rebate on the weighted average price. Utilisation beyond the second cap would attract a substantially higher rebate (approximately 90%), designed to protect against uncertainty arising from additional unforeseen indications or excessive utilisation [6]. In effect, the agreement allows for full public funding for all advanced and metastatic cancer indications for nivolumab and ipilimumab, while sharply limiting government exposure to unforeseen use through high rebates. See Fig. 1 for a conceptual diagram of the agreement.

Fig. 1.

Conceptual diagram of the utilisation-based rebate structure of the broad listing agreement. A–D represent hypothetical indications of a multi-indication medicine. * The weighted average price represents an averaged consolidation of previously assessed indication-specific prices, calculated by weighting each indication’s effective price by its estimated utilisation. PBS Pharmaceutical Benefits Scheme

Strengths of the Proposal

The PBAC’s acceptance of the nivolumab and ipilimumab broad listing agreement has the potential to address the sustained public criticism concerning delays in patient access to these medicines. There has been growing pressure for the Australian HTA system to respond more efficiently to these multi-indication medicines [7]. This agreement reflects several key characteristics that we identified in a previous scoping review as desirable features for a multi-indication medicine reimbursement framework, including reducing the workload burden on HTA agencies, following the principles of indication-based pricing, not requiring complex utilisation-data infrastructure and reducing the risk of arbitrage (using a lower-priced indication to access treatment in a higher-value indication) [1]. Repeated indication-specific HTA evaluations and appraisals are now no longer required for patients to access these PD-(L)1 inhibitors to treat additional advanced and metastatic cancer indications, alleviating the assessment burden, at a time when evaluation capacity is increasingly constrained relative to need [8].

Beyond considerations of efficiency, this may also represent a more proportionate policy response. The traditional HTA process involves a full indication-specific appraisal, irrespective of the size of the eligible population. As oncology medicines expand into increasingly narrow, biomarker-defined indications, the requirement for a full HTA for very small patient indications may become disproportionate to the utilisation or budget impact of each additional indication. In such circumstances, consolidating pricing and managing the budget impact through utilisation-based caps may represent a pragmatic alternative to repeated appraisals for each indication, noting that evidence appraisal would be the responsibility of other actors within the health system (discussed further below).

The use of a single weighted average price for each medicine, anchored by their cost-effective price across each indication previously assessed by the PBAC, preserves indication-based pricing principles and allows budget uncertainty to be addressed through a utilisation-based risk-sharing arrangement without the need for complex digital infrastructure, i.e. for monitoring use by indication (this is a double-edged sword, however, as we discuss below). This approach also reduces the risk of arbitrage, as the medicine is the same price for all indications. Importantly, this approach facilitates improved access for patients in indications where generating traditional comparative evidence for HTA appraisals is difficult, such as rare cancers or genetic conditions. This is a difficulty that the PBAC has previously acknowledged [7].

Following the recommendation of the nivolumab-ipilimumab broad listing agreement in September 2025, the PBAC also recommended a similar multi-indication listing for pembrolizumab (Keytruda^®) in advanced or metastatic cancers in December 2025 [6]. The Committee indicated that pembrolizumab would join the same risk-sharing arrangement structure with harmonised restriction wording across the three medicines [9]. The establishment of three broad listing arrangements on the PBS suggests that this listing model is not an isolated arrangement but may represent an emerging policy approach for multi-indication medicines. However, despite aligning with several desirable attributes for a multi-indication framework, the agreement also includes some contestable trade-offs and introduces unresolved challenges that warrant closer examination.

Structural Limitations of a Single PBS Item Number

A central structural feature of the agreement is the consolidation of all eligible indications under a single PBS item number. While public policy documents have not provided justification for this approach, this design choice presumably simplifies administration and aligns with the overall intention of the agreement with the industry sponsor (i.e. having a single broad listing). However, having a single PBS item number also removes the ability to use standard PBS dispensing data to easily and routinely observe utilisation by indication. This represents a loss of meaningful data relative to other single or multi-indication medicines that have been, or will be, listed on the PBS where different item numbers are each associated with a different indication.

