All Your Site Are Belong To Us

'Competitive enrollment' is exactly that.

This is a graph I tend to show frequently to my clients – it shows the relative enrollment rates for two groups of sites in a clinical trial we'd been working on. The blue line is the aggregate rate of the 60-odd sites that attended our enrollment workshop, while the green line tracks enrollment for the 30 sites that did not attend the workshop. As a whole, the attendees were better enrollers that the non-attendees, but the performance of both groups was declining.

Happily, the workshop produced an immediate and dramatic increase in the enrollment rate of the sites who participated in it – they not only rebounded, but they began enrolling at a better rate than ever before. Those sites that chose not to attend the workshop became our control group, and showed no change in their performance.

The other day, I wrote about ENACCT's pilot program to improve enrollment. Five oncology research sites participated in an intensive, highly customized program to identify and address the issues that stood in the way of enrolling more patients.  The sites in general were highly enthused about the program, and felt it had a positive impact on the operations.

There was only one problem: enrollment didn't actually increase.

Here’s the data:

This raises an obvious question: how can we reconcile these disparate outcomes?

On the one hand, an intensive, multi-day, customized program showed no improvement in overall enrollment rates at the sites.

On the other, a one-day workshop with sixty sites (which addressed many of the same issues as the ENACCT pilot: communications, study awareness, site workflow, and patient relationships) resulted in and immediate and clear improvement in enrollment.

There are many possible answers to this question, but after a deeper dive into our own site data, I've become convinced that there is one primary driver at work: for all intents and purposes, site enrollment is a zero-sum game. Our workshop increased the accrual of patients into our study, but most of that increase came as a result of decreased enrollments in other studies at our sites.

Our workshop graph shows increased enrollment ... for one study. The ENACCT data is across all studies at each site. It stands to reason that if sites are already operating at or near their maximum capacity, then the only way to improve enrollment for your trial is to get the sites to care more about your trial than about other trials that they’re also participating in.

And that makes sense: many of the strategies and techniques that my team uses to increase enrollment are measurably effective, but there is no reason to believe that they result in permanent, structural changes to the sites we work with. We don’t redesign their internal processes; we simply work hard to make our sites like us and want to work with us, which results in higher enrollment. But only for our trials.

So the next time you see declining enrollment in one of your trials, your best bet is not that the patients have disappeared, but rather that your sites' attention has wandered elsewhere.

What (If Anything) Improves Site Enrollment Performance?

ENACCT has released its final report on the outcomes from the National Cancer Clinical Trials Pilot Breakthrough Collaborative (NCCTBC), a pilot program to systematically identify and implement better enrollment practices at five US clinical trial sites. Buried after the glowing testimonials and optimistic assessments is a grim bottom line: the pilot program didn't work.

Here are the monthly clinical trial accruals at each of the 5 sites. The dashed lines mark when the pilots were implemented:

4 of the 5 sites showed no discernible improvement. The one site that did show increasing enrollment appears to have been improving before any of the interventions kicked in.

This is a painful but important result for anyone involved in clinical research today, because the improvements put in place through the NCCTBC process were the product of an intensive, customized approach. Each site had 3 multi-day learning sessions to map out and test specific improvements to their internal communications and processes (a total of 52 hours of workshops). In addition, each site was provided tracking tools and assigned a coach to assist them with specific accrual issues.

That’s an extremely large investment of time and expertise for each site. If the results had been positive, it would have been difficult to project how NCCTBC could be scaled up to work at the thousands of research sites across the country. Unfortunately, we don’t even have that problem: the needle simple did not move.

While ENACCT plans a second round of pilot sites, I think we need to face a more sobering reality: we cannot squeeze more patients out of sites through training and process improvements. It is widely believed in the clinical research industry that sites are low-efficiency bottlenecks in the enrollment process. If we could just "fix" them, the thinking goes – streamline their workflow, improve their motivation – we could quickly improve the speed at which our trials complete. The data from the NCCTBC paints an entirely different picture, though. It shows us that even when we pour large amounts of time and effort into a tailored program of "evidence and practice-based changes", our enrollment ROI may be nonexistent.

I applaud the ENACCT team for this pilot, and especially for sharing the full monthly enrollment totals at each site. This data should cause clinical development teams everywhere to pause and reassess their beliefs about site enrollment performance and how to improve it.

The Accuracy of Patient Reported Diagnoses

Novelist Phillip Roth recently got embroiled in a small spat with the editors of Wikipedia regarding the background inspiration for one of his books.  After a colleague attempted to correct the entry for The Human Stain on Roth's behalf, he received the following reply from a Wikipedia editor:

I understand your point that the author is the greatest authority on their own work, but we require secondary sources.

Report: 0% of decapitees could
accurately recall their diagnosis

The editor's response, as exasperating as it was to Roth, parallels the prevailing beliefs in clinical research about the value and reliability of Patient Reported Outcomes (PROs). On the one hand, who knows the patient better than the patient? On the other hand, our SOPs require expert physician assessment and diagnosis -- we, too, usually require secondary sources.

