As highlighted in a recent issue of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR)’s Value & Outcomes Spotlight, the introduction of Most Favored Nation (MFN) in the US has created one of the most significant changes to drug pricing and access policies. MFN moves the US toward international reference pricing (IRP), a mechanism long used in many other markets, including across Europe, thereby creating a convergence of pharmaceutical pricing systems that once operated in separate domains. In this article, we revisit this critical and evolving topic in HEOR and market access.

By linking US reimbursement to ex-US price benchmarks, MFN adds complexities for manufacturers, policymakers, and healthcare systems and raises questions about the impact on affordability, access, and innovation. It brings the US into the central issue surrounding IRP: the effect that pricing decisions in one country have on others through reference baskets (groups of socioeconomically comparable countries), benchmarking formulas, and pricing revision cycles.

For health economics and outcomes research (HEOR), evidence generation, and health technology assessment (HTA) leaders, the addition of the US to the IRP discussion means that evidence strategy must be able to support global value defensibility, launch sequencing, and uncertainty management across interconnected markets.

Key takeaways

Complex and colliding pricing and access policies

The data insights company GlobalData monitors more than 75 countries where IRP is used as a policy tool to inform or regulate medicine prices. The role IRP plays varies by market, creating a complex landscape for pricing negotiations and requiring regular adjustments and updates to IRP models. 

Key elements of IRP include:

• Basket size, or the number of reference countries included; 
• Referencing application — whether only at launch or updated periodically; 
• Benchmark methodology, such as average, median, or lowest price; 
• Adjustment factors, such as purchasing power parity, to account for differences in the general cost of living across countries and for exchange-rate considerations;
• Price level referenced (ex-manufacturer or wholesale price).

IRP policy change is common, and some countries in Europe have sought to shift away from it. One such example is Germany, which recently amended its Medical Research Act to introduce optional confidential discounted reimbursements so companies could keep their reimbursement price negotiations with statutory insurance funds private, and therefore not jeopardise their negotiations with other countries. 

Many questions about how MFN will be applied and its longer-term impact remain. What is known is that MFN, which President Trump issued as an Executive Order in May 2025, seeks to tie US drug prices to those in similarly developed countries.

In December 2025, Centers for Medicare & Medicaid Services (CMS) published the Global Benchmark for Efficient Drug Pricing (GLOBE) Model and the Guarding US Medicare Against Rising Drug Costs (GUARD) Model as mandatory IRP-style initiatives, using a 19-country reference basket for MFN benchmarking. 

Both GLOBE (Medicare Part B) and GUARD (Medicare Part D) include two IRP benchmarks: a default CMS-derived international benchmark that is based on international pricing data sources, and an optional manufacturer-submitted volume-weighted average net price benchmark.

The administration has also introduced a voluntary CMS model called GENEROUS (GENErating cost Reductions fOr US Medicaid), which adjusts Medicaid pricing based on manufacturer-reported average prices from 8 countries: the United Kingdom, France, Germany, Italy, Canada, Japan, Denmark, and Switzerland.

How GUARD and GLOBE will evolve remains uncertain, as both are proposed models covering 25% of their respective Medicare populations, equivalent to roughly 5% of the US population, given that Medicare covers approximately 20% of the population; however, the share may be larger in Medicare-concentrated therapeutic areas. The impact of GENEROUS, meanwhile, will depend on how many states and manufacturers choose to participate. Beyond Medicare and Medicaid, MFN’s implications across the US healthcare ecosystem remain uncertain. 

Implications for global drug pricing policy

The impact of reference pricing on launch sequencing and the pricing corridor is well understood in Europe. Typically, companies choose to delay or avoid launching a product in a country with a mandated low price to avoid a potential price decrease in countries that use reference pricing. Thus, lower-income countries in Europe face delays or even no access at all because pricing is anchored to countries that can afford to pay more for the product. 

With MFN, some manufacturers are now delaying European launches, opting not to launch, and even withdrawing existing products from markets for fear of price erosion in the US. Instead, manufacturers of some products — particularly more costly, innovative products — are opting to launch first in markets that offer incentives for innovation and pose a lower risk of IRP spillover than European markets, for example, Japan.

