Is clinical trial design complexity behind the high turnover rate for principal investigators?

This article is the first of a two-part series looking at principal investigators and the challenges they are facing in their profession.

I can make more generals, but horses cost money.  — Abraham Lincoln

Principal Investigators (PI) may not be the generals Lincoln had in mind when he made this statement, nevertheless they are one of the key players in the clinical trial efficiency equation. They are ultimately responsible for the conduct of the trial at the investigative site. Achieving operational efficiencies at investigative sites is key in the efforts to control costs and ensure successful clinical trials. Unfortunately, the pharmaceutical industry is experiencing a shortage of experienced PIs.

Ps are responsible for all clinical research activities at a study site. They assure that the study subjects receive appropriate study-related medical care. They also ensure that all study-related activities follow the principles of Good Clinical Practice (GCP) – internationally recognized ethical and quality standards that serve to assure that the rights and well-being of trial participants are protected, and that the results of the clinical trials are accurate and credible.

As PIs have a huge impact on the success and efficiency of a study, sponsors are hesitant to use inexperienced PIs to oversee a study site. Yet, the data overwhelmingly suggests that many PIs choose not to continue with clinical trial research. Lack of experienced PIs can contribute to inefficiencies in site selection, qualification, training, and startup that result in cost increases for sponsors.

The high turnover of principal investigators

Before they begin participation in a clinical study, investigators must sign an FDA form 1572 to certify that they will abide by the guidelines detailed in the Code of Federal Regulations for the use of drugs in an investigational setting. A recent assessment by the Tufts Center for the Study of Drug Development found that there are nearly 40,000 unique active investigators worldwide that have conducted at least one FDA-regulated clinical trial. Roughly half of these 40,000 were new to the job in 2013, the most recent year for which data are available. In addition, although the highest turnover rates are observed among the least active investigators, turnover rates have been getting progressively worse among more active investigators. Other findings from this analysis suggest that a relatively small number of PIs are overseeing more trials every year:

• Only 10 percent of PIs that have filed 1574 forms conduct more than five studies per year.
• The percentage of form 1572 filers per year that are first-timers seems to be increasing – the above-cited 50 percent figure for 2013 was up from 40 percent in 2009.
• Growth in the number of unique investigators is beginning to decelerate: the most recent four-year annual growth rate was 3.3 percent compared with the prior four-year period of 4.1 percent and an average of 5.6% over the last 15 years.
• During the 2009 – 2013 period, the numbers of active investigators in India and China, areas once expected to see the most dramatic relative growth, have declined by 16 percent and 5 percent, respectively.

“Since 2006, 55 percent of PIs in Europe, 53 percent in Asia/Pacific, and 40 percent in North America have not conducted another clinical trial,” according to Ken Getz, associate professor and director of sponsored research at Tufts CSDD. “This high level of PI turnover is very concerning for the industry. The high percentage of inexperienced investigators suggests that most investigators are not in the industry long enough to master their profession.”

Another concern is that the experienced PI pool seems to be aging. Data from 2002 showed that only 8 percent of investigators conducting industry-sponsored clinical trials were younger than 40 years, and inadequate numbers of new investigators were available to replace the older generation.

The average PI’s age has risen from 43 years to 50 years, according to Tufts CSDD. Recent data from the National Institutes of Health (NIH) paints a similar picture – there are not enough new PIs to replace those planning to retire. AMA and NIH data show that the demographics of physician-scientists have shifted dramatically over the past decade, with the proportion of NIH-funded PIs in their 60s and 70s soaring and the share under 60 declining.

So why is there such a high turnover rate for PIs? And why are the numbers of young physicians entering the field declining?

Causes of principal investigator turnover

High PI turnover seems to be primarily centered around the fact that it has become a very demanding job without adequate compensation, financial or otherwise.

“The fundamental problem,” says Getz, “is the needlessly complicated design of clinical trials shaped by complex regulatory requirements from the FDA.”

• Due to risk aversion and a challenging economic environment, sponsors are putting pressure on PIs to deliver more with less.*

• Narrow subject eligibility requirements make subject recruiting difficult.

• New technologies increase costs for sites: Electronic Case Report Forms (eCRFs) move data entry costs from the sponsor to the investigator; eDiaries generate reminder phone calls.

• HIPAA and ICH are increasing regulatory compliance costs both directly and through more stringent sponsor and IRB requirements. HIPAA, in particular, increases the cost of subject recruitment and informed consent.

• Study budgets are flat while procedures per subject are increasing.

Regarding this last point, sites have seen increases in paperwork, protocol complexity leading to challenges with patient recruitment, management and performance metrics, patient screening and informed consent complexity, site staff GCP and IT training requirements, and compliance requirements. Site budgets, however, have not increased to address all this added overhead. Adding to the problem is the fact that a complex reimbursement process for patient care costs from clinical trials often results in inaccurate and late payments to sites.

“Things have gotten more complex and complicated. I regret not enjoying the golden days—10 years ago,” said Terry Poling, medical director Heartland Research Associates. “Today’s landscape is financially tougher. We’ve seen an increase in demand, but the costs have increased more than the rewards. Twenty years ago, it was simpler to start up—if I were faced with the current demands, I would not have survived.”

Practicing physicians might decide to participate in a trial to make some extra money and gain access to new therapies for their patients, only to find that they lack the resources and time required to effectively serve in the PI role. Essentially, they realize that serving as a PI while maintaining a medical practice is more than they bargained for, and they thus join the growing ranks of the “one and done” PIs. The complex task of seeing a clinical trial through from beginning to end is making the clinical research career path unattractive for many, contributing to the aging PI population.

Additionally, sites are being overloaded by sponsors with multiple eClinical technology solutions that do not communicate with each other. A 2016 study by CenterWatch revealed that sites used about 10 different software applications to manage clinical studies in 2015.

“I am a proponent of these technologies,” said Jeremy Rigby, executive director of Advanced Clinical Research. “But the difficulty is the need to use so many different systems, which are hard to keep track of and don’t talk to each other. All of these systems work differently, have different login credentials and require training.”

Instead of supporting improved efficiencies, these technologies end up adding to the complexity of conducting trials by requiring interaction with third-party vendors and increasing training needs.

Photo: REB Images, Getty Images

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