Study sites have numerous responsibilities and must perform a daunting number of tasks. The one aspect of conducting clinical trials that sites usually spend the most time working on is Patient Recruitment, and yet, statistics show that despite their efforts, reaching enrollment goals per timeline is frustratingly elusive in many studies. The September 2011 volume of Applied Clinical Trials provides the current statistics: “Today, nearly 80% of clinical trials fail to meet enrollment timelines and up to 50% of research sites enroll one or no patients.” (Kremidas, J. (2011). Recruitment roles. Applied Clinical Trials, 20 (9), p. 32.)
Recruitment Strategies Today
Numerous strategies and billions of dollars are used to recruit study subjects, including databases to identify potential subjects, media campaigns using TV, radio, newspapers and more recently, the internet, mailing thousands of “Dear Dr.” Letters requesting referrals to the study, and enough flyers, posters and brochures to level all the trees in an Amazon forest. Yet, one of the most difficult parts of clinical trial conduct has been, and continues to be, meeting enrollment requirements, and even after working so hard to recruit subjects, on average, only 75% are retained. Statistics on Patient Recruitment and Retention have actually worsened rather than improving in spite of all these efforts. According to CISCRP:
- “In an analysis of 25,855 study volunteers in the United States 73.2% of participants completed. (CenterWatch, 2003)
- “Recent studies show that enrollment rates have dropped from 75% in 2000 to 59% in 2006 and retention rates have fallen from 69% to 48% during same period. (Getz, “Public Confidence”)
- Surveys have shown a trend toward poor volunteer retention in studies, because overall one out of every four stick with a study until its completion. Most participants dropout during phases II and III. (CenterWatch, 2005)
What are we missing?
If we put ourselves in the shoes of the study subject, we may understand the missing link. This approach is easy and costs absolutely nothing. By putting yourself in the shoes of a potential study subject, or one that is enrolled, it is actually quite easy to understand why patient recruitment and retention is so difficult. You then can think of ways to mitigate the challenges.
To understand why patient recruitment (and retention) are so difficult, just think about this from your own perspective. What are reasons you might not volunteer for a trial? When we ask people to become study subjects, we are asking a lot of them. People asked to join a clinical trial are no different than you and me: they are people with busy lives, responsibilities, and similar concerns. Imagine you, a busy professional, with family obligations, were asked to join a clinical trial. Once we realize the challenges study subjects face, we can address those issues. By stepping into their shoes, you will be able to easily identify what would demotivate you, and understand these same barriers study participants have.
What are holding Patients back?
What are some barriers that would stop you from volunteering for a trial or staying in it? Would any of these aspects of participating affect your decision or ability to enroll or stay in the trial? Here are some facts about participation in that trial that you consider when trying to decide whether to do so or not. Please check any of the factors below that might lead you to decide to not enroll in a clinical trial or lead you to drop out before completing the study:
□ You are extremely busy with your job and family responsibilities, and participating in the trial would take a lot of time
□ Your work will not give you time off for study visits, the site is not open evenings or weekends, so you will have to use your vacation time to go to your visits
□ There are study visits twice weekly for the fist month, then weekly for two months, then twice monthly for another year
□ It takes 45 minutes each way to drive to the study site
□ The protocol requires that you have invasive procedures such as blood draws at every visit
□ You would have to complete a Study Diary 3 times per day, and your days are already extremely busy
□ You will have to stop taking a medication that is helping your condition.
□ You may be randomized to a placebo.
□ You may experience adverse events from the experimental drug.
□ If something goes wrong, your medical bills may not be completely paid by the sponsor, nor your insurance
□ The site staff was not friendly, one was actually rude.
□ You had to wait over an hour in the waiting room to even be called by the site staff.
□ The study site was dirty, the furniture torn and uncomfortable, and there were no magazines or TV to pass the long period of time in the waiting room
□ Your visits will take more than 2 hours and you are very tired at the end of a long day.
□ You are thirsty after a long day and there is nothing to drink at the site.
□ You would have to spend at least $25 for gas and parking and $15 for a babysitter for every visit, and there are 40 visits in the study
□ The parking for the site is over a block away, and your arthritis, which is the indication for the study, makes it difficult for you to walk that distance, especially during the long, snowy winters where you live in Minnesota.
□ Part of the walk to the site was dimly lit and you stumbled, injuring your knee most affected by your arthritis, causing pain and swelling, on your way to your first visit at the site when you were scheduled to sign the Informed Consent. You are now told you must stop taking all medicines for pain and swelling to participate in the study.
