For Principal Investigators, the One-and-Done Syndrome Persists

Clinical Researcher—September 2018 (Volume 32, Issue 8)

SPECIAL FEATURE

Ann Neuer, MBA

Leon Rosenberg, a self-proclaimed physician-scientist at Princeton University and the former president of the Pharmaceutical Research Institute at Bristol-Myers Squibb Company, wrote a fascinating piece in The Journal of Clinical Investigation about the declining number of clinical investigators.{1} He declared, “In the absence of physician-scientists, the bridge between bench and bedside will weaken—perhaps even collapse.” The thing is, Rosenberg wrote this article nearly 20 years ago. Moreover, he reported that the number of clinical investigators was declining even then. In fact, he referred to them as an “endangered species,” and perhaps he was channeling the future, given how strongly his words resonate today.

Current research suggests that this trend continues as clinicians who are principal investigators (PIs) routinely come and go in somewhat of a one-and-done fashion.{2} This was a key finding of a 2015 survey of 201 investigators, funded by the U.S. Food and Drug Administration (FDA) and the Clinical Trials Transformation Initiative (CTTI), in which 54.2% of respondents were classified as one-and-done.{2}

Similarly, a 2017 study from the Tufts Center for the Study of Drug Development (CSDD) found that the PI landscape remains highly fragmented, and is typified by heavy turnover, particularly among inexperienced investigators. To reach this conclusion, CSDD analyzed information from the Bioresearch Monitoring Information Database from 2008 to 2015, determining that half of all PIs filing a single Statement of Investigator form 1572 with FDA each year chose not to file again in subsequent years.{3} These results follow on the heels of earlier work from CSDD, which showed that in 2013, nearly half of the 40,000 global PIs were new to the job, suggesting ongoing turnover.{4}

Physicians are, of course, fundamental to the clinical trial process, but in an ever-more challenging clinical trial environment, what motivates them to become investigators and what is the industry doing to engage and retain them? What tactics are sponsors using to attract new PIs to the industry? These are important questions, as difficulties plaguing investigators have been widely reported—for example, in terms of trial conduct being more complicated due to tougher protocols, growing use of technologies and portals, greater regulatory scrutiny, and ongoing issues of financial viability at the site level. With this scenario, it is hardly surprising that investigators overwhelmed by their responsibilities in clinical trial conduct are heading to the nearest exit.

This article will explore:

  • The status of the one-and-done syndrome—is it changing?
  • What is needed for investigators to be successful and stay engaged in this industry.
  • Steps a major pharmaceutical sponsor is taking to retain PIs and boost their chances for site sustainability.

Changing Direction

There is extensive and highly visible reporting on the challenges facing PIs, so it is worth asking what draws physicians into conducting clinical trials in the first place. Are they aware of the high barriers to entry? What about the need for infrastructure and an understanding of their responsibilities as defined by the internationally recognized tenets of Good Clinical Practice (GCP)?

David Morin, MD, FACP, CPI, FACRP, director of clinical research with the Holston Medical Group and a long-time PI, explains, “My 30 years of experience tell me that investigators who do this for the science are more likely to be successful in the long term. They want access to the next wave of treatments and to work with like-minded professionals. Financial motivation may play a role, but hopefully not the primary one.”

Participating in research to help develop much-needed new treatment options for patients is a noble cause, and it offers personal and professional rewards. However, as Jeff Kingsley, DO, MBA, CPI, FACRP, founder and CEO of IACT Health, points out, “Doctors get involved in research because they think it sounds great—like it’s the right thing to do—but they have no idea how ill-prepared they are.”

According to Kingsley, investigators discover that research takes dramatically more time than expected, involves volumes of paperwork, and too often, they choose protocols not well-suited to their practice. A growing body of research substantiates this claim; the FDA/CTTI survey, which explored the one-and-done syndrome, found a litany of reasons{2} (see Table 1 for the most common). These focus largely on the burdensome, time-consuming nature of clinical trial conduct and the inadequate clinical trial infrastructure in many physicians’ offices. Still, there’s more to the story; despite the difficulties, 44.4% of the one-and-done respondents reported that they are interested in continuing to participate in FDA-regulated studies, but they have been unable to find opportunities to do so.

