Oncology is one of the most active areas in drug development. Cancer accounted for roughly 35% of all new drugs approved by the FDA in 2025, with an even larger pipeline behind them.[1] Yet that innovation is not distributed evenly. Some cancers have seen their treatment and outcomes transformed by successive generations of targeted therapies, immunotherapies and new treatment modalities, while patients with other cancers still face remarkably few effective treatment options.
The reasons extend well beyond clinical need. New therapies emerge where biology can be understood and acted on, where clinical trials can be realistically run, and where there is a viable path through development, regulation, and financing.
Rare cancers bring many of these pressures into particularly sharp focus. Collectively, they account for approximately one quarter of cancer diagnoses worldwide, yet each individual cancer may affect only a small number of patients.[2] This combination creates a distinctive development challenge: the clinical need may be substantial, while the populations available for research and clinical trials are limited and securing the sustained investment needed to advance development can be more difficult.
Rare cancers therefore provide a useful lens through which to examine why therapeutic progress remains uneven. Biology determines whether there is a viable point of intervention; patient numbers and disease characteristics determine whether clinical evidence can be realistically generated; and development economics influence whether a program can secure the sustained investment needed to advance.
When those constraints reinforce one another, areas of significant unmet need can remain underserved, despite the extraordinary pace of innovation elsewhere in oncology.
Innovation Follows Biology, But Some Cancers Are Harder to Target
The first constraint is biological. Some cancers offer a relatively clear point of intervention. Chronic myeloid leukemia is a well-established example: the disease is driven by a well-defined molecular abnormality that provided a well-defined therapeutic target and led to major improvements in outcomes for many patients.
But many cancers present a far more complex biological picture. A tumor may depend on several overlapping pathways rather than a single dominant driver. The biology that sustains it may involve targets that are difficult to drug, or alternative pathways may compensate when one is blocked. Anatomical and structural barriers can further limit treatment: brain tumors are protected by the blood-brain barrier, while pancreatic tumors are often surrounded by a dense stroma that restricts both drug penetration and immune-cell access.
Beyond identifying a biologically important target, that target must be accessible to the chosen therapeutic modality, sufficiently differentiated from healthy tissue to allow an acceptable therapeutic window, and present in a clinically meaningful patient population.
The result is that some cancers present far fewer actionable opportunities than others. Each additional layer of biological uncertainty increases the complexity, duration, and risk of drug development before a therapy ever reaches the clinic.
Clinical Development Adds a Second Constraint
A compelling biological hypothesis still has to be tested in patients. Even where the biology is compelling, a therapy has to be testable. For rare cancers, which account for approximately 25% of cancer diagnoses worldwide, this can be difficult from the outset.[2]
Each individual indication may involve only a small number of eligible patients, often distributed across specialist centers and multiple countries. Molecular subtyping can narrow that population further, while aggressive disease may leave only a limited window in which patients are well enough to enroll in a study. In some settings, heterogeneity or rapid disease progression can also make conventional randomized trials difficult to design or complete. Recruitment therefore affects not only the pace of development, but which study designs are feasible in the first place.
The challenge is compounded by the evidence that a new therapy must generate. Clinical endpoints must be meaningful, measurable, and persuasive to regulators. Where an effective standard of care already exists, a new treatment may need to demonstrate superiority or meaningful additional benefit against an established benchmark. In settings with few effective options, the comparator may be different, but the evidence must still support a favorable benefit-risk profile.
These constraints help explain why rare cancers have historically been associated with poorer outcomes. Five-year survival has been reported at approximately 47% for rare cancers compared with 65% for common cancers.[3]
Rarity itself does not determine prognosis. But when a small patient population coincides with difficult biology, limited treatment options, and challenging trial recruitment, the barriers to therapeutic progress become significantly harder to overcome.
The Economics of Development Matter Too
Unfortunately, high unmet clinical need does not automatically translate into a viable development program. Bringing a new medicine from discovery through clinical development requires substantial and sustained capital. Published estimates place median research and development costs for an approved drug in the hundreds of millions of dollars.[4]
For a common cancer with a large addressable population, those costs may fit within a conventional commercial model. For a rare indication involving only a few thousand eligible patients, the economics are fundamentally different.
The challenge is not simply market size; smaller populations often coincide with slower recruitment, fewer specialist treatment centers, more complex trial logistics, and a higher risk that development costs will be spread across very few eventual patients.
This creates a structural tension in rare-disease drug development: some of the areas with the greatest unmet need may not fit conventional large-market development models, creating the rationale for alternative regulatory and commercial frameworks.
Research funding adds another dimension. A 2026 U.S. analysis found substantial differences in federal research funding relative to mortality, including approximately $69,800 per estimated death for breast cancer and $126,992 for prostate cancer, compared with $8,945 for pancreatic cancer and $2,818 for small cell lung cancer.[5]
These figures do not, by themselves, determine whether a disease is appropriately funded. Research investment is shaped by prevalence, scientific opportunity, survivorship, existing infrastructure, and other factors. They do, however, illustrate that research investment and mortality burden are not distributed proportionately across cancer types.