This decision to forgo indication-level itemisation is particularly notable in the Australian setting, where infrastructure to monitor utilisation by indication is already well established through indication-based listings. While prescribing outside PBS-listed indications is likely to be limited in practice because of existing governance structures (i.e. doctors need to specify the patient’s indication when prescribing PBS-subsidised treatments), the loss of indication-level visibility remains a key limitation. In the multi-indication medicine reimbursement literature, the ability to monitor use by indication is frequently identified as a desirable characteristic of frameworks that rely on blended or averaged pricing [1]. Belgian HTA stakeholders have noted that when weighted average pricing approaches are applied, the ability to monitor utilisation by indication and periodically re-weight prices based on updated utilisation data is a critical design feature [10]. This is because patterns of clinical use are not likely to be static. As evidence evolves and practice changes (especially in a rapidly evolving field such as oncology), the utilisation of medicines in each indication will change over time. For example, a new medicine may become available for one indication and predominate in the market share, while for another indication of the same medicine, where the comparator is different, the market share does not increase. Without the ability to observe and respond to these shifts, the weighted average price may no longer accurately reflect the overall value of the medicine that it is intended to capture. The PBAC has, in fact, implicitly acknowledged this limitation, by noting that indication-based utilisation could be tracked using linked data (i.e. linking an individual’s PBS data to other health data, such as hospital data) instead of just PBS dispensing data. However, such approaches are not routinely implemented because they are burdensome and unlikely to support routine or timely monitoring [11]. Historically, managed access arrangements that are reliant on linked data have faced persistent practical challenges in Australia, including delays in data availability and governance complexity [12]. The agreement’s reliance on linked data may offset some of the efficiency gains associated with the broad listing approach (i.e. while there is no longer a need for indication-based assessments, there is now a need for complex linked data analyses to determine accurate pricing). In reality, this represents a sub-optimal solution given that the infrastructure already exists within Australia for routine indication-level monitoring. This design choice therefore reflects a deliberate trade-off between administrative simplicity and empirical oversight. This is an important observation for multi-indication medicine reimbursement policy more broadly.

Comparator Pricing and Value Signalling

Under this newly agreed utilisation-based rebate structure, a cost-effective price for each indication of nivolumab and ipilimumab is no longer defined or, for new indications, ever established, undermining one of HTA’s key functions: to provide formal value signals [13]. A central purpose of indication-based HTA is to establish a cost-effective price for a medicine within a defined population. However, when the price of the medicine, as a whole, is derived from a range of existing indications and adjusted through aggregate utilisation rebates, the published price does not correspond to the value at the indication level, thus contravening the principles of indication-based pricing.

This has important implications when these medicines are used as comparators in future HTA evaluations. Economic analyses require comparators to reflect the opportunity cost borne by the health system in the specific clinical context [14, 15]. Under this new arrangement, the price no longer reflects the clinical benefit, opportunity cost or prior HTA value judgements associated with a specific indication, effectively breaking the price-value link. If the weighted average price of nivolumab or ipilimumab is used as the comparator price and it exceeds the medicine’s true value in a given indication, the incremental cost-effectiveness ratio may be artificially lowered, overstating the value (making new medicines appear more cost effective and be able to command higher prices that would not be warranted). Conversely, if the weighted or rebated price is below the multi-indication medicine’s true indication-specific value, innovative medicines treating patients with the same indication may appear to be of poor value and potentially result in delayed, restricted or denied access. In principle, it would still remain possible to reference the original indication-specific price established through prior PBAC assessments. However, this presents practical challenges, as the price is not technically what is paid by the government for the medicine under the current utilisation-based rebate structure. More importantly, for future indications that will not undergo formal HTA appraisal, no indication-specific cost-effective price will ever be formally determined. In these settings, there is no value-anchored benchmark available for use in subsequent economic evaluations.

Similar concerns have also been raised in the indication-based pricing literature. Preckler and Espin [16] note that weighted average pricing approaches may misalign price and value and establish inappropriate benchmarks for subsequent entrants, with implications for access and payer expenditure. Beyond economic analyses, the loss of indication-based pricing for these multi-indication medicines also removes reference points for future price negotiations as well as anchors for reassessment as the evidence base matures, an issue of particular relevance given the planned retrospective review of this agreement. It further obfuscates the use of price benchmarking and reference pricing, over and above the current discrepancies observed between effective and published prices or confidential discounts [17].