Would you, could you join this trial?
Is it any wonder that it is hard to recruit people to volunteer for a clinical trial? On top of huge inconveniences, we ask them to trust us with their health when they will be given experimental products that have unknown safety profiles. These are some of the risks and burdens study subjects accept; what are the benefits to them? Once we identify with how study participants feel and the benefit / risk ratio they are presented with, we can decrease the negative aspects of participation in clinical trials.
The Forgotten Link to Patient Recruitment and Retention
By putting yourself in the shoes of a potential study subject, or one that is enrolled, it is actually quite easy to understand patient recruitment and retention. This humanistic ‘High Touch’ point of view can help you identify ways to mitigate barriers to clinical trial participation.
About the Author
Sherry Reuter is President of Sherry Reuter & Associates, LLC, a consulting firm that focuses on the conduct of clinical trials, Site Selection, Study Start Up, Training, and Patient Recruitment and Retention. Sherry may be contacted at sreuter@gwu.edu or 203.775.6031.
Image Credit: jscreationzs / FreeDigitalPhotos.net
{ 26 comments… read them below or add one }
Sherry,
You are absolutely right about the need to take time to seriously consider the patient point of view. Sites that are naturally attuned to the needs of patients will usually, though not always, recognize these potential issues as they arise. And in many cases, patients will tell sites when there is an issue causing concern or discomfort.
The challenge is in how we deal with these issues. For some issues, sites can alleviate the problem. For instance, transportation can often be arranged for patients who have difficulty making it to the site. But in other instances, sites have little power to alleviate patient concerns due to restrictions imposed by the sponsor, CRO, vendor, protocol design, study drug, or the realities of conducting research.
Even seemingly insignificant decisions early in the process of designing a trial can have a big impact on recruitment and retention across multiple sites. Sponsors and CROs need to carefully consider the impact of these early decisions on patients since they are often very difficult to undo at a later date. A seemingly cost-effective decision can sometimes prove to be extremely costly in the long run.
Great article, Sherry. We should always be thinking of ways to improve the clinical trials experience for patients.
Thanks for your response, Rahlyn,
Your ideas are excellent. Nothing that can be solved should be left as a barrier that could lead potential subjects to decide to not participate or not to remain in a trial. Just by providing transportation, reimbursing for transportation costs, providing taxi vouchers, and/or providing Valet Parking, many subjects would enroll and complete trial trials. Compared to the costs of advertising and recruitment campaigns, as well as the earnings at stake by marketing a new product, these costs are minimal.
Study subjects hopefully will discuss concerns that could lead them to decide to not participate or to drop out of a trial, but we cannot assume this, as many subjects just drop out without providing a reason and are lost to follow up. Site staff can proactively broach this subject by letting subjects know that the site wants to do everything they can to assist in making participation in the study as smooth as possible and request that the subject not hesitate to talk to a staff member if any challenges arise.
You are correct in that the more difficult factors often stem from protocol requirements or logistics that occur from poor planning. Moving to a more “Patient-centric” model in the entire process of clinical research is needed to address recruiting and retaining the study subjects that no clinical trial can be conducted without!
Kind regards,
Sherry
When Sponsors design studies that taste better, more patients will be interested in coming to the table. When Sponsors design a one to two page informed consent versus the 25+ page version of today, busy Sites will have time for the consent process.
Thanks for this article, but I don’t really think this is the “site’s side” as much as it is the “patient’s side.” I would be interested to hear what the sites’ views on patient enrollment and recruitment, and their challenges juggling study requirements, sponsor expectations, etc. with patient load and how we could better support them as well.
Hi Melissa,
Great ideas for future discussions; we will address them! I hope people working at study sites presently or in the past will chime in to let us know “how we could better support them” as you say.
You are right, this blog presented clinical trial involvement through the eyes of study participants. Since study sites are the stakeholders that directly interface with them, site staff are on the first lines to be able to pick up on barriers to recruitment and retention and mitigate them by addressing the issues under their control and communicating others to the other stakeholders who can do so.
Kind regards,
Sherry
Hi John,
Thank you for pointing out the influence of sponsors and other stakeholders on sites’ abilities to recruit subjects and achieve the goals of the trial. We are all linked to achieve the same goal, so protocols written by sponsors that are “doable” in the real world will not only make recruitment more feasible for sites, but also give sponsors what they want – completed trials with the required number of subjects within reasonable timelines.