Implications for HEOR, evidence generation, and HTA strategy

These developments create new strategic implications for HEOR, evidence generation, and HTA teams. As MFN and IRP-style policies increase the consequences of price differences across markets, evidence becomes more than a requirement for local reimbursement; it becomes a foundation for global value defensibility. HEOR leaders will need to anticipate how payer and HTA critiques in one market may affect pricing expectations, launch sequencing, and value perception in others. Common evidence challenges include inappropriate comparators, non-representative populations, immature or non-clinically meaningful endpoints, limitations in indirect treatment comparisons or external controls, insufficiently reliable real-world data sources, and uncertainty over long-term outcomes.

In this environment, HEOR, evidence generation, and HTA leaders can play a more strategic role by taking four practical steps:

Conclusion

How MFN weighs on reference baskets, revision cycles, and pricing responses could result in significant disruption to affordability, access, and incentives for innovation. 

Much of MFN’s longer-term impact is difficult to predict. However, it will require manufacturers to think carefully about evidence, launch planning, and pricing. In a more globally interconnected pricing environment, it will increasingly be up to HEOR and HTA teams to find ways to address payer uncertainty, support value recognition, and prepare for more HTA-like scenarios in the US and other markets. Manufacturers that bring evidence generation closer to global pricing and access strategy will be better positioned to manage the risks ahead.

Note: Sources listed below

Disclaimer:
The information provided in this article does not constitute legal advice. Cencora, Inc. strongly encourages readers to review available information related to the topics discussed and to rely on their own experience and expertise in making decisions related thereto.

Sources

• Centers for Medicare & Medicaid Services. GENEROUS (GENErating cost Reductions fOr U.S. Medicaid) model. Last modified 23 December 2025. Accessed 23 April 2026. https://www.cms.gov/priorities/innovation/innovation-models/generous  
• Centers for Medicare & Medicaid Services. GLOBE (Global Benchmark for Efficient Drug Pricing) model. Last modified 29 December 2025. Accessed 23 April 2026. https://www.cms.gov/priorities/innovation/innovation-models/globe 
• Centers for Medicare & Medicaid Services. GUARD (Guarding U.S. Medicare Against Rising Drug Costs) model. Last modified 29 December 2025. Accessed 23 April 2026. https://www.cms.gov/priorities/innovation/innovation-models/guard 
• Fick M, Satija B, Patton D. Drugmakers delay some European launches with a wary eye on Trump’s pricing policies. Reuters. Published 31 March 2026. Accessed 19 May 2026. https://money.usnews.com/investing/news/articles/2026-03-31/drugmakers-delay-some-european-launches-with-a-wary-eye-on-trumps-pricing-policies 
• Grueger J, Martin K, Sullivan SD. Referencing drug prices of other countries may not sustainably lower prices in the United States: Lessons from Europe. Value Health. 2025;28(9):1305-1308. doi: 10.1016/j.jval.2025.06.010.
• KFF. The facts about Medicare spending. Published 4 August 2026. Accessed 27 August 2026. https://www.kff.org/medicare/the-facts-about-medicare-spending/ 
• Kleja M. US cholesterol drug withdrawn in Denmark, MFN pricing policy blamed. Euractiv. Published 6 March 2026. Accessed 8 May 2026. https://www.euractiv.com/news/us-cholesterol-drug-withdrawn-in-denmark-mfn-pricing-policy-blamed/  
• Maini L, Pammolli F. Reference pricing as a deterrent to entry: Evidence from the European pharmaceutical market. Am Econ J Microecon. 2023;15(2):345-383. doi:10.1257/mic.20210053.
• Melck B. All change in Germany – confidential pricing in, IRP out. Pharmaceutical Technology. Published January 2025. Accessed 23 April 2026. https://www.pharmaceutical-technology.com/analyst-comment/all-change-germany-confidential-pricing-irp/ 
• Schott M, Brupbacher O, Batache D. Consultation opened on amendments to pharmaceutical pricing. Bär & Karrer Briefing. Published March 2026. Accessed 19 May 2026. https://www.baerkarrer.ch/userdata/20260318-ld-briefing-revision-kvv-klv.pdf 
• Sullivan SD, Grueger J, Martin K. International reference pricing comes to America: the MFN policies explained. Value Outcomes Spotlight. 2026;12(1). 
• Takamura K, Jinnai G, Niwa Y, Kondoh M. Overview of the Japanese rapid introduction premium as a drug pricing framework to enhance patient access to innovative drugs. Health Econ Rev. 2025;16:1. doi: 10.1186/s13561-025-00705-9.
• Watt A. International Reference Pricing (IRP) 2024: A year in review. Pharmaceutical Technology. Published 20 March 2025. Accessed 19 May 2026. https://www.pharmaceutical-technology.com/analyst-comment/international-reference-pricing-irp-2024/
• WhiteHouse.gov. The White House: Delivering Most Favored Nation Prescription Drug Pricing to American Patients [executive order]. Published 12 May 2025. Accessed 23 April 2026. https://www.whitehouse.gov/presidential-actions/2025/05/delivering-most-favored-nation-prescription-drug-pricing-to-american-patients/ 
• Wissinger E, Ringger D, Paardekooper C, Smith D, and de Alencar R. Most-favored nation policy and international reference pricing reshape global market access interdependencies. 2026. Value and Outcomes Spotlight. May/June. https://www.ispor.org/publications/journals/value-outcomes-spotlight/vos-archives/issue/view/drug-pricing-policies/when-worlds-converge–how-most-favored-nation-policy-and-international-reference-pricing-reshape-global-market-access-interdependencies  