How Orphan Drug Policy Changes the Development Equation
Recognizing that conventional drug-development economics could leave small patient populations at a structural disadvantage, regulators have introduced mechanisms intended to make these programs more viable. In the United States, the Orphan Drug Act established a framework of incentives for therapies targeting conditions affecting fewer than 200,000 people, including a tax credit against qualified clinical testing expenses, waiver of the substantial application user fee, and seven years of market exclusivity following approval.[6] The European framework provides an analogous package, including protocol assistance from the European Medicines Agency, fee reductions, and ten years of market exclusivity.
The significance of orphan designation extends beyond these financial incentives. It can also provide greater regulatory support for development in populations where conventional large-scale trial strategies may not be practical. In well-defined populations with high unmet need, clinical studies can sometimes be smaller and more focused than those required in common, highly competitive treatment settings. Of the sixteen new cancer drugs approved by the FDA in 2025, six were supported by clinical trials enrolling fewer than one hundred patients.[1]
Smaller studies should not be mistaken for a lower evidentiary standard. Approval still requires evidence of a favorable benefit-risk profile in the intended population. The appropriate development program depends on the disease, the available treatment options, then endpoints that can meaningfully demonstrate benefit, and the strength of the effect observed. In a small, well-characterized population, a focused study can generate compelling evidence without reproducing the scale of a trial designed for a much more common disease.
What orphan policy changes, therefore, is not the scientific standard a therapy must meet, but the feasibility of developing it in the first place.
The effect on the landscape has been substantial. Orphan indications now account for more than half of new drug approvals overall, and within oncology there is a clear trend toward developing therapies for progressively smaller and more precisely defined disease subsets.[7]
Orphan designation is not itself a predictor of approval. In the European Union, approximately 8.5% of orphan designations ultimately translate into approved products.[8] The figure underscores that these incentives facilitate development without removing the scientific and clinical standards a therapy must ultimately meet.
When the Barriers Converge: Leukemia Relapse After Allogeneic Stem Cell Transplantation
The importance of these mechanisms becomes particularly clear in treatment settings where several barriers converge at once. Relapse following allogeneic stem cell transplantation in acute leukemia is one such example.
Blood cancers are, in many respects, an oncology success story. Targeted inhibitors, bispecific antibodies, antibody-drug conjugates, and cell therapies have transformed the treatment of many leukemias, lymphomas, and multiple myeloma.
Post-transplant relapse remains a particularly difficult exception. Allogeneic stem cell transplantation is a potentially curative treatment for many patients with high-risk acute leukemia, but relapse remains a major cause of treatment failure. Once the disease returns, outcomes are poor and therapeutic options become substantially more limited.
In a large Center for International Blood and Marrow Transplant Research study of patients with acute myeloid leukemia who relapsed after allogeneic hematopoietic cell transplantation, approximately 23% of patients were alive one year after relapse.[9] More recent single-center data have reported median survival of approximately six months, with no single standard treatment approach established across the population.[10]
The challenge extends beyond prognosis. These patients have already undergone intensive treatment, and many are heavily pretreated and clinically vulnerable by the time relapse occurs. The eligible patient population is relatively small, while the disease itself is aggressive and difficult to treat. Clinical trials must therefore contend simultaneously with biological complexity, limited recruitment pools, and a narrow window in which patients may be eligible to participate.
This is where the challenges of rare-cancer and orphan-drug development converge. The clinical need is substantial, while the patient population is small and development is complex, precisely the type of setting in which orphan-drug frameworks can help make a focused development program viable.
Rethinking Where the Opportunity Lies
The areas of oncology that remain underserved are not all underserved for the same reason. In some, the biology has resisted effective intervention. In others, small patient populations can make trials harder to conduct and sustained development more difficult to finance. Often, several of these factors operate together.
Rare cancers make this interaction especially visible. But they also show how the development landscape is changing. Orphan frameworks have improved the viability of developing therapies for smaller populations, while advances in molecular biology are creating new points of intervention in diseases and disease subsets that were once difficult to address.
At the same time, precision oncology is making smaller, biologically defined patient populations an increasingly familiar part of oncology drug development rather than an exception to it. Increasingly, therapies are development not for every patient with a particular tumor type, but for smaller groups defined by a molecular target, biomarker, or specific clinical setting. In that context, population size alone is becoming a less useful measure of the potential importance of a program.
A therapy developed for a relatively small population can still have substantial clinical value when it addresses a setting in which outcomes remain poor and effective options are limited. For drug developers, a well-defined orphan population can also offer a focused development opportunity: the biology may be clearly characterized, eligible patients can be identified precisely, and regulatory frameworks are designed to accommodate the realities of developing therapies for small populations.
The measure of progress in oncology, then, is not only how many new therapies are approved, but also whether that progress extends into the diseases and treatment settings that have historically proved hardest to change.
References
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3. Gatta G, van der Zwan JM, Casali PG, et al; RARECARE Working Group. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer. 2011;47(17):2493-2511. doi:10.1016/j.ejca.2011.08.008
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9. Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2015;21(3):454-459. doi:10.1016/j.bbmt.2014.11.007
10. Zuanelli Brambilla C, Lobaugh SM, Ruiz JD, et al. Relapse after allogeneic stem cell transplantation of acute myelogenous leukemia and myelodysplastic syndrome and the importance of second cellular therapy. Transplant Cell Ther. 2021;27(9):771.e1-771.e10. doi:10.1016/j.jtct.2021.05.011