Top 10 Reasons for Patient Recruitment Failure in Clinical Trials
This episode and post highlights the Top 10 Reasons for Patient Recruitment Failure in Clinical Trials from the site investigator’s perspective.
My goal here is to share how sponsor companies (pharmaceutical, biotech, and/or medical device) and clinical research organizations (CRO) including technology vendors can best support site investigators meet or exceed their patient recruitment.
It is our shared responsibility as clinical research professionals to ensure trials complete enrollment with as few recruitment challenges as possible.
Let’s review the top reasons for patient recruitment failures and what a clinical research professional can do to prevent or manage such failures. Our ultimate goal is to complete study enrollment on or before schedule.
- Initial funding insufficient to reimburse recruiting staff/sites
- Context-specific logistic obstacles (e.g., urgent transfers from intensive care, different treatment availabilities at different centers or on weekends)
- Lack of methodological/logistical support (e.g., from contract research organization or clinical trial unit)
- Prejudice against effectiveness of trial interventions
- New evidence from other study about effectiveness of trial interventions
- Administrative burden/time constraints
- Lack of eligible participants – Overestimated prevalence (mostly reported as overly narrow eligibility criteria)
- Concurrent competing trials
- Recruiter related/ motivation. Prejudice against effectiveness of trial interventions
- High burden (e.g., many visits, invasive procedure, questionnaires, costs)
Now let’s review them one by one in greater detail.
Initial funding insufficient to reimburse recruiting staff/sites
Research sites need to be paid sufficiently. There is a misunderstanding that research sites cannot profit, because it’s research.
Even if the research site is a nonprofits, they can and should make a profit that they can invest in further development of their research capabilities such as better equipment, software, and personnel training.
By paying sites top dollar, you can expect high recruitment and quality data. At Netflix, one of the world’s most innovative companies, senior management is hiring the best people and paying them top of the market salary. This type of thinking can and should extend to clinical research sites as well.
Sites must get paid for indirect (overhead) and fringe benefits (insurance, vacation, etc.) or use a higher billable rate.
If you pay sites at the maximum fair market value rates, there are less headaches down the road.
Sites are less likely to nickel and dime when you implement minor protocol or operational changes, because they know you’re already paying them well.
Study design/ context-specific logistic obstacles (e.g., urgent transfers from intensive care unit, different treatment availabilities at different centers or on weekends)
Is your study going to be a logistical nightmare for the clinical trial site and/or site personnel?
Does the study require site personnel on nights and weekends?
If yes, you need to map out the logistics early on in the start-up process, not after the site is activated for enrollment.
If you haven’t discussed your protocol with at least a couple of research coordinators who will be responsible for executing the protocol, chances are that you’re going to run into operational issues.
My recommendation is to write down everything a site will need from a logistical standpoint to be successful with patient recruitment.
Lack of methodological/logistical support (e.g., from contract research organization or clinical trial unit)
Site investigators (doctors or nurses) are busy people with clinical responsibilities i.e. they have to see their patients and conduct research on top of their regular job. For this reason, site investigators are relying heavily on CROs and CTUs to provide logistical support
For example, let’s consider a multi-center Investigator Initiated Study(IIS) with one lead investigator and over two dozen clinical trial sites.
Some of these sites are unresponsive to email requests made by the IT vendor personnel. The IT vendor escalates this to the lead investigator.
The lead investigator says, “I’ll email each site PI personally and get them to respond to you, the IT vendor”.
This approach is quite challenging for the lead investigator to execute. She is a busy person with clinical responsibilities. If she is tasked with emailing each site, it would take her a full day to deal with this administrative task, which is probably not a good use of her time.
A better approach would be for the IT vendor or clinical trial unit (CTU) personnel to take ownership of the issue and offer to email the site investigators and CC the lead investigator. Then the lead investigator easily hits “reply all” to this follow-up email and reminds the site investigators to address the open items with the IT vendor as quickly as possible.
Alternatively, rather than relying heavily email, the IT vendor can pick up the phone and call each site individually and discuss what needs to happen to address the open items b before escalating the issue to the lead investigator
If you’re a CRO, IT vendor, and/or CTU personnel, think about everything you can do to resolve logistical issues before passing on the responsibility to the lead investigator.
Recruiter related/ prejudice against effectiveness of trial interventions
Below are some examples of a site investigator’s prejudice against trial effectiveness.
Clinical equipoise: When it comes to randomized clinical trials, there may be genuine uncertainty in the medical community where one treatment is better than another. For this reason, it is important for site investigators to think and believe there is clinical equipoise.
Concerns about disadvantages for patients: Site investigators may believe that in the long term, the experimental treatment is disadvantageous for the patients.
For example, in one randomized clinical trial involving patients with heart disease, physicians had concern about enrolling patients in the “stent” arm vs. “cardiac surgery” arm. Physicians felt it was disadvantageous for patients to get a stent in the long run because stents were known to cause late stent thrombosis.
Trial questioning current practice: If the clinical trial questions the doctors current practice, she may be less likely to enroll patients.