Incentives for Evidence Generation

Above, we have suggested that the utilisation-based price-volume agreement improves access to all patient indications for a medicine, particularly indications otherwise unlikely to progress through a formal HTA process because of insufficient evidence [18]. However, such arrangements may also alter sponsors’ incentives in more subtle ways. Under the traditional indication-specific HTA model, reimbursement for each indication is contingent on the sponsor demonstrating comparative clinical and cost effectiveness. This structure creates a clear incentive for sponsors to generate evidence on a per indication basis and seek both regulatory and reimbursement approval even for smaller or lower-value indications where commercial returns are modest.

By contrast, if a broad listing is routinely adopted as reimbursement policy for multi-indication medicines in other countries’ HTA systems, such agreements may encourage sponsors to prioritise evidence generation for a select few high-value indications and then secure a broad listing that will then encompass additional indications. This aligns with established industry practice, whereby sponsors often first pursue reimbursement for narrow high-value indications followed by expansion into broader indications [18]. A broad listing may therefore reinforce this practice by allowing higher valued indications to anchor the overall price and reimbursement structure of the agreement, which may not reflect the overall value of the medicine across all indications.

A further implication is that, once broad reimbursement has been achieved, the marginal benefit of undertaking additional studies or submitting separate evidence for small or low-value indications may be reduced from the sponsor’s perspective. In such circumstances, access to multiple indications may occur without the corresponding development of robust indication-specific evidence, shifting the evidentiary burden toward clinicians and payers, who must interpret heterogeneous or extrapolated data in the absence of a formal evidence-based appraisal (this is discussed further below).

Over time, such dynamics may contribute to differential evidentiary standards across indications of the same medicine, with higher-prevalence populations supported by a formal HTA review and smaller populations relying on indirect, extrapolated or less systematically appraised evidence. Evidence of this asymmetry is already observable. For many rare and less common cancers, clinicians are reporting a lack of robust phase III data to guide treatment options for their patients, noting that a group of 200 rare and less common cancers represent 40% of all cancer deaths in Australia [19]. While patients with rare and less common cancers will have better access to a multi-indication medicine under this arrangement, the uncertainty regarding the safety and effectiveness of these medicines in those indications may be even higher in the future without systemic incentives to generate an appropriate evidence base (where feasible). This is a problem of equity. Broad listing arrangements may inadvertently reinforce existing disparities in the evidence base, as these populations, already difficult to study, may become less likely to be the focus of future evidence generation efforts.

However, a note of caution is warranted, as this issue is multi-dimensional. Incentives for evidence generation are shaped by multiple factors beyond a single reimbursement approach, including regulatory approval requirements and the need to support market access and competitive positioning in other countries’ HTA systems [20]. As such, while broad listings may alter local incentives, their impact on evidence generation is also dependent on these broader factors.

Clinical Practice Implications

As discussed above, where PBS funding is available under a broad listing, future patient indications for the medicine may never undergo a formal HTA, as the HTA process is no longer the gateway to reimbursement for those indications. While clinical evidence may continue to be generated for regulatory or clinical purposes, the absence of indication-specific assessments, relative to existing standards of care, would limit formal evidence synthesis for value assessments and the consequent value signalling within the wider health system.