Table 1: Drivers of the One-and-Done Syndrome (n = 93)

Very Challenging

Challenging or Somewhat Challenging

Not Challenging

Workload Balance      
Finding time to devote to activities fostering promotion

44%

30%

16%

Long work hours

28%

64%

8%

Finding time to devote to other work activities (non-clinical)

28%

64%

6%

Time Requirements
Amount of time required to prepare for trial start-up

28.8%

71.2%

0%

Amount of time required by investigator to support trial and site staff

28.8%

61.5%

9.6%

Amount of time required by staff to support the trial

26.9%

59.6%

5.8%

Extremely Burdensome

Moderately or Somewhat Burdensome

Not Burdensome

Data and Safety Reporting
Amount of safety data to report

32.7%

63.3%

4.1%

Frequency of reporting

29.2%

66.7%

4.2%

Amount of non-safety data to report

28.6%

67.3%

4.1%

Source: Adapted from Corneli A, et al.{2} 2017 under Creative Commons license.

While the one-and-done trend seems headed in the wrong direction, work toward a growing number of solutions to this dilemma is under way. Several organizations have stepped up to the plate with data highlighting this problem and strategies for moving the needle (see Figure 1). Most notably, there is a focus on training investigators to be aware of their responsibilities. Also, there is an emphasis on infrastructure to support PIs, not only in the form of technology, but also with staff skilled at handling the many business issues that are standard fare in study startup, clinical operations, and study execution.

Figure 1: Some Organizations with Efforts to Support PIs and Improve Infrastructure
Academy of Physicians in Clinical Research (APCR)
Association of Clinical Research Professionals (ACRP)
Clinical Trials Transformation Initiative (CTTI)
Drug Information Association (DIA)
Model Agreements & Guidelines International (MAGI)
Society for Clinical Research Sites (SCRS)
TransCelerate BioPharma

In October 2017, CTTI published a report with numerous suggestions to address PI turnover and to strengthen the investigator community.{5} The broad-based suggestions are site- and sponsor-focused concerns, and are grouped into four categories:

  1. Developing site-based research infrastructure and staff
  2. Optimizing trial execution and conduct
  3. Improving site budget and contract negotiations
  4. Discovering additional trials to conduct

The recommendations highlight the multi-step process of launching a successful clinical trial, starting with selecting the right protocols, developing realistic patient recruitment and enrollment plans, and managing cash flow concerns. In addition, there is discussion on training for all site-level staff, including the sub-PI. Using this approach, the sub-PI learns the ropes before taking the leap to becoming a full-fledged PI.

Gerrit Hamre, a project manager for CTTI, notes that the recommendations are a starting point because, “There isn’t a lot of accessible information on the type of staff and infrastructure that investigators need—basically, the nuts and bolts. That’s where new PIs get tripped up, as it’s tough to get through the first several trials without that operational knowledge. One of our recommendations is to start as a sub-PI along with some formal mentorship. That’s a wonderful way for potential investigators to get their feet wet.”

Similarly, Morin of the Holston Medical Group comments, “PIs at our site almost always start in research as a sub-investigator, which is a good way to get involved and begin to understand the process without ultimately being responsible for the trial. They work on about five studies as a sub-PI, and then transition when the right study comes along. Also, we have our own investigator training program and we mentor [them]. Once they become a PI, they are supported by a very experienced team of certified coordinators, a regulatory and financial/contract specialist, quality assurance monitoring, internal training, and a formal PI oversight process.”

A Data-Driven Approach to Positive Change—A Look at Merck

In the midst of this industry turmoil, forward-thinking sponsors are listening and mobilizing as the status quo is no longer an option. In order to keep investigators engaged and nurtured so they can develop into excellent researchers, stakeholders are implementing data-driven programs to bring disruptive change.

