Choosing sites for a rare disease trial: the questions to ask
In rare disease, a wrong site is rarely a slow one. It is usually a site with almost no one to enroll. These are the 21 questions to ask before a site makes the list, with why each one matters and what a strong answer looks like.
- Ask first how many patients who meet the protocol each site actually treats. A diagnosis total is not the answer.
- Separate the patients under the investigator’s own care from the wider hospital count.
- Check the investigator’s record on trials in this disease, not their reputation in the field.
- Map the referral routes. Patients are often diagnosed in one place and treated in another.
- Be ready to explain every well-known center that is not on the list.
Rare disease trials work with very small numbers. There may be only a few hundred patients in the whole country who meet a protocol, spread across institutions no single expert can see. That changes what a site list has to prove. The concept is covered in rare disease site selection on real data. This guide is the practical companion: the questions to ask about every candidate site.
Group 1Patients Start here
Start here. In rare disease a wrong site is rarely a slow site. It is usually a site with almost no one to enroll.
How many patients who meet this protocol does the site actually treat?
A diagnosis total overstates the pool. In rare disease, a single eligibility criterion can remove a large share of the patients who have the condition.
A count against this protocol’s inclusion and exclusion criteria, not the number of patients with the diagnosis.
Are those patients under the investigator’s own care, or elsewhere in the institution?
Patients the investigator already treats are the most reachable. Patients seen by colleagues in the same hospital usually need a referral first.
Both numbers, kept separate: the qualifying patients under the investigator’s care, and the wider count at the institution.
How many qualifying patients are there in the whole country, and how much of that pool does the site list reach?
There may be only a few hundred qualifying patients nationwide. A list can look long and still miss most of them.
The national count, and how much of it the proposed sites reach between them.
How far do qualifying patients live from the site, and how often must they visit?
Rare disease patients often travel long distances to specialists. A demanding visit schedule can lose patients who qualified on paper.
A realistic view of travel for this population, and the support the site and sponsor can offer.
Group 2Investigators
In a small field, the right person matters as much as the right institution.
Has the investigator enrolled trials in this disease, or a closely related one?
A record on similar trials is the best evidence an investigator can deliver again.
Named trials, the indication and phase, and how enrollment went against plan.
Does the investigator treat this population, or mainly lead research in the field?
A respected name in a disease area does not always see patients who meet a specific protocol. We have seen well-known centers with almost none.
Evidence that the investigator’s own practice includes patients who meet these criteria.
How many other trials are competing for the same patients at this site?
When the pool is tiny, two trials at one site split it.
The competing studies at the site, and whether they target the same patients.
Is the investigator still at the site, and have they confirmed interest and time?
Investigators move between institutions, and a list built on old information sends outreach to the wrong place.
Recent confirmation of where the investigator works, and their interest and capacity, with dates.
Group 3Referral routes
Rare disease patients are often diagnosed in one place and treated in another.
Where are patients diagnosed, and where are they treated afterwards?
The center that makes the diagnosis is not always the one that manages long-term care.
A picture of the care path for this disease, and which sites sit on it.
Can the site accept referrals from other physicians and centers?
A site with an open referral route can reach patients beyond its own clinic.
Existing referral relationships, and how referred patients are screened.
Does the site work with patient advocacy groups for this disease?
Advocacy groups are often closely connected to the patient community in a rare disease.
Named relationships, and how the site has worked with them on past trials.
Group 4Protocol fit
This is where the protocol and the site list meet. It overlaps with feasibility.
Which eligibility criteria remove the most patients?
Every criterion has a cost in patients, and in rare disease the cost is steep. Knowing it before the protocol is locked is far cheaper than an amendment later.
What each criterion costs in qualifying patients, and whether any could change without hurting the science.
Can the site perform the protocol’s specialised assessments?
Rare disease protocols often call for specific testing, imaging or procedures that not every site can do.
Confirmation, assessment by assessment, of what the site can do on site and what must be sent out.
Does the site have experience with this kind of therapy?
For cell and gene therapies in particular, sponsors look for sites that have handled them before.
Past studies with comparable therapies, and the infrastructure in place to support them.
Does the visit schedule work for the patients this site would enroll?
Frequent visits are hard for patients who travel far or need a caregiver with them.
Which visits could be local or remote, and what support is planned for travel.
Group 5Site readiness
A site with patients still has to be ready to start.
Is the site a recognised center for this disease?
Recognition can signal experience and patient access. It is a useful signal, not proof.
The recognition, plus the qualifying patient count that should sit behind it.
How long does the site usually take from contract to activation?
In a small pool, a slow start can mean patients join another trial first.
Past activation times at this site, not a company average.
Who at the site will run the study day to day?
Rare disease trials depend on coordinators who know the patients and their families.
Named study staff, and their experience with rare disease trials.
Group 6The list as a whole
Step back and test the shortlist itself.
Which well-known centers were left off, and why?
Sponsors expect certain names. If they are missing, the reason has to be clear.
The specific evidence for each omission, such as few or no patients who meet the protocol.
Does the list include strong sites outside the usual names?
The conventional shortlist is chosen by reputation. Some of the best sites for a rare disease are regional clinics nobody would think of.
At least some sites chosen on counted patients and investigator record rather than reputation.
Do we need more than one country, and how sure are the numbers in each?
Small pools often mean recruiting across countries, and the quality of patient data differs from country to country.
A patient figure for each country, and an honest note on how each one was arrived at.
Worked exampleTwo sites, one decision
Two candidate sites for the same rare disease protocol. The figures are illustrative.
Leads research in the disease and publishes widely. Treats 3 patients who meet this protocol. The investigator has not run a trial in this disease recently.
Treats 24 patients who meet this protocol, 10 of them under the investigator’s own care. The investigator has enrolled two similar trials on plan.
Site A is the name a sponsor expects. Site B is the site that can enroll. The questions above are what tell them apart before activation, not months into recruitment. In one rare disease program, counting this way changed both the protocol and the site list.
In practiceHow to use this list
- Ask the patient questions first. If a site cannot show qualifying patients, the other questions do not matter.
- Ask every site the same questions, so the answers can be compared side by side.
- Write down the reason for each site, and for each well-known center you leave off.
- Revisit the list before activation. Investigators move and competing trials open.
Rare disease trial sites, answered
What questions should you ask when choosing rare disease trial sites?
Start with the patients: how many who meet the protocol the site actually treats, and whether they are under the investigator’s own care. Then the investigator’s record on similar trials, the referral routes into the site, whether the site can run the protocol’s assessments, how quickly it can start, and which well-known centers were left off the list and why.
What is the most important question when choosing a rare disease site?
How many patients who meet the protocol the site actually treats. In rare disease a diagnosis total can be far larger than the number who qualify, and a site with no qualifying patients cannot enroll, however strong its reputation.
Why do well-known centers sometimes fail in rare disease trials?
Reputation and patient access are different things. A center can lead research in a disease and still see few patients who meet a specific protocol. In rare disease we have seen well-known centers with almost no qualifying patients, and strong regional sites the conventional lists never surface.
How do eligibility criteria affect enrollment in a rare disease trial?
Every criterion has a cost in patients, and in rare disease it can be steep. Measuring that cost before the protocol is locked shows where it can safely open up. In one rare disease program, the final protocol qualified nearly three times the patients of the initial draft.
What makes an investigator right for a rare disease trial?
A record of enrolling trials in the same or a closely related disease, and a practice that includes patients who meet the protocol. Both matter: a strong record with no qualifying patients, or many patients with no trial experience, are each a risk.