Indication-based PBAC assessments in Australia do not directly inform the development of clinical guidelines, unlike the situation with the National Institute for Health and Care Excellence in the UK [21]. However, the PBAC’s recommendations indirectly influence clinical practice through its indication-based restriction criteria (e.g. by specifying the eligible population, treatment-sequencing requirements and continuation rules) [22]. These restrictions are put in place to ensure treatments are clinically effective and cost effective. When these restrictions are obscured by a broad listing arrangement, clinicians may have reduced guidance regarding the effectiveness and cost effectiveness of treatments across different patient indications, increasing the risk that more effective treatment options may be foregone. With the new agreement, a greater share of evidence interpretation and clinical decision making will devolve to individual clinicians, potentially increasing variations in practice by placing greater emphasis on professional judgement to ensure the quality use of medicines. This is particularly true with regard to the PD-(L)1 inhibitors because, contrary to the usual practice in Australia, the use of these medicines for the additional (likely rare) indications may not require a separate indication-specific assessment by the Australian regulator (the Therapeutic Goods Administration), which assesses the benefit and risk profile of a medicine for market authorisation (as distinct from the PBAC, which assesses for reimbursement) [23, 24]. For example, pembrolizumab has received a provisional market authorisation for the treatment of unresectable or metastatic cancer for certain tumour types, irrespective of the site of origin [24]. So, not only is there no guidance associated with the development of a detailed restriction in a PBS item number, but there is also no regulatory advice concerning the safety and efficacy of PD-(L)1 inhibitors for these new specific indications. Of course, it may also be argued that the safety of these specific medicines is very well established and so the patient risks and any uncertainties around medicine efficacy for PD-(L)1 inhibitors are likely to be low. While variation in practice is likely to ensue, this may be less pronounced in the present agreement as the broad listing is confined to advanced and metastatic cancers, where standard treatment options are likely to have been exhausted and therapeutic alternatives are often limited. The new agreement appears to have considered that the benefits of a broad listing, in terms of patient access, outweigh the risks of possible harms in this particular instance (for PD-(L)1 inhibitors). As this agreement is intended for last-line use, the issue of effective treatments being foregone will not apply [25]. Where there might be a real concern, is if this agreement becomes a precedent for multi-indication medicines with less established safety and efficacy profiles and where other more effective treatment options for the rarer indications might be available.

Timing

The timing of these price-volume agreements may be an important determinant of their feasibility and acceptability among different stakeholders. At the point of the implementation of this agreement, PD-(L)1 inhibitors are well established in clinical practice, with a well-known safety profile and multiple indications already separately assessed and listed on the PBS [6]. Much of the value associated with these major indications has already been accepted by both the sponsor and the government.

The timing may have increased the government’s willingness to engage in this agreement as the clinical risk/benefit trade-offs for patients is well characterised. It may also have influenced the sponsor’s willingness to accept a utilisation-based rebate structure, particularly as patent expiry approaches and revenue growth slows as competing medicines enter the market for specific indications. It is uncertain whether similar arrangements would be acceptable for multi-indication medicines earlier in the product life cycle, when the risk/benefit trade-off is more uncertain and when sponsors may still anticipate substantial revenue from future indications.

Additionally, the risk associated with unforeseen utilisation in additional indications or excessive use may be lower later in the product life cycle, as the major tumour types have already been explored and additional expansions are likely to involve smaller sub-populations. This reduces the uncertainty regarding potential utilisation growth, allowing for better budget predictability, benefiting both the government and the sponsor.

However, the late adoption of such an arrangement carries opportunity costs. Where indications are, for the sponsor, less commercially attractive and therefore of lower priority, patients may experience prolonged delays in access. In addition, when such agreements are reached sooner, any efficiency gains in the HTA workload and administrative burden may be realised earlier. These insights raise important questions regarding the optimal timing of a broad listing agreement and consideration of whether earlier implementation could enhance or undermine the HTA system.

Conclusions

The broad listing agreement for PD-(L)1 inhibitors is an example of how an established HTA system has responded to the growing challenge posed by multi-indication medicines. While this analysis draws on the design elements of this specific agreement, the observable trade-offs are likely to be relevant for future agreements as multi-indication medicines become more common. The PBAC has shown that it may be possible to improve timely patient access, reduce HTA workload and manage financial uncertainty without needing repeated indication-specific public funding submissions for multi-indication medicines. However, these gains are not without compromise, including reduced utilisation monitoring capacity, weakened indication-level price, and value signalling and through shifting risk and decision-making responsibility to other actors within the health system.

This paper does not argue against the use of broad listing reimbursement arrangements. Instead, it highlights the importance of awareness of the different design features and the trade-offs such arrangements can entail. As HTA is primarily a local activity [26], this may be particularly relevant for jurisdictions exploring more pragmatic reimbursement approaches for multi-indication medicines.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions. This work received no specific grant from any funding agency, commercial or not-for-profit sectors. Adelaide University has sponsored the open access fee.

Declarations

Conflicts of Interest

The authors receive funding from the Australian Federal Government to undertake HTAs of new medicines submitted for public funding under the PBS. The Australian Government had no role in the conception or development of this study.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Authors’ Contributions

All authors contributed to the paper conception and design. The first draft of the manuscript was written by IL and all authors commented on subsequent versions of the manuscript so as to influence interpretation. All authors read and approved the final manuscript.