The European Union (EU) is embarking on the most important overhaul of its pharmaceutical legislation in over two decades. Following the political agreement reached by co-legislators on December 11, 2025, the EU is replacing its outdated framework with a new Directive and Regulation (Pharma Package) that are poised to shape the future landscape of research, development, and manufacturing of medicines in Europe. ¹

Announced in April 2023 as a “reform,” the European Commission’s initial proposal soon also became referred to as a “revision,” with the two terms becoming used interchangeably in the public debate. ² But “reform” and “revision” have subtle and crucial differences in their meanings. Reform refers to the process of restructuring or fundamentally improving a system by addressing its flaws, while revision involves making specific corrections or adjustments to an existing model. The final compromise text disseminated by the European Parliament after long negotiations appears to combine both. ³

Is drawing attention to the reform-vs-revision terminology used by the European Commission just a matter of semantics? The term semantics was coined by the French philologist Michel Bréal in 1883, establishing the foundations of linguistics and logic focused on the study of meaning. It examines the structure of language at different levels, analyzing both the lexical meaning of individual words and compositionality, i.e., the implications of words that combine to form the meanings of phrases or sentences. Semantics encompasses both literal (denotative) and implied (connotative) meanings, and differs from “definition,” which refers to a precise and concise explanation of what a word or concept means, typically found in a dictionary.Reference Bréal ⁴

The implications of semantics are pervasive in medicine. In the landmark work of the seminal epidemiologist Archibald (Archie) Cochrane (1909-1988), entitled Effectiveness and Efficiency: Random Reflections on Health Services and published in 1972, Cochrane described the distinction between efficacy and effectiveness. Both assess how well a treatment, drug, or intervention works; however, efficacy refers to performance under the controlled conditions of a trial, while effectiveness pertains to performance in routine clinical use situations, in which conditions are variable and strict oversight of prescribing is not found.Reference Cochrane ⁵

Semantics are important because words can inherently have multiple meanings, and semantics can therefore directly shape policies and behaviors. In pharmaceutical regulation, attention to the specific, actionable meaning behind regulatory text and terminologies can help ensure that legal frameworks are interpreted to protect public health. But literal linguistic meanings alone are not sufficient to translate a text into action; they require contextual interpretation to be understood and correctly applied. Preventing ambiguities in word choice, interpretation, and application is therefore essential. While the upcoming implementing and delegated acts, as well as guidelines, will offer specific definitions for statutory interpretation, a broader conceptual and philosophical discussion surrounding these changes is needed.

For instance, the Pharma Package establishes that medicinal products addressing a rare disease with no currently available medicinal treatment resulting in a clinically relevant reduction in disease morbidity or mortality for the relevant population could be assigned the term “breakthrough orphan medicinal products,” a subcategory benefitting from up to eleven years of market exclusivity instead of nine years in the European Union as for the other products indicated for rare diseases. The extent to which a “clinically relevant reduction in disease morbidity or mortality” will qualify a product for this additional period of market exclusivity will presumably be clarified in future European Medicines Agency (EMA) guidance. Nevertheless, one may ask what the term “breakthrough therapy” means in this context. According to the dictionary, a breakthrough is an important, sudden advance that removes a barrier to progress. This notion seems to be differently captured in the US Food and Drug Administration Breakthrough Therapy designation, which qualifies a drug for a process designed to expedite its development and review if that drug is intended to treat a serious condition and for which preliminary clinical evidence indicates substantial improvement over available therapy on clinically significant endpoints.Reference Darrow, Avorn and Kesselheim ⁶

The term “breakthrough” is routinely used in press releases and prescribing resources, and evokes the notion of exceptional innovation. Breakthrough represents a potential game-changer and leads consumers to overly optimistic beliefs about drug effectiveness. Such high expectations among the public may influence decision-making, from regulatory approval processes to subsequent pricing and reimbursement decisions. But we have learned, at least from the US so far, that drugs receiving Breakthrough Therapy designation are not necessarily innovative, in part because the term can be attached to drugs at early stages in their development, before they are subject to late-stage, comparative clinical testing. Many physicians themselves reportedly misinterpreted the term breakthrough—believing these drugs are supported by stronger evidence than the statute requires.Reference Kesselheim ⁷

Thus, how should Health Technology Assessment (HTA) bodies and payers in Europe approach an EMA-designated “breakthrough orphan medicinal product” when it is not a genuine breakthrough? While in the US, the Breakthrough Therapy designation has continued the trend towards increasingly flexible evidentiary standards for expedited development and approval pathways, in the EU the term may evoke the notion of a highly effective medicine for a rare, or “orphan,” disease. This leads to a second semantic debate: what should define an orphan medicine?