Regards,
Sherry
Hi Sherry,
As a former SC, I would be happy to share my experience and perceptions. The first issue we had to tackle was increasing the time dedicated to recruiting patients and increasing patient flow. As someone on the blog mentioned earlier, study coordinators have numerous responsibilities and I believe I read one stat that indicated only 10% of an SC’s time is spent on recruitment. At my previous site, we had a dedicated recruitment coordinator who handled all of the marketing efforts for all of the studies. Granted, with the economic strains, many sites are working with a slimmed down staff, so investing in this position is difficult. But, we found an increase of 65% in recruitment after establishing this position and 50% increase in the number of studies we were able to conduct as a result.
Second, we had to work with the challenges of work-life balance with the patients. The SC staff was very open to being flexible with their schedules to accommodate early appointments and late appointments; however, we were challenged when the PI was required to participate in certain visits. Their schedule is not as flexible, so we countered this by having an arsenal of Sub-Is to help ensure we were able to accommodate patients.
Finally, with respect to patient incentives, I have found that guidelines set forth by the FDA are being taken by sponsors as regulations. They are erring on the conservative side, so many of the incentives we were able to provide previously (i.e. gas cards, tote bags, pens, etc) are no longer permitted by some sponsors. As a site, we would do our best to provide patient comfort items and essentials that could not be construed as coercive (water, snacks, magazines, TV/DVD player). This came out of our budget, but was paid for by our ability to meet or exceed enrollment numbers.
Bottom-line, we did our best to acknowledge patients for their commitment and time, through both our words and our actions. This was all possible because we had a PI that was very engaged and committed to his patients, his staff and his research company as a whole. He impressed upon the team to do what was necessary to make the research patients priority patients.
Sherry,
You are absolutely right to point out that patients will not always communicate their needs. Sites need to be solicitous in getting feedback from patients, particularly early in a trial. Patients who have not had time to build rapport with study staff might be less comfortable bringing up these issues, so this communication is particularly critical early in a trial. I think it really boils down to good customer service.
A couple of observations:
- I think that eventually social marketing/media will help (not solve) the patient recruitment issue. We are social beings. If one of our friends is involved in a trial and we are eligible, we are more likely to be evaluated for participation.
- The article covers several points about the inconvenience of clinical trial participation. I was recently exposed to a company that provides “Certified Mobile Research Nurses” for clinical trials. Essentially these nurses are authorized by the PI to GO TO THE PATIENT (home, workplace, etc.) to perform the protocol visits. Now, this approach won’t work for some therapeutic areas (oncology, in-patient, etc.), but for those conditions that might impact a broader population, and especially for post-marketing surveillance, this is a very clever approach. This has the potential to knock down a major hurdle in patient recruitment. I’d bet that these types of services will expand in the coming years. Oh, and I am not related to one
.
Thanks for this article. Patient recruitment and retention is a critical task for Sponsors and is worth the spotlight which will hopefully allow us to focus the issue.
Many good points and arguments presented. I have some more basic questions though: At what point during selection or start up does a site say, “hmmm, yes I can recruit 20 subjects for this study.” And what are the key elements about a study that lead a site to this conclusion? What are the top three typical things that occur such that they create a situation where the initial assumptions of success are no longer feasibile?
Dear Nicole,
Thank you so much for sharing this information. You have included a number of tips that can be very helpful to sites who try so hard to accommodate study subjects!
Kind regards,
Sherry
Hi Rahlyn,
Great points about the value of open communication. Some site staff may feel reluctant to talk to subjects about this, but explaining to participants the rationale for completing the study (barring any recommendations from the PI to the contrary,) the importance of not dropping out without discussing it with the staff and telling them that the site staff is there to help them solve any issues that might make this a challenge can be reassuring to them. They will understand they are supported by a team that wants to help them rather than feeling they are alone in their efforts, making it more likely they would tell staff about any issues that may arise instead of just dropping out.
Best regards,
Sherry
Dheeraj Mehta • Hi Sherry,
A very comprehensive and read-worthy article, which I hope catches the eye of the stakeholders sooner than later. All the points are very realistic and practical and need practical solutions in return. I work as a CRA for an Organization, and from my monitoring experiences, I have learnt that some sites are still not at par with sponsor & subject expectations. I feel that it all boils down to a joint responsibility between the major stakeholders to focus on subject care & interest, which in turn will benefit the broader sponsor interest.
Hi Dave,
“Taking the study to the patient” rather than the patient always having to assume the burden of going to the study site is indeed the type of out-of-the-box solutions needed to retain more subjects. Data from these companies have shown that they do improve patient retention. They go to wherever the patients are – home,, work, vacation, college, etc so that patients don’t have to drop out of their trials.