Loss of professional autonomy: Enrolling patients in a trial means the site investigator needs to follow the study protocol. This can lead to loss of professional autonomy for the physician, and hence they may be less likely to enroll patients.
Concerns about randomization to unwanted interventions: The site investigator may feel it is unethical to have a certain patient go through unwanted intervention. For example, if a patient is randomized to cardiac surgery and she has to go through extensive open heart surgical procedures, when the patient could receive a minimally invasive stent instead.
Worry about doctor-patient relationship: Most doctors care about their patients and the relationship they have with him/ her.
For example, if a doctor is being asked to refer her patients to a clinical trial where the patient will be randomized to a stent versus surgery arm.
But if the doctor has personal belief (not based on facts/ evidence) that one treatment is better than another, the doctor would worry about how such a referral would impact her relationship with the patient.
The doctor would be less motivated to refer patients into such trials, hence having a negative impact on patient recruitment.
Recommendation from opinion leaders: Key opinion leaders (KOLs) provide input on trial design and strategy. Many KOL also hold credentials in the academic world but may not have much of
may be well-known in the academic world with lots of expert papers under her belt. But an academic physician who does not see patients on a regular basis and hence may not fully understand the challenges with patient care. Hence, site investigators may disagree with the recommendation from opinion leaders
Media information favoring a particular treatment: ex: reports in media that the stent is being recalled. This may lead the patients and doctors to believe that stents are not effective and safe medical devices
New evidence from other study about effectiveness of trial interventions
There may be new evidence suggesting that the trial interventions are less effective. This may slow or cease recruitment as patients may no longer be motivated to participate in the study. There is nothing you can do when this happens.
Administrative burden/time constraints
If a study requires time consuming administrative effort on part of the investigator, there will be a negative impact on patient recruitment. Ex: Investigator is expected to sign and date every source document that is sent to the sponsor/ CRO. The investigator may not see any value in this work, especially if it is not required per regulations. Avoid any administrative activities that are not required as part of the government regulations.
Lack of eligible participants: Overestimated prevalence (mostly reported as overly narrow eligibility criteria)
Lasagna’s Law: The incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed. Hence over estimating potential accrual.
There are a few ways you can avoid Lasagna’s Law. You can modify the inclusion/ exclusion criteria, review the number of patients seen at the clinic/hospital for your medical product indication and how many of those patients were seen by the investigator, discuss screening and enrollment workflow with the site personnel to identify any bottlenecks and more.
For more insights on how to boost patient recruitment, I recommend you check out my previous episode “17 Strategies to Increase Patient Recruitment in Clinical Trials”
Concurrent competing trials
There could be competing trials at the same institution with the same investigator or competing trials at different institutions. Either way, competing trials and their outcomes could end up negatively impacting patient recruitment
Patient recruitment is being spread across two or more studies
Clinical trial results from a competing trial may impact your recruitment. Example: investigator initiated study, which may be fast and nimble, may show results that are not in favor of your trial intervention
Competing trial sponsors are paying sites more than you have to offer
In most cases, you cannot do much about concurrent competing trials.
Recruiter related/ Motivation. Prejudice against effectiveness of trial interventions
As stated earlier, doctors may have certain beliefs about one intervention vs. another.
Potential patients may be influenced by their primary care doctor or family member
Concerns with randomization and not being randomized to the treatment of choice – ex: patient may not want to be enrolled in the placebo arm
Not wanting to be a guinea pig
Media representation that one treatment is better than another. Numbers may be presented as relative vs. absolute risk, confusing the patients even further
This may make the doctor less motivated to enroll in the study
High burden (e.g., many visits, invasive procedure, questionnaires, costs)
Many visits – frequent and multiple visits may not be appealing to potential patients. Consider eliminating unnecessary visits or conducting them on the phone
I was enrolled in a clinical trial for healthy volunteers.
The study required me to undergo a 5-6 hour insulin sensitivity test. I had to be in a fasting state for this test. The test could only be started at around 9:30am because that is when the doctor was available. In other words, I had to fast for 12-hours and then undergo this 5-6 hour insulin test starting at 9:30am and ending at 3:30pm. As a patient this was extremely burdensome because I was not allowed to eat any food until late in the afternoon. Such trials are extremely difficult to enroll
In this same healthy volunteer study, I had to undergo a biopsy of my fat cells from the belly area. This invasive procedure was not appealing to me as a patient because it was painful and on one of my visits, the bleeding did not stop. I was discharged home with lots of bandages around my belly area. Again, such trials are difficult to enroll because healthy patients would generally not prefer to undergoing such procedures
If patient needs to travel from far away distances given the geographical location of a site, there is time and financial cost to the patient and this may discourage them from participating in the study and hence leading to recruitment failure.
You now understand how sponsor and CRO personnel including technology vendors can best support investigators meet or exceed their patient recruitment.
In other words, the goal is to bring more awareness on how to prevent patient recruitment failure and complete enrollment as planned.
Let’s learn from our mistakes and not repeat them.
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