In medicines regulation, the term “orphan” emerged in the mid-1960s. In the wake of the thalidomide tragedy, the introduction of more stringent regulatory requirements by the Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act led to the withdrawal of numerous ineffective medicinal products, highlighting the fact that certain diseases were therapeutic orphans. It soon became apparent that some diseases were disproportionately affected by this phenomenon. Owing to limited patient populations, these conditions attracted little interest from the for-profit pharmaceutical industry, as the substantial costs of research and development were rarely justified by the commercial returns that such small markets could offer at the time. The passage of the US Orphan Drug Act in 1983 represented an intervention intended to address this situation. By establishing targeted financial and regulatory incentives, the Act sought to overcome the limited market attractiveness of these conditions. Since then, drugs designed by the Orphan Drug Act have acquired the linguistic short-hand of “orphans” and become a well-established regulatory category; they are now widely regarded by the public as synonymous with drugs for rare diseases.Reference Mikami ⁸

However, orphan drugs and drugs for rare diseases should have important semantic differences. The term “orphan” evokes the notion of a condition lacking attention, sponsorship, or therapeutic support, whereas “rare” refers simply to low prevalence within a population. Although both US and EU legislation have established specific criteria for special designation, including prevalence thresholds and incentives, some research has highlighted how the drugs that emerge do not invariably target rare diseases. Indeed, many Orphan Drug Act-designated drugs in the US have multiple other FDA-approved indications, often for non-rare conditions. In addition, the prevalence thresholds adopted in the US (<200,000 affected individuals) and the EU (<5 per 10,000 inhabitants) allow the special designation to be granted to medicinal products targeting conditions that do not lack in scientific research or investment, such as subsets of certain common forms of cancer. Similarly, the status may also be conferred on products developed for conditions that are not even characterized by unmet need, having already benefited from the availability of one or more approved treatments.Reference Costa, Ross and Kesselheim ⁹

The limitations of such definitions are further underscored by proposals to introduce a distinct ultra-orphan designation, coupled with enhanced financial incentives, to stimulate and accelerate research into ultra-rare conditions, which are often challenging to investigate and may remain underserved within the current regulatory and economic framework.Reference Michaeli, Jürges and Michaeli ¹⁰ With the advent of personalized medicine, some scholars have argued that most diseases may be stratified into extremely small patient populations. In this context, the term hyper-rare has been proposed to describe conditions affecting fewer than 1 in 10 million individuals.Reference Smith, Bergman and Hagey ¹¹

So what should be considered rare? We believe that advances in genetics and molecular biology should inform the modernization of an otherwise sound regulatory framework. Today, rare disease drugs constitute a substantial proportion of new medicinal products approved each year in both the US and the EU. At the same time, their often exceptionally high prices can make them quite profitable and are exerting growing pressure on health care budgets. Because the designation can heighten patient expectations and fuel demands for rapid access to new therapies, irrespective of the magnitude of their clinical value, it may be timely to revisit the terminology, definitions, and broader semantics surrounding these drugs. Such a reassessment could help ensure that regulatory incentives and policy priorities are more effectively directed towards addressing truly unmet medical needs among rare diseases.Reference Costa and Kesselheim ¹²

To this end, it is essential also to define the semantics of an unmet medical need, or a situation in which a serious health condition lacks satisfactory methods of diagnosis, prevention, or treatment. Unmet medical need has probably become yet another overused locution in medicines regulations. Addressing unmet medical needs is very proper, functional, and politically salient. Everyone, from politicians to regulators to patients, talks about unmet medical needs. It has been so overused that at a certain point, it threatened to become not apt any longer to signal what society should prioritize, so someone introduced the notion of “high” unmet medical needs to differentiate from the “regular” ones.Reference Vreman ¹³

However, there is no universally accepted definition of unmet medical need. Stakeholders frequently rely on factors such as the availability of existing treatments, disease severity, and the size of the affected patient population. Although the Pharma Package introduces criteria for identifying medicines that address unmet medical needs, including the absence of an authorized treatment for a life-threatening or severely debilitating condition and the potential to achieve a meaningful reduction in disease-related morbidity or mortality, these concepts remain open to interpretation and difficult to operationalize in a consistent manner.Reference Wens ¹⁴

Not surprisingly, the vast majority of medicines approved in recent years have been intended for life-threatening or severely debilitating conditions, raising questions about the discriminatory value of this regulatory criterion in steering research and development towards areas of greatest need. The prospect of addressing an unmet need in a serious or life-threatening condition already represents itself a powerful incentive for developers. In many cases, products entering these therapeutic areas may face lower hurdles to demonstrate value since they lack alternatives, and may also benefit from favorable pricing and reimbursement conditions. Over the next few years, accumulated evidence will shed light on whether these regulatory concepts and definitions effectively steer innovation towards previously overlooked areas of medical need or simply add to a reductant and overstructured system.Reference Costa ¹⁵

Refining semantics is not a purely theoretical exercise, but a subtle yet powerful element that has the potential to make the pharmaceutical system more efficient in setting priorities and more reliable in meeting societal expectations and needs. While terminologies like “breakthrough,” “orphans,” or “unmet medical need” may help capture stakeholders’ attention, it risks undermining the clarity and precision essential to a sound regulatory framework if their intended purpose does not reflect their true meaning. In addition, as pharmaceutical investments and clinical research have become increasingly globalized, the adoption of commonly accepted terminology and regulatory definitions across settings can extend far beyond semantics, fostering alignment in strategies and priorities among investors, governments, regulators, researchers, healthcare professionals, and patients. Different definitions, scopes, eligibility criteria, and incentives for the same expression may hamper efficient convergence of efforts in drug development and access. Addressing these issues could contribute to transforming a revision into meaningful reform of modern regulatory systems.