There are also “Mobile study sites” that use vans to take site staff to subjects in remote areas.
Thank you for bringing up this option!
Sherry
Dear Dheeraj,
You are so right. To meet the goals of a study, it takes a team. All stakeholders must work together. Study sites have so much on their plate; realistically, they cannot do everything on their own. More studies will reach their goals on time if the entire team realistically assesses how the trial can be conducted in the most expedient manner. If sponsors want their trails completed as quickly and efficiently as possible, they might find that modest amounts of money to assist the site with recruiting and retaining patients will pay off in the end many times over. CROs can train their CRAs new ways to analyze how to recruit for specific trials and use this understanding to provide support to sites. A team approach is required to reach the goals of all stakeholders; we are all in this together.
Sherry
Hi Kathryn,
You are right on target! We plan to do exactly what you recommend. This is a forum to focus on the challenges of conducting clinical trials, particularly from the site’s perspective. But all stakeholders are involved (and should be) in many aspects, especially the tough tasks of recruiting and retaining subjects. Since sponsors benefit the most, they have a big interest in supporting these efforts.
Kind regards,
Sherry
Joe,
I think most sites would come up with a number when it comes time to fill out the sponsor’s questionnaire during site selection. The 5 biggest factors I can think of when a site is trying to predict enrollment numbers are:
- Number of prospective patients in existing database
- Past results of advertising for that particular therapeutic indication
- Previous enrollment numbers for trials in that therapeutic indication with a similar inclusion/exclusion criteria
- Inclusion/Exclusion criteria with particular attention to any criteria that are likely to weed out a lot of patients
- Perceived attractiveness of the the protocol and investigational product to potential patients. As an example, patients tend to like open label extensions but they do not like the idea of washing out of their existing medications.
Research sites will have different ways of assessing each of these variables, some probably more process-driven than others, but I think most are considering these variables in one way or another. In terms of factors that may derail the accuracy of predicted enrollment numbers, here’s my three:
- AEs – It’s about severity of the AE but also the patients willingness to tolerate it. If you have a trial that is primarily enrolling women and your drug causes weight gain, it’s going to be a challenge to keep your subjects in the study. This is an AE that some people will not tolerate even though it’s not necessarily causing physical discomfort.
- Inclusion/Exclusion – If the protocol has some sort of exclusion that is common to the patient population, that’s an issue. If the site has plenty of experience with the patient population, this is a challenge that they should be able to predict in many cases though.
- Advertising that does not produce predicted results – If a site is planning to supplement enrollment from its database with advertising, their advertising may not produce the interest they had hoped for.
Of course, keep in mind this is just my experience and my perception of other sites’ experience. I’d be curious to hear the opinion of others.
Hi Rahlyn,
Many thanks for responding to Joe’s questions.
You note that sites should know the number of subjects they think they can enroll in a trial after answering the questions on the Pre-trial Questionnaire, but how reliable is this information? Does the process of completing the Questionnaire provide the information sites need to know if they can successfully complete a trial?
With about 1/3 of selected sites never enrolling a subject or enrolling only 1, it seems there is a disconnect between the information supplied on the Questionnaire and sites’ performance. Lasagna’s Law has predicted this phenomenon for decades, when Dr. Louis Lasagna described this phenomenon “Investigators overestimate, many-fold, the pool of available subjects who meet the inclusion criteria and would be willing to enroll in a particular trial.” Research I conducted for my Master’s Thesis “How Effective are Research Site Questionnaires in Predicting Site Performance?” found that Lasagna’s Law was in effect for 79% of the sites in the study. Furthermore, the data supplied by the sites to answer questions on the Questionnaire was not found to be a predictor of their performance. Sites’ performance was not correlated to the data they provided.
How good are Pre-Trial Questionnaires in helping sites and sponsors understand if a trial is one that the site can successfully conduct? Is this tool, used routinely in selecting sites, in need of change?
Kind regards,
Sherry
Hi Sherry,
My use of the phrase “come up with a number” with regard to answering questionnaires was very purposeful. Coming up with a number is very different than *knowing* (or being able to make an accurate prediction) how many patients one can enroll.
I agree that, as an enrollment prediction tool, the questionnaire is not a good one. But the reality is that many sponsors continue to use them. Thankfully, I think that will change.
Many sponsors are developing tools that leverage historical and other relevant data to make predictions about site performance. If you are interested, I wrote a blog post that discusses this shift (among other things):
http://rebarinteractive.com/patient-recruitment-business-development/
Though I don’t think these questionnaires are useful for accurately predicting enrollment, they do have some value. Namely, the act of coming up with a number forces sites to think about potential barriers to enrollment early on. I think this is a good exercise, and if sites and sponsors have good communication, sites can alert sponsors to potential enrollment problems.
