Navigating Brand-Brand Combinations Complexity:

Articles
Written By Adam Foster

P&MA Essentials for the EU4/UK Challenges for Demonstrating Value of Combination Therapies

Navigating Brand-Brand Combinations Complexity: P&MA Essentials for the EU4/UK Challenges for Demonstrating Value of Combination Therapies

Article written by Adrian Jung, Windrose Consulting Group

“Brand-brand” combination therapy launches have become an increasingly popular strategy for manufacturers looking to maximize the value of their successful monotherapy launches. “Brand-Brand” combinations generally offer incremental improvements in efficacy but are associated with significantly higher costs [1] .HTA / P&R agencies assess and price “Brand-Brand combinations” under the same decision criteria and have the same evidence expectations as monotherapies. As such, they often restrict or deny access to “brand-brand” combinations or request significant discounts. [2]

Currently, combinations are assessed similarly to monotherapies as there are no combination- specific HTA processes. However, in practice, combinations face increased efficacy expectations to 1) justify the increased costs of combination treatment and 2) achieve a favorable risk-benefit ratio (as combinations are generally associated with increased toxicity compared to monotherapies). [1,3] In markets that conduct cost-effectiveness (CE) assessments, (i.e., CA, the UK), combinations are also held to the same CE requirements as monotherapies but is more challenging to demonstrate for combinations given the increased costs and potentially prolonged treatment duration of both components vs. standard of care (SoC). [1,4]

DE – Only Formal Pricing Rule for Combination Therapies

Germany is the only market that has a formal pricing rule for combinations with a 20% rebate requirement for combination products. To define the scope of combination therapies subject to the rebate, the Federal Ministry of Health (BMG) has stepped in. The 20% rebates only apply to prescription medicines which do NOT receive a “considerable added benefit rating” and is applied to each component of the combination therapy [5]. Combination therapies are identified by health insurance billing data and defined as a combination if both components are active substances that are prescribed / dispensed on the same day or alternately dispensed at least twice within 5 months [5]. Since the rule applies exclusively to combinations in which both components are classified as “new active substances” (i.e., branded agents), it will no longer apply to combinations involving Keytruda from 2028 onwards [a] , following the expiration of its EMA regulatory data protection —even if the other component remains a “new active substance”.

[1] Keytruda originally received 8 years of data protection in 2015, but this was updated in 2020 with an extension on the data protection period until 2018; however, biosimilars will not be allowed to enter EU markets until 2031, following the expiration of market exclusivity [12-14].

 Table 1: Overview of Criteria for 20% Mandatory Rebates for Combination Therapies [5, 11]

Component-Level Pricing Challenges

Beyond the challenges of achieving a price for the combination, label expansions will also have a material impact on the price potential of each component. Given anti-competition concerns, HTA / pricing bodies are only able to conduct pricing negotiations with the manufacturer leading development of the combination [9, 10]. Combinations in which both components are owned by the same manufacturer are the least complicated, as payers and manufacturers are able to negotiate the price for all components. In these cases, payers across markets will likely afford manufacturers reasonable flexibility to allocate the total price pressure / discount across the combinations’ components.

On the other hand, combinations with a different manufacturer’s product(s) (excluding products that have been co-developed with another manufacturer) are more complicated as the leading manufacturer (i.e., manufacturer initiating the label expansion) bears the entire burden of providing a price discount. While true workarounds are limited, there are, in theory, frameworks that could help spread pricing pressure between the different manufacturers. In the UK, for example, the ABPI framework provides a potential pathway for manufacturers to manage such challenges. Under this approach, a leading manufacturer launching in combination with a competitor’s product could secure cross-company payments from the other manufacturer without changing their list price. However, this is unlikely to be implemented in practice, as manufacturers will likely be unwilling to offer a rebate proactively.

While the leading manufacturer (i.e., manufacturer initiating the label expansion) bears all the price pressure, a combination launch may still have knock-on implications for the non-leading manufacturer’s product, typically arising post-launch. Non-leading manufacturers often choose not to update their label or engage in co-promotion, partly to avoid triggering price renegotiations for their existing product. However, given that payers are BI-sensitive, increases or projected increases in volumes for the non-leading manufacturer’s product as a result of the combination launch may provide payers with leverage for price re-negotiations, particularly if price-volume agreement thresholds or budget impact forecasts are excessed.