Merck is one company that is taking some particularly bold steps. Jennifer Sheller, regional head for North America with Country Operations at Merck, explains that driving the firm’s initiatives is the recognition that PIs alone cannot be expected to run all aspects of research—from business functions, such as administration and staffing, to study startup, clinical matters, and operations. They need support from a proper infrastructure and team within their practices and institutions, and from sponsors and contract research organizations (CROs) to alleviate the administrative burden of conducting clinical trials.

“Collectively, our industry is addressing this with solutions such as the TransCelerate Shared Investigator Platform with which we are currently working to get our sites registered,” Sheller says.

To find the right PIs, Sheller’s team has enhanced its collective knowledge of clinical trial activity (i.e., start-up, enrollment, data management) with a robust internal database coupled with a partnership with a large central institutional review board (IRB) consortium that offers a comprehensive database of trial and site performance, representing 95% of all industry-sponsored protocols worldwide. That consortium keeps a massive data warehouse with data coming from more than 400 public domain data sources, plus the 25 companies under its own roof. With this capability, they consult with sponsors to help them work as quickly as possible to answer these two questions—does this drug work, and is it safe?

Sheller’s group, which oversees more than 200 trials, including many oncology studies, as well as infectious disease, vaccines, and more, accesses both data sources to help identify the PIs and sites with the right infrastructure and metrics to support the likelihood of their reaching enrollment targets within timelines and conducting top-quality clinical research. According to Suzanne Caruso, vice president of clinical solutions at WIRB-Copernicus Group (WCG), “This approach is possible because we have data on how quickly investigators are able to enroll patients, based on how many trials they have completed in specific therapeutic areas, and how many they have ongoing. These are two major indicators as to whether a specific investigator will be able to enroll. The goal is to reach ‘last patient/last visit’ as quickly as possible.”

In a competitive market for the best sites, this approach is a win-win situation for Merck and for PIs with the right stuff, who are benefiting from filling their pipeline with studies, thereby boosting their chances for site sustainability, and possibly creating an environment for greater PI retention.

To continue in this direction, Merck has launched several initiatives; one effort involves targeting fewer sites with proven performance to enroll more patients. This is a critical departure from what is happening across the industry, whereby many sponsors and CROs are hiring large numbers of sites, with the expectation that each will enroll only a small number of patients.

According to Sheller, “In some trials, this makes sense, but for most, it does not, and reflects that the majority of sites fail to reach their enrollment targets. Our team, however, is working toward investing resources in fewer sites with a supportive research infrastructure and access to patients, while making our start-up processes more efficient. Our goal is to drive greater productivity while maintaining the highest quality.”

This is a meaningful approach, as PIs and sites tend to chafe at being asked to enroll just a handful of subjects while being expected to maintain a costly infrastructure that could support more patients (see Figure 2). Further, contracting to enroll more subjects and actually doing so allows the site to maintain an optimal research infrastructure and conduct even more trials. According to Sheller, in 2018, her region has targeted a reduction in the number of sites by approximately 30% as compared to 2017. This is being accomplished by focusing on increasing site partnerships and matching trials with sites having the appropriate patient population and infrastructure.

Figure 2: Fewer Patients Per Site Per Study Discourages PIs

[Christine Senn, chief operations and implementation officer at IACT Health, mentions that over the past few years, the company has seen a sharp decline in the number of patients it is asked to enroll for studies. “In some studies, such as COPD, we used to recruit seven times the amount of patients we are asked to recruit now—from about 30 to 40 down to about five or six today,” she says. This chart shows the decline in the mean number of patients IACT Health has been asked to recruit per study.]