While recent FDA guidance has helped to solidify our approaches to incorporating PROs into traditionally-structured clinical trials, there are still a number of open questions about how far we can go with relying exclusively on what patients tell us about their medical conditions.  These questions come to the forefront when we consider the potential of "direct to patient" clinical trials, such as the recently-discontinued REMOTE trial from Pfizer, a pilot study that attempted to assess the feasibility of conducting a clinical trial without the use of local physician investigators.

Among other questions, the REMOTE trial forces us to ask: without physician assessment, how do we know the patients we recruit even have the condition being studied? And if we need more detailed medical data, how easy will it be to obtain from their regular physicians? Unfortunately, that study ended due to lack of enrollment, and Pfizer has not been particularly communicative about any lessons learned.

 Luckily for the rest of us, at least one CRO, Quintiles, is taking steps to methodically address and provide data for some of these questions.  They are moving forward with what appears to be a small series of studies that assess the feasibility and accuracy of information collected in the direct-to-patient arena. Their first step is a small pilot study of 50 patients with self-reported gout, conducted by both Quintiles and Outcomes Health Information Services.  The two companies have jointly published their data in the open-access Journal of Medical Internet Research.

(Before getting into the article's content, let me just emphatically state: kudos to the Quintiles and Outcomes teams for submitting their work to peer review, and to publication in an open access journal. Our industry needs much, much more of this kind of collaboration and commitment to transparency.)

The study itself is fairly straightforward: 50 patients were enrolled (out of 1250 US patients who were already in a Quintiles patient database with self-reported gout) and asked to complete an online questionnaire as well as permit access to their medical records.

The twin goals of the study were to assess the feasibility of collecting the patients' existing medical records and to determine the accuracy of the patients' self-reported diagnosis of gout.

To obtain patients' medical records, the study team used a belt-and-suspenders approach: first, the patients provided an electronic release along with their physicians' contact information. Then, a paper release form was also mailed to the patients, to be used as backup if the electronic release was insufficient.

To me, the results from the attempt at obtaining the medical records is actually the most interesting part of the study, since this is going to be an issue in pretty much every DTP trial that's attempted. Although the numbers are obviously quite small, the results are at least mildly encouraging:

• 38 Charts Received
• 28 required electronic release only
• 10 required paper release
• 12 Charts Not Received
• 8 no chart mailed in time
• 2 physician required paper release, patient did not provide
• 2 physician refused

If the electronic release had been used on its own, 28 charts (56%) would have been available. Adding the suspenders of a follow-up paper form increased the total to respectable 76%. The authors do not mention how aggressively they pursued obtaining the records from physicians, nor how long they waited before giving up, so it's difficult to determine how many of the 8 charts that went past the deadline could also potentially have been recovered.

Of the 38 charts received, 35 (92%) had direct confirmation of a gout diagnosis and 2 had indirect confirmation (a reference to gout medication).  Only 1 chart had no evidence for or against a diagnosis. So it is fair to conclude that these patients were highly reliable, at least insofar as their report of receiving a prior diagnosis of gout was concerned.

In some ways, though, this represents a pretty optimistic case. Most of these patients had been living with gout for many year, and "gout" is a relatively easy thing to remember.  Patients were not asked questions about the type of gout they had or any other details that might have been checked against their records.

The authors note that they "believe [this] to be the first direct-to-patient research study involving collection of patient-reported outcomes data and clinical information extracted from patient medical records." However, I think it's very worthwhile to bring up comparison with this study, published almost 20 years ago in the Annals of the Rheumatic Diseases.  In that (pre-internet) study, researchers mailed a survey to 472 patients who had visited a rheumatology clinic 6 months previously. They were therefore able to match all of the survey responses with an existing medical record, and compare the patients' self-reported diagnoses in much the same way as the current study.  Studying a more complex set of diseases (arthritis), the 1995 paper paints a more complex picture: patient accuracy varied considerably depending on their disease: from very accurate (100% for those suffering from ankylosing spondylitis, 90% for rheumatoid arthritis) to not very exact at all (about 50% for psoriatic and osteo arthritis).

Interestingly, the Quintiles/Outcomes paper references a larger ongoing study in rheumatoid arthritis as well, which may introduce some of the complexity seen in the 1995 research.

Overall, I think this pilot does exactly what it set out to do: it gives us a sense of how patients and physicians will react to this type of research, and helps us better refine approaches for larger-scale investigations. I look forward to hearing more from this team.


Cascade, E., Marr, P., Winslow, M., Burgess, A., & Nixon, M. (2012). Conducting Research on the Internet: Medical Record Data Integration with Patient-Reported Outcomes Journal of Medical Internet Research, 14 (5) DOI: 10.2196/jmir.2202



Also cited: I Rasooly, et al., Comparison of clinical and self reported diagnosis for rheumatology outpatients, Annals of the Rheumatic Diseases 1995 DOI:10.1136/ard.54.10.850

Image courtesy Flickr user stevekwandotcom.