Rare Disease Trials: Execution Risks No One Warns You About

A conversation between Jurate Lasiene, Ph.D., fractional VP of Clinical Operations, and Elizabeth Urbanek, Executive Editor, Clinical Supply Leader

Rare disease trials can expose weaknesses in a clinical trial plan that might not be obvious in a more conventional study.

When the patient population is small and spread across countries, every patient matters. A site may have access to the right patients but little research experience. A country may be necessary for one or two participants but it still brings all the regulatory, import, supply, and vendor requirements that come with opening a country. And if enrollment slows, adding sites may not help if those sites do not have access to the patients.

For clinical supply, that can change everything from forecasting and inventory to resupply, dispensing, and getting investigational product to the patient.

In this Q&A, Jurate Lasiene, Ph.D., fractional VP of clinical operations, discusses some of the execution risks that can get overlooked in rare disease trials, including how the patient journey should shape site and country selection, supply planning, and protocol design. She also explains why clinical operations and clinical supply need to be involved earlier, before those decisions are already baked into the study.

1. How does a rare disease patient population change the operational assumptions sponsors make when planning a clinical trial?

Patients are counted one at a time, not as an average enrollment rate per site per month; each screen failure, withdrawal, or missed referral may remove a real person from an already very small and potentially nonreplaceable pool.

Country selection follows the patients and their treating experts, rather than regulatory speed alone: sponsors may need to open in countries with slower approvals if that is where diagnosed patients, disease registries, advocacy networks, or specialist centers are concentrated.

That choice must be costed deliberately, because a country brings substantial fixed regulatory, contracting, import/export, pharmacovigilance, supply chain, monitoring, and vendor management overhead even if it contributes only a few participants.

Feasibility must distinguish prevalence from the reachable, diagnosed, eligible, and willing population, while also accounting for competing trials, diagnostic delay, genotype or phenotype restrictions, caregiver capacity, and patients’ ability to travel or complete complex assessments.

Site selection also changes: the center with the patients may have little research experience, so the sponsor may need to invest in intensive protocol and GCP training, embedded coordination, dedicated sub-investigator time, local specialty laboratory capability, and equipment or home health support.

In one-site or highly concentrated studies, this investment can be more realistic (and more valuable) than seeking a conventional network of experienced research sites that do not actually see the disease.

Other expert centers may be essential referral hubs rather than enrolling sites, requiring a deliberate referral pathway, referral agreements where appropriate, clear prescreening, and closed-loop communication so potential participants are not lost between clinicians and trial sites.

Protocol design becomes an operational necessity: unnecessary exclusion criteria, repeated travel, burdensome procedures, and narrow visit windows can be more damaging than in common disease trials, so decentralized elements and patient/caregiver input should be considered early.

The first assumption to discard is, “If enrollment is slow, we will just add sites.” In rare disease, there may be no additional sites with meaningful access to patients, and opening more low-yield sites can consume time and budget without increasing recruitment.

The plan therefore has to be built around the limited expert ecosystem that exists, with early natural history and registry work, realistic screen failure assumptions, strong retention planning, and enough contingency to protect every enrollment opportunity.

2. What challenges do geographically dispersed or highly specialized patient populations create for trial execution and clinical supply planning?

Dispersed patients mean that participation often depends on travel rather than proximity to a research site, so the study must plan early for travel booking, lodging, cross-border arrangements, caregiver accompaniment, reimbursement, visas where relevant, and practical support during long or repeated visits.

For pediatric, severely affected, or highly specialized patients, the caregiver burden can be as important as the patient burden. If families cannot realistically manage the visit schedule, consent, dosing, or follow-up, recruitment and retention assumptions will fail.

Sponsors should therefore build flexibility into the protocol wherever scientifically and regulatorily appropriate. For example, this could include using telemedicine, local safety laboratories, home nursing, mobile assessments, or direct-to-patient investigational product delivery while retaining appropriate investigator oversight and data quality controls. FDA guidance recognizes that decentralized elements can include remote visits, home visits, local healthcare providers, and direct distribution of investigational product to participants.

Highly specialized care may also be concentrated in only a few expert centers, creating capacity constraints in clinical rooms, specialist staff, imaging, procedure slots, laboratory processing, pharmacy support, and scheduling around standard-of-care appointments.

Supply planning becomes particularly difficult in low-volume countries: a country enrolling a single patient will require country-specific regulatory and import planning, qualified distribution routes, local language labels, temperature-controlled storage, drug accountability processes, and trained pharmacy staff.

The costs and lead time for each additional country can be disproportionate to the expected enrollment and should be assessed against alternatives such as patient travel to a regional expert center, where legally and ethically feasible.

Forecasting cannot rely on a standard monthly demand curve, because enrollment timing is uncertain and resupply may be triggered by one patient event rather than a predictable pattern.

This means sponsors need scenario-based forecasting, adequate IMP expiry at release, contingency stock, rapid resupply capability, temperature excursion plans, and a clear approach to replacement stock, especially for biologics, short shelf-= life products, or treatments requiring complex administration.

