For health policymakers at a national level, rare diseases are those affecting a tiny fraction of the population. Worldwide, however, this adds up to over 300 million people. And it has emerged as a major growth area in the biopharmaceutical industry.
Thanks to incentives like the Orphan Drug Act and advances in genetics, drug development for uncommon ailments is booming. According to GlobalData projections, global orphan drug sales are projected to reach nearly $275鈥痓illion by 2028, reflecting roughly 12% year-on-year growth. Investment is pouring in from many biopharma firms; orphan therapies account for an ever-rising share of new drug approvals.
Despite this potential, developing treatments for tiny, dispersed patient populations is extraordinarily challenging. 80% of trials fail to meet enrolment timelines, and over half are forced to end early due to low patient accrual. The orphan drug arena may be lucrative and fast-expanding, but it remains a risky, highly complex territory for researchers hoping to navigate it.
The Recruitment and Retention Challenge
What are the most significant hurdles standing in the way of rare disease trial success? Recruitment and retention are undoubtedly forbidding obstacles. Eligible patients are few and geographically scattered, forcing even early-stage studies into complex multinational setups. And conventional recruitment methods struggle to reach rare patients. One recent analysis found that 81% of patients screened for rare disease trials were ineligible to enroll – 34 percentage points higher than in non-rare trials – reflecting these conditions鈥� highly selective study criteria. Teams are left scrambling to sift through dozens of referrals to find a single qualified patient.
The consequences of this enrolment crunch have hit rare disease research hard. On top of struggles to reach recruitment targets, rare disease development cycles run about four years longer on average than those for non-rare diseases, largely due to site and patient recruitment delays. One study of 659 rare disease trials registered in the early 2010s found over half were discontinued or went unpublished within four years, mostly due to inability to enroll enough patients. GlobalData鈥檚 clinical trial database confirms this picture; of the rare disease trials in the database that were suspended, terminated or withdrawn over the past two years, by far the largest reason was 鈥渦nspecified鈥� – meaning that the trial had failed to gather enough traction to initiate in the first place.
Retention is the other side of the coin. On average, about 30% of participants drop out of clinical studies before completion. In a rare disease trial where patients can be counted in the low dozens to begin with, losing even a couple can undermine the result鈥檚 statistical validity. In short, every patient counts. Keeping them engaged and supported is as important as recruiting them in the first place.
Reducing Burden through Patient-Centric Design
Patient-centric trial designs – re-engineering studies around the patient鈥檚 life rather than the reverse – could help turn the tide. By analysing where patients receive care, how they travel, what support they need and what obstacles they face, trial designers can craft protocols that fit into patients鈥� routines instead of upending them. One transformative trend is the rise of decentralized and hybrid clinical trials in rare diseases. Comprising telemedicine visits, home nursing services, direct-to-patient drug shipments and a variety of other in-home, mobile and wearable approaches, decentralized trial components can bring research to the patient. Although their popularity has declined since post-lockdown peaks, trials that incorporate decentralized methods are seeing concrete benefits. In addition to shortened timelines, GlobalData figures suggest trials with decentralised elements see higher success rates than the overall average.
Drilling into the data, it is clear that rare disease researchers are using the potential advantages of decentralisation in unique ways.
While the overall trends are the same 鈥� mobile healthcare is the most popular approach to decentralised trials across the board, and external control the least 鈥� there are some distinctive differences between decentralised rare and mainstream clinical trials. For example, mobile healthcare is nearly 10 percentage points more prominent in rare disease trials. And, although the raw numbers are small, rare disease researchers are over twice as likely to utilise external control compared with their mainstream counterparts. It highlights the tailored techniques needed to access hard-to-reach populations, and how particular decentralised trial elements can help researchers get to them.
Utilising adaptive trial designs, master protocols or surrogate endpoints can achieve meaningful results with fewer patients. In fact, according to analysis of GlobalData鈥檚 clinical trial database, rare disease trials are around 51% more likely to use adaptive endpoints compared with mainstream diseases. Regulators have encouraged novel approaches – from adaptive dose-finding to historical control comparisons – to make trials more feasible in small populations. Combining scientific rigor with ease of access for participants, these measures yield both higher recruitment and retention.
