Orphan drugs: The final frontier in the fight against rare diseases

Introduction Historically, a significant portion of research and development in the pharmaceutical industry had been devoted to common disease. With advancing scientific knowledge and technology, this trend is slowly changing toward innovating novel treatment modalities, precision medicine, and therapies for underserved populations, balancing between common and rare diseases. For such rare diseases, orphan drugs are the last straw. However, the journey from discovery to access of these orphan drugs is puzzled with scientific, regulatory, and economic difficulties that slow down or completely obstruct the development of these therapies. Applying serious scrutiny to this area is the need of the hour. Orphan Diseases and Orphan Drugs Orphan diseases, also known as rare disease, are diseases which occur infrequently in a population. Although there is no one universally accepted definition, each country has its own variation, primarily basing on the prevalence of the disease and the availability of treatment.[1] The World Health Organization defines orphan diseases as those affecting <6.5–10 per 10,000 people.[1] India has no fixed definition for orphan disease yet; however, the New Drugs and Clinical Trial (NDCT) rules describe orphan drugs as drugs used for the treatment of diseases targeting <500,000 patients.[2] There are more than 7000 rare diseases documented all around the globe,[3] impacting millions of people, but <5% of these diseases currently have an approved treatment. Given the small cohort, therapies for these diseases demand specialized research and regulatory flexibility when compared to the usual diseases. Challenges Scientific and clinical Small patient population makes it difficult to recruit enough participants for conducting statistically powered randomized controlled trials (RCTs)[4] Use of historical controls in trials and conducting single-arm studies may be required but may introduce bias and compromise the quality of evidence generated Many rare diseases have heterogeneous presentations, complicating trial inclusion criteria and outcome measurement.[5] Regulatory Inconsistent definitions across countries and differing approval requirements add to the complexity of conducting a multicentric trial and, in turn, delay the availability of these therapies[6] Furthermore, many low-and middle-income countries lack formal guidelines dedicated to orphan drugs, making the development process and postapproval accessibility complicated. Ethical Target population usually being patients of the pediatric age group or are cognitively impaired, complicating the informed consent process[7] While conducting an RCT, to generate good-quality evidence, the use of placebos in severe or fatal conditions raises ethical concerns Resource allocation, dilemma of whether allocating large resources to such a small patient group is sound.[8] Economic Small market of consumers results in high development costs per patient, often not recoverable through traditional pricing models. Thus, fewer companies invest in developing orphan drugs[8] In addition, many health systems and insurance policies do not cover orphan drugs, leading to high out-of-pocket expenses, burdening the patients. Global Regulatory Framework To tackle the above challenges, countries around the world have developed suitable policies to further orphan drug development [Table 1].[9]Table 1: Global regulatory framework for orphan drugsContrary to regular drugs, for orphan drugs, the rarity of disease slightly alters the drug discovery and development process. Clinical testing is often directly done in patients. Trials are usually smaller with single-arm studies or historical controls. Regulatory agencies allow for accelerated pathways by offering waivers of local trial requirements, priority reviews, conditional approval, and market exclusivity incentives.[10] This regulatory flexibility and tolerance of small evidence base shorten the bench to market time modestly by 1–3 years for orphan drugs.[10] As a result, the burden is shifted to postmarketing surveillance, to collect confirmatory evidence after initial market entry. India India’s approach to orphan drugs is evolving. According to NDCT Rules (2019), orphan drugs are defined as drugs intended for conditions affecting <500,000 people.[2] Key features include: Waiver of local clinical trial requirements for orphan drugs approved in certain other countries Exemption from application fees Accelerated review processes. Despite these incentives, India has still not caught up in this race to tackle the problem of orphan drugs.[3] Lack of expensive diagnostic tools and awareness restricts the identification and diagnosis of these diseases to tertiary care hospitals There is no dedicated Orphan Drug Act, streamlining the process as in other countries and no structured incentives for domestic companies Even after approval, owing to the high costs, most of these therapies are inaccessible to the common people. In 2021, the Ministry of Health and Family Welfare, Government of India, released the first revision of the National Policy for Rare Diseases in 2021. Key features:[11] Focusing on research and development of these drugs and providing financial incentives to the companies Improve access to these drugs by the patients by offering financial support and other support services To establish a National Registry for Rare Diseases, a hospital-based project under the aegis of the Indian Council of Medical Research addressing the problem of lack of epidemiological data. Innovations The landscape of orphan drugs is undergoing a constant upgradation in various areas. N-of-1 trials These types of trials where the whole clinical trial is conducted in a single patient, are an attractive option for rare and ultrarare diseases[12] Milasen, a customized antioligonucleotide therapy, was approved after conducting the trial in a single patient with Batten disease.[13] Digital twins and in silico modelling Use of computational models to simulate disease and treatment outcomes reduces the risks involved in conducting clinical trials and can also aid in obtaining a statistically powered sample size.[14] CRISPR-Cas9 gene editing Exa-cel, approved in 2023 for β-thalassemia and sickle cell disease, is the first Food and Drug Administration-approved CRISPR therapy[15] Development of such one-time curative treatments for orphan diseases appears economically more attractive. AI and drug repurposing Rather than going through the tedious development and approval process of a drug, pharmaceutical companies are more attracted to the idea of repurposing and already approved drug to treat the orphan disease[16] Various platforms, such as Healx and BenevolentAI, identify new uses for existing drugs. Organoid and induced Pluripotent Stem Cells (iPSC) models It allows for drug testing in patient-derived tissues, helping tailor treatments to individual genetic profiles. Decentralized clinical trials Use of telemedicine and wearable technology like smartphones and smart watches, to run trials across wide areas, making participation feasible for patients in remote areas This becomes a valuable option, especially when patients are few and widely dispersed. Nongovernment organizations and patient organizations These groups play an important role in raising awareness, funding research, and pushing for policies for orphan diseases and drugs[17] Organizations such as ORDI (India), NORD (USA), and EURORDIS (Europe) act as a vital clogs linking patients, researchers, and policymakers. Patient registries Crucial for estimating disease prevalence, identifying trial candidates, and monitoring long-term treatment outcomes[18] The Cystic Fibrosis Foundation Patient Registry (USA) has played a major role in monitoring survival trends, guiding clinical trial design, and influencing regulatory approvals In India, although still in the developing stage, the National Rare Disease Registry aims to provide reliable epidemiological data and support recruitment for clinical studies in orphan diseases. Conclusion Innovations such as the use of artificial intelligence, gene editing, and digital medicine are transforming the outlook on orphan diseases and drugs. These innovations not only accelerate development but also make the trials more ethical and inclusive, arriving on evidence-based personalized treatment. However, these breakthroughs must be accompanied by strong regulatory frameworks, public–private partnerships, and global data-sharing mechanisms – especially in countries like India, where infrastructure lags behind potential. Orphan drugs reflect a healthcare system’s commitment to equity and innovation, that no disease is too rare or too orphan to matter. The way forward is not only through innovation but also through inclusive policy, compassionate leadership, and sustained collaboration among the various stakeholders.