Direct-to-patient or direct-from-patient models can reduce travel burden and support adherence, but they add country-specific requirements for importation, chain of custody, privacy, qualified couriers, temperature monitoring, return/destruction, and confirmation that the patient can receive and use the IMP.

In summary, the clinical supply plan must be designed around individual patient journeys because a delayed shipment, expired kit, or failed travel arrangement can jeopardize a meaningful fraction of the entire study population.

3. How should sponsors incorporate the real patient journey into decisions about site selection, activation, and supply readiness?

I suggest mapping the end-to-end patient journey before finalizing the protocol and selecting countries or sites. Think about diagnosis, treating physician, referral route, prescreening, informed consent, baseline assessments, travel, each treatment visit, investigational product dispensing or administration, safety monitoring, and long-term follow-up.

Then pressure-test the schedule of events with two or three expert sites and people living with the condition (ideally including caregivers and patient advocacy representatives) before the protocol is final. Patient engagement can improve visit design, travel support, rest periods, and the practical use of home visits.

Site selection should follow the patient’s treating physician and referral ecosystem. A highly experienced research site without access to the relevant patients is less valuable than an expert treatment center that needs operational investment to become trial-ready. Each activated but non-enrolling site creates fixed cost, start-up workload, training needs, investigational product management, monitoring activity, and oversight risk.

If visits are combined to reduce travel, dispensing quantity, kit configuration, accountability plan, and expiry requirements must match the longer interval between on-site contacts.

4. How can strong site and KOL relationships help sponsors manage the operational and supply challenges of hard-to-reach patient populations?

KOLs know the real disease ecosystem: they treat patients directly, lead or influence referral networks, collaborate with laboratories and registries, and often trained the specialists who now manage patients elsewhere.

Early KOL input should help shape the protocol. When KOLs co-develop eligibility criteria, assessments, visit frequency, and standard-of-care assumptions, the study is more likely to fit the phenotype, disease stage, comorbidities, and treatment pathways of patients who actually exist.

KOLs can also identify the referral routes that matter: regional physicians, geneticists, specialist nurses, diagnostic laboratories, disease registries, and neighboring expert centers. This allows the sponsor to build a credible referral plan rather than relying on a site’s enrollment forecast. Rare disease feasibility is often determined more by patient pathways and referral networks than by conventional research infrastructure.

Trusted sites provide early operational feedback. They will say when assessment is too burdensome, when a competing study has changed the recruitment landscape, or when staffing and pharmacy capacity make the planned activation date unrealistic.

It’s crucial to build relationships with sites: frequent contact, clear escalation routes, rapid protocol or logistics decisions, and practical training and mentoring. In a single-site study, an in-country monitor with near-daily site contact (if merited) can solve problems within days, rather than allowing them to wait until the next routine monitoring visit.

Patient advocacy groups provide a view that neither the KOL nor the site can fully provide. They can help understand what families can realistically tolerate, how information flows through the community, what kind of language and support arrangements build trust, and where travel, financial, or caregiver barriers will prevent participation. Meaningful patient and caregiver engagement is intended to make research planning more responsive to real patient experience.

5. What is one execution mistake in rare disease trials that sponsors should identify before the first patient is enrolled?

Science and endpoints may all be defensible, yet the study can still fail operationally if nobody has walked through the protocol as a sequence of physical events for one actual patient at one actual site.

Before the protocol is finalized, test the full journey: referral and prescreening, consent, eligibility assessments, visit duration and sequencing, caregiver and travel requirements, sample collection, processing, storage, courier collection and laboratory turnaround, pharmacy receipt and storage, investigational product preparation, dispensing or administration, safety follow-up, and return, reconciliation, or destruction of unused product.

In rare disease, even one impractical eligibility criterion, unavailable local test, restrictive window, unnecessary invasive assessment, or supply delay can eliminate a big part of the entire recruitable population.

The usual consequence of discovering these failures late is a protocol amendment. Amendments cause cost increases as well as country-level ethics and regulatory submissions, contract and budget updates, retraining, revised consent materials, supply relabeling or resupply, database changes, and maybe even a pause or disruption to enrollment.

Identify the problem with a structured “one patient, one site, one shipment” dry run before first patient in. Put the schedule of events and all the manuals in front of the study coordinator, investigator or sub-investigator, pharmacist, relevant laboratory or imaging staff, monitor, supply lead, and a patient or caregiver representative.

Clinical operations and clinical supply must be involved from the first protocol draft, with authority to change the design. I believe the biggest mistake companies make is to involve clinical operations too late in the process of designing a trial.

About The Expert:

Jurate Lasiene, Ph.D., is a fractional VP of clinical operations. A neuroscientist by training (Ph.D., University of Washington), she spent years working for a CRO before moving to the sponsor side, and now works with seed and Series A/B biotechs running their first Phase 1 and 2 trials, with particular focus on rare disease. Her work covers outsourcing strategy, vendor selection and oversight, protocol operational feasibility, enrollment strategy for small patient populations, and budgets that make sense in front of investors. She has led trials across Europe, North America, Latin America, Australia, and Asia Pacific, and speaks regularly on how small sponsors can outsource without losing ownership of their studies. Jurate is based in Europe.