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With the release of the first Joint Clinical Assessment (JCA) reports, a picture of the process and future implications is starting to emerge. Manufacturers are gaining insight into how the methods are being applied and the challenges these present. 

The next area of focus will be how the findings impact decisions at the country level and how they achieve the overarching goal of improving patient access across each European Union market. 

In an ISPOR panel discussion — Understanding the First JCAs: Practical Takeaways for Key Stakeholders – held on 23 June 2026, key stakeholders from industry, health technology assessment (HTA) authorities, patient advocacy groups, as well as a respected market access analyst came together to discuss the early reports and what the implications are for industry, innovation, and patient access.

Questions and concerns from early reports

As of mid-July 2026, the European Commission had published three JCA reports: one with critical findings relating to tovorafenib (Ojemda®) and two discontinuations. For industry stakeholders, the early reports pose questions about whether the framework has the necessary flexibility to adequately evaluate products for rare diseases where, in some cases, the gold standard of randomized controlled clinical trials (RCTs) is not feasible or ethical. 

During the panel discussion, James Ryan, Director, Global HTA Policy, HTA and Modelling Science at AstraZeneca, raised concerns about what would be feasible in evidence terms in the context of a rare disease and the real-world decision-making factors that surround it. However, Anja Schiel, PhD, Senior Advisor, Norwegian Medical Products Agency, disagreed, noting that the JCA assessors do consider indirect treatment comparisons and do not narrowly focus their reviews on randomized controlled clinical trials (RCTs). 

“When we do an HTA, we either assess the added benefit or we focus on cost-effectiveness, then we model and create scenarios, and we’re very open to all kinds of other constructs of evidence that will help us to understand the uncertainty around the methodology itself,” she said. However, she added that manufacturers need to ask how their single-arm trial can be designed to fit the real-world data, not the other way around. “Many HTAs are asking for real-world evidence. Make it convincing. Sometimes you have to generate your own. You can use different inclusion-exclusion criteria, you can look for a different population.”

The early reports also raise queries about patient input. Antonella Cardone, CEO of Cancer Patients Europe, a pan-European all-cancer patient association, noted that although patients and healthcare professionals were consulted per the JCA process and guidance, it is not clear how that feedback impacted the decisions in the report. 

“What is documented is that the patient asked for the quality-of-life assessment on the long-term safety, real-world comparators, discontinuation, and tapering, and equity of access,” she said. “But those criteria were considered non-accessible. So, what is the purpose of involving the experts if what they recommend cannot be taken into consideration?”

She added that there are several issues with regards to the meaningful involvement of experts in the process, including how experts are selected, whether a single individual or patient group is sufficient to represent an entire patient community, how their input influenced the definition of the PICOs (Population Intervention Comparator Outcome), the number of PICOs identified, and the final conclusions of the report. 

“We heard from the coordination group that they will be looking into ways to fix these problems and to be more transparent,” she said. 

Responding to the PICOs

In its own assessment of its evidence, Ipsen – the recipient of the first JCA report – flagged limitations inherent in their matching adjusted indirect comparison analysis, noting that they were attempting to answer the PICO. However, none of the company’s commentary on their own evidence was included in the report; only the assessor’s criticism.

As has been highlighted, there is a lack of evidence available on the very varied standards of care in the particular disease setting, pediatric low-grade glioma. While the JCA places the onus on manufacturers to expand their analysis, without the evidence required to conduct the analysis or to carry out a comparison arm, the credibility of the process is open to question, which then leaves those manufacturers at risk of criticism in the JCA report. 