Windrose’s Take

Strategic decisions around combination therapies must be considered across the full product lifecycle—from early clinical development to HTA assessment, pricing negotiations, and post-launch management. Given the complexity and pricing pressure often associated with brand-brand combinations, especially when multiple manufacturers are involved, success depends on anticipating payer expectations and proactively aligning development, evidence generation, and access strategy from the outset.

Combination Development

Manufacturers must weigh the trade-offs between pursuing a brand-brand combination or a fixed-dose combination (FDC), as each presents distinct pricing and access challenges. Brand-brand combinations often face tough pricing negotiations and require strong clinical justification to support their higher cost. Whether the launch is viable largely depends on whether expected volume gains can offset potential price reductions to existing monotherapies. These combinations may be more feasible when the leading manufacturer owns all components, allowing flexibility to distribute discounts internally—though payers may still expect steeper cuts on higher-volume products. FDCs like Opdualag may offer greater pricing protection, as they are assessed as new products rather than indication expansions, shielding individual component prices such as Opdivo. In France, for example, Opdualag received an ASMR IV rating relative to Opdivo monotherapy, which effectively anchored its price to that of Opdivo and helped preserve the monotherapy’s value. However, FDCs may be less clinically viable in some settings, as they limit the ability to independently adjust dosing for tolerability or toxicity.

HTA

While HTA bodies assess combination therapies under the same frameworks as monotherapies, in practice, they impose higher evidentiary expectations to justify added cost and toxicity. This makes clinical development strategy critical to HTA success. Including a monotherapy arm in pivotal trials can offer flexibility in pursuing either a monotherapy or combination reimbursement path, depending on the strength of results. Manufacturers should align trial design with payer expectations while preserving strategic options for access.

Combination Pricing

Combination therapies are assessed and priced under the same frameworks as monotherapies—there is no preferential treatment for brand-brand combinations. As such, manufacturers should conduct a robust early landscape assessment to identify pricing benchmarks, understand how similar combinations have been valued, and anticipate payer expectations. Payers will expect the price of the combination to reflect its clinical value in line with monotherapies, regardless of how many branded components it includes.

Given Germany’s role as a large and strategically important revenue market, special attention should be paid early in development to whether the combination could fall under mandatory rebate rules by launch. Manufacturers should assess whether the combination is likely to meet the legal criteria for Germany’s 20% combination rebate—considering factors such as component dosing and whether either product remains under patent or retains data exclusivity. These assumptions should be incorporated into commercial forecasts and trade-off analyses to evaluate whether the combination remains viable under likely pricing pressure.

Component Pricing

Manufacturers need to factor in how component ownership impacts pricing risk. When all components are owned by the same manufacturer, there is flexibility to allocate discounts strategically and protect overall portfolio value. In contrast, if a competitor’s product is part of the combination, the leading manufacturer must secure reimbursement independently—often absorbing the full discount. Even in rare, co-promotion scenarios where both manufacturers update their labels, each must enter separate negotiations without visibility into the net price of the other component. While payers are aware of both net prices and may attempt to coordinate pressure across manufacturers, this setup still exposes each party to unilateral pricing risk. Without co-ownership or a cost-sharing arrangement, the imbalance in negotiation dynamics can create substantial commercial risk and should be addressed early in launch planning.

Post-Launch

Choosing not to update the label is a common strategy for non-leading manufacturers seeking to avoid formal price renegotiations, but this does not eliminate risk. In budget impact–sensitive markets, increased volumes driven by combination use can still prompt payers to call a product into negotiation or ask for additional discounts at schedule price re-negotiations. The key challenge is entering these discussions without a well-developed value narrative or negotiation strategy tailored to the combination context. Even without a formal label update, manufacturers should proactively prepare for this scenario by establishing baseline messaging and assessing potential trade-offs in advance.

Adrian Jung Windrose Consulting Group


 
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