Harnessing Advocacy and Global Reach
When it comes to building patient-centric rare trials, early and deep engagement with patient advocacy groups (PAGs) is critical. Rare disease PAGs, often founded by sufferers and their families to advocate for their conditions, have become invaluable partners in trial design and recruitment. Maintaining robust networks via social media, registries and annual conferences, they can connect widely dispersed patients; one recent study found 81% of rare disease advocacy organisations have contributed to clinical studies, 54% have helped to build patient registries and 16% have even sponsored their own trials.
Figure 5: Contributions of rare disease PAGs to various research activities in a recent survey. Over 80% have contributed to rare disease clinical trials; a further 16% have actually initiated their own. Source: Young et al. (2023).
Involving PAGs from the outset allows sponsors to tap into these networks to raise trial awareness and pre-screen potential participants who might otherwise be missed. And advocacy groups serve as the voice of the patient in trial planning. They can advise on the outcomes that matter to patients, what schedules or procedures are realistic and how best to communicate with the community. Via a collaborative ethos putting patient needs at the centre, it increases the odds that patients who volunteer in a trial truly advance the quest for a cure – and neither their nor trial sponsors鈥� time will be wasted.
Effective rare disease studies invariably cast a global net. International trials introduce layers of complexity: multiple regulatory frameworks, languages, cultural differences and logistical hurdles in moving samples or treatments across countries. But they also offer the only way to reach critical mass. Sponsors have learned that opening sites in dozens of countries may be needed to find as few as 15% of the typical number of volunteers per trial. Going to where the patients are is a key to success in Rare disease studies and targeting untapped regions such as the emerging markets can significantly bolster your enrolment rates. When working on a study in FOP, we were able to utilize China to significantly add patients to the study because it was untapped patient population to decrease the timelines of the study significantly. Working with PAGs who can get researchers where they need to be, and the specialised partners who can make those connections, is crucial.
The Road Ahead: Partnerships with Purpose
To navigate the intersecting challenges of rare disease trials 鈥� sparse patients, complex logistics, evolving regulations 鈥� drug developers are increasingly turning to clinical research organizations (CROs) with global infrastructure and a patient-centric mindset. In an arena where no one company can easily maintain a presence in every country or expertise in every disorder, strategic partnerships are essential.
A rare disease-savvy CRO who understands the patient pathway can work to design a patient centric study to both recruit and retain the patients effectively., Operational agility and flexibility are also key. Experienced partners know that, in rare disease trials, plans often change rapidly – an inclusion criterion might need loosening, an assay might fail, a patient may need accommodations – and being able to pivot to adjust to new information or changing needs is a prized capability. Unlike large bureaucratic organizations, a nimble CRO can make quick decisions and tailor the trial on the fly, and within regulatory guardrails, to keep it on track.
Caidya, for example, offers a personalized approach tailored specifically to sponsor needs. zIt deploys customized teams and flexible operational models tailor-made for each project鈥檚 specific needs, from single trials to full-service partnerships. Sponsors partnering with Caidya gain direct access to senior leadership, ensuring strategic alignment and swift responsiveness at every step. By rallying technology, PAGs, and regulatory know-how under one roof, the right partner can ensure that logistical execution matches scientific ambition, allowing researchers and biopharma innovators to focus on what they do best: the science
As the orphan drug sector continues its expansion towards the $270+ billion horizon, the stakes for patients and innovators are high. But the industry is learning to design trials with patients, not just for them. And evidence suggests this shift will pay dividends in faster enrolment, better retention and more meaningful outcomes. Much work remains: thousands of rare diseases still have no approved therapy, and barriers to entry still seem daunting for many researchers. But by listening to patients, meeting them where they are and forging global partnerships to support them, new pathways are being established all the time. To learn more about what these pathways are, how they are developing and the CROs leading the way in making them more accessible than ever before, download the whitepaper on this page.