Ryan noted that later JCAs that are based on large RCTs will have larger dossiers and will have much bigger JCA reports with far more available outcomes, including a lot of comparators and potentially many subpopulations. “When we get dossiers running to thousands of pages, we will get very large JCA reports and the question will be, how do people handle that and use it in a way that ultimately is focusing on the key bits that the decision maker needs to focus on?”

What’s next at the country level?

For the discontinuations and for any JCAs with negative findings, the question as to what happens to those products at the country level becomes pertinent. Do the products become blocked at a country level? If not, does that undermine the integrity of the JCA? And what are the implications for future JCAs and access to innovative products at a time when the European market is viewed negatively, especially in light of concerns over the impact of Most Favored Nation (MFN) policies and tariffs. 

Industry scrutiny will intensify as the JCA process progresses and as products from that process start to make their way into the country assessment and pricing process. “Countries are preparing and adapting their templates, but we don’t know how the JCA report is going to impact HTA decisions in the Member States,” said Cardone. 

While Schiel says HTA authorities have committed to reuse as much of the JCA as possible, it depends on the kind of assessment each member state wants to do and whether the report is relevant. “If the report contains nothing that is relevant for my decision-maker’s framework, then there’s little I can reuse.”
She added that many countries have different assessment criteria, including alternative pathways, simplified procedures and other approaches, and in very rare diseases the Norwegian Medical Products Agency does not do cost utility analysis at all and that decision-makers understand that they are often dealing with uncertainty. 

“Companies can submit something that’s not identical to the JCA, and they probably will because they will read the JCA and realize they haven’t addressed the relevant PICOs,” she said. “We are not actively going out reading JCAs and making HTA assessments because we rely on what is submitted to us.”

The JCA also has the potential to influence HTA markets outside of Europe, which will be looking at how they can bring something similar into their processes, panelists noted. 

“The limitations of taking a JCA report and applying it across healthcare and HTA systems that operate on different principles and standards of care may be open to question,” said Neil Grubert, independent pharmaceutical market access specialist.  “That being said, I’m sure there’s going to be enormous interest because it is new, it does represent a multi-country perspective, and it is in English. I know from panel discussions that NICE (UK’s National Institute for Health and Care Excellence) will be studying those first JCA reports with interest, but to what extent that influences their work remains to be seen.”

Impact of the JCA into the future

In 2028, orphan medicines will be subject to the mandatory JCA, which some observers have noted will raise further questions about the process and whether its methods support decision-making for medicines that may not fit traditional clinical evidence data models. 

“When the new HTA regulation came into place we hoped it would take some of the burden away from the HTA assessment in the countries and accelerate access to treatment. But will this happen? Nobody can tell,” Cardone said.

Ryan said it is his hope that the reports or the use of the regulatory dossier will provide some context at the local level, adding that if decision-makers depend solely on the JCA report, or more concerningly the summary report, it could pose a risk for how HTA decisions are reached across Europe. 

“The interesting thing to observe going forward will be what role the assessor and co-assessor play, and to what extent they may influence the output, even if that’s unintentional,” said Grubert, adding that he expects that over time there will be methodological convergence in the approach that different agencies bring to their work on the JCA as assessors and co-assessors. 

“I’m sure everyone is going to be studying not just this first one, but the others that follow and see what common features there are, and indeed what problems may arise that we need to address,” he added. “And that perhaps also speaks to the review process that is meant to start in a matter of months with a view to submitting a report in January 2028 to the Commission in terms of what adaptations may be required.

The overall goal of the European Commission and Member States is to promote broader availability, accessibility, and affordability of new medicines, and JCA plays a role in that objective. However, some of the core elements of the HTA lie beyond the scope of the JCA, Grubert noted, added to which there are geopolitical uncertainties impacting the launch of drugs in Europe. 

“The JCA is just one element in that broader picture, but if it goes to plan, it should lead to a convergence in terms of approaches to HTAs, which we hope will result in faster and more uniform access and reduction in the disparities in standard of care,” he said. 

Disclaimer:
The information in this article is intended to inform readers about a topic related to Cencora’s capabilities and is not legal or purchasing advice. Cencora, Inc. encourages readers to review the cited references in this article and use their own knowledge and experience when making decisions.

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