Year

Number of Patients/Site (Mean)

2011

20.86

2012

17.22

2013

16.21

2014

11.04

2015

  8.79

2016

  9.59

2017

  9.90

2018

  7.67

Source: IACT Health 2018

To reduce administrative burden for PIs while accelerating study start-up, Merck has taken additional steps. Sheller’s region has set a target for use of central IRB services to maximize efficiencies, especially at large institutions. “Our target is to secure [that] 70% of selected sites within a given trial will use a central IRB,” she notes. Every few weeks, she receives a report as to where the sites are versus the target, and currently, the team is meeting this goal.

Merck also launched a Master Suite program in late 2017 to facilitate laborious documentation, budgeting, and contracting processes. This program entails using core negotiated documents, such as a master confidentiality agreement, master contract, consent form, and master fee schedule. To further minimize PI and site frustration, the company has instituted a central point of contact for select partner sites who are participating in multiple trials.

“Each site has a site account manager, who is an experienced operational point of contact dedicated to partnering with sites, which ensures we understand each other’s infrastructures, processes, and needs,” Sheller explains. “Sites know they have a dedicated operational expert at Merck whom they can call if they aren’t sure how to navigate something. PIs and sites really appreciate this. With all of these changes, we can move a lot faster and reach patients sooner.”

Taking Steps

At a time when the industry is wrestling with a range of issues meant to improve operational and clinical quality while accelerating study conduct, improving the longevity of PIs who are active in clinical trials ranks among the top challenges. This well-known problem is supported by data, but with a flurry of initiatives meant to retain and nurture investigators, it is possible that the pendulum will start to swing in a more positive direction.

To take the first steps, there is a basic need for infrastructure. Without a staff of qualified, trained personnel, it is nearly impossible for a PI to conduct quality clinical trials with any degree of efficiency and timeliness. Creating this infrastructure can start with developing the physician through a sub-PI program, whereby eventually, the physician can assume PI status—and this is where the challenge to retain PIs begins.

According to Morin, “PIs are retained by earning and keeping their trust, by engaging them in the process of study conduct, by the availability of content experts on staff, by compensating them for the time they spend out of the office to attend meetings and onsite training, and through profit sharing.”

Further, it is critical to thank PIs for their vital work. The industry has long realized that patients must be thanked for their contributions to scientific research, whether it’s in the form of gift cards, dinner vouchers, parking reimbursement, or birthday cards. Similarly, physicians should be thanked as they forge ahead in the development of much-needed therapies.

With this mix of strategies and the broad-based initiatives described earlier, time will tell if the experts behind these efforts will make the desired impact to engage and retain PIs—one of the industry’s most enduring challenges.

References

  1. Rosenberg LE. 1999. The physician-scientist: an essential—and fragile—link in the medical research chain. J Clin Invest 103(12):1621–6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408393/
  2. Corneli A, Pierre C, Hinkley T, Lin L, et al. 2017. One and done: reasons principal investigators conduct only one FDA-regulated drug trial. Contemp Clin Trials Comms 6:31–8. https://www.sciencedirect.com/science/article/pii/S245186541630093X
  3. Getz KA. Taking stock of today’s global site landscape. 2017. Applied Clinical Trials 26(6). www.appliedclinicaltrialsonline.com/taking-stock-today-s-global-site-landscape
  4. Peters S. 2015. High turnover and protocol noncompliance continue to plague the global investigative site landscape, according to the Tufts Center for the Study of Drug Development. Tufts CSDD. www.marketwired.com/press-release/high-turnover-protocol-noncompliance-continue-plague-global-investigative-site-landscape-1983271.htm
  5. Clinical Trials Transformation Initiative. 2017. Recommendations for strengthening the investigator site community. https://www.ctti-clinicaltrials.org/sites/www.ctti-clinicaltrials.org/files/investigator_community_recommendations_final_0.pdf

Ann Neuer, MBA, (aneuer@cinci.rr.com) is President of Medical deScriptions, LLC. Her earlier article for Clinical Researcher,Patient Engagement Goes Mobile,” appeared in the January 2018 issue.