I just wouldn’t put much weight into the actual number that sites come up with, unless that site is known to have a history of making accurate enrollment predictions. Of course, it would be even better for sponsors to collect site feedback about enrollment barriers and other important information *before* the site selection process.
Rahlyn,
Thank you so much for sharing the link to your blog post! It is excellent, and I hope others take the opportunity to read it.
Your point “historical recruitment performance data will emerge as a crucial selection factor” is right on. Using systems that track these metrics automatically for sites will make this very easy for them to provide this data during site selection.
Thanks for your comments,
Sherry
A few considerations regarding the site’s side that pose barriers to recruitment:
– protocols written with I/E criteria that are not reflective of that population being sought, i.e.:
1. Diabetic trials excluding patients w/ a BMI >34 (many patients’ BMIs are >34)
2. Patient trials excluding commonly-prescribed medications for that patient population (i.e. Hepatic trials excluding pain meds or antidepressants).
3. Patient trials excluding OOR lab values, EKG parameters, or other criteria that are common for that patient population (dialysis patients, renal patients, HVC+ patients, etc.)
4. Patient trials requiring a 90-day medication stability prior to enrollment – very difficult to enroll a patient when they need to be stable on all their current meds for min. of 90 days.
5. Sponsors who change the criteria mid-study by adding I/E that is not included in the protocol – i.e. currently attempting to enroll a patient with moderate renal impairment, and the patient must be male with a weight of </= 60kg. Virtually impossible in our patient population! Is this in the I/E? Nope.
There's a few to chew on!
Pamela Brule, BS, BS, CCRP
Patient Recruitment
DaVita Clinical Research
Minneapolis, MN
Dear Pamela,
Thank you for adding this to the list of challenges.
Inclusion / Exclusion Criteria that knocks out most of the population indeed makes recruitment like finding a needle in a haystack! I sometimes felt the I/E made me find left-handed people with 1 blue eye and 1 green eye!
- Why do you (all readers) think sponsors write protocols like this?
- What happens if you give sponsors feedback about the I / E criteria being unrealistic and making recruitment difficult?
Kind regards,
Sherry
Happy New Year, Sherry and all in this discussion.
- Why do you (all readers) think sponsors write protocols like this?
I think there are a variety of reasons why protocols are written with I/E that doesn’t seem to fit the patient population (i.e. a diabetic trial with a BMI criteria of 18-30):
– sometimes I think it’s a simple matter of copy/pasting the I/E from one protocol to the next (avoiding re-creating the wheel each time)
– to cherry-pick the “most suitable” patients
– possibly an attempt to reduce extremes or outlyers in data analysis
– medication exclusions may another attempt to reduce the complexity of the data anaylsis
– lack of knowledge of a patient population or disease state
– unrealistic expectations and high hopes!
– I may have missed a few – other input?
- What happens if you give sponsors feedback about the I / E criteria being unrealistic and making recruitment difficult?
It depends!
– Some sponsors are really great, seek input and act on it as if we know what we’re talking about – which produces a wonderful result re: recruitment.
– Other sponsors are at the other end of that spectrum and don’t want to hear any input whatsoever, and won’t permit any waivers or exceptions, either, with predictable recruitment delays and issues, depending on the level of difficulty.
– Sometimes the latter group will, after months of screen failures and little enrollment progress, will then sit down for a t-con to discuss recruitment barriers and subsequently make protocol amendments which then speed up the enrollment, which they could have avoided if they had been willing to discuss up front.
Happy New Year to you as well, Pamela,
And thank you for taking time to put so much thought into your responses.
Your list of reasons covers quite a span. Some of your points make me think of situations in which all kinds of criteria that seemed like stretches were added for marketing purposes, meaning what could be proven for labeling claims. This was especially the case for products in the same class when a company’s sales would benefit if they could offer the product in different circumstances than competitors.
You show that there is no one answer, as you said “it depends.” Trying to analyze such situations will give you insight on how best to deal with each one. Using your Emotional Intelligence, why they might have done what they did and considering how collaborative the other party is will help you decide how to proceed, and if you do, how best to do it.
Best regards,
Sherry
I found answers for many things. But i have a doubt that when PI gets information from participant before consenting, whether participant can stay or drop from trial.If so, can any one explain about how a clinical trial site would ask the patient to stay in trial