Have We Pushed Our Pis Too Far?

The rigors of being a clinical investigator are mounting. Protocols have become more cumbersome, ambitious, and demanding. Patient recruitment and retention, the largest cause of study delays, has become more onerous. Regulatory reforms—most recently around privacy protection and financial disclosure—have increased the burden of compliance. And performance and financial pressures have hit investigators particularly hard.

Kenneth A. Getz

In turn, there are growing signs that the base of clinical investigators in the United States is weakening¹:

• The number of principal investigators (PIs) in the United States dropped 11% between 2001 and 2003.

• Turnover rates of clinical investigators are double what they were 10 years ago. Nearly half of all principal investigators will not return to the clinical research enterprise after completing a clinical trial.

• The proportion of PIs conducting industry-funded research is decreasing in the Northeast and Midwest, but is growing 6% annually in the South, where study costs are lower. The five-year growth in active clinical trials being placed here also far outpaces growth in the Northeast and Midwest regions.

• Women represented only 12% of all PIs in 2003, a figure that has been steadily declining for a decade. Meanwhile, more trials focus on diseases manifest and prevalent in women.

• The rate of investigator noncompliance with good clinical practice (GCP) guidelines in the 2000's, for example, has increased tenfold over levels observed in the 1990s.²

• According to an evaluation recently conducted by a major IRB, once each quarter an investigative site is filing for bankruptcy protection. Many more investigators may be exiting the clinical research enterprise under less formal circumstances.³

This tenuous and changing PI landscape poses several major threats to research sponsors and CROs. Declining numbers of investigators and high turnover rates strain the capacity to conduct clinical studies and hinder efforts to establish a well-trained, experienced base of study conduct professionals. In addition, regional and gender disparities limit professional opportunities, diminish scientific and economic benefits to declining regions, and may contribute to future difficulties in recruiting representative populations.

A question of survival

"Pharmaceutical companies are literally driving good sites in the United States out of business," an investigator in California recently told me. "The struggles of being an investigative site today are chronic and systemic across the industry," added a Maryland-based principal investigator. "The question I often ask myself is 'Why stay in this enterprise?' At the core is an altruistic desire to contribute to science and the advancement of treatment. The picture is bleak, but it is not so horrendous that those who understand the business of clinical research cannot survive."

It is important for sponsors and CROs to understand how "bleak" the picture may actually be. Through recent interviews and discussions with principal investigators, I am finding that—with few exceptions—individual and network-based investigators are struggling with a myriad of challenges.

Cash flow woes

The largest concerns expressed by investigators revolve around the size of grant amounts and the slow payment process. Investigators may have a legitimate concern: A review of more than 52,000 study contacts shows that grant size has been relatively flat since 1998 while the number of procedures per study protocol has risen dramatically. The average dollars paid to PIs per procedure per patient has declined by 27% in that time period.⁴ And it now takes sponsors half a year, almost 140 business days, to pay an investigator for work already performed. This represents a 77% increase over 2001 levels. Payment deadlines are often violated. Screen failures may not be paid for at all. Then there's the laundry list of expenses that are not remunerated and over which sites have no control, like serious adverse event reporting and add-on amendments to the study protocol.

"I enjoy investigating new and interesting drugs, take pride in the work our site produces, and have a degree of prestige in the patient and medical community as a result," said a Texas-based investigator. "But I pay the price in stress, and more work for less pay."

An investigator in Atlanta told me that some community-based physicians get involved as clinical investigators only to find that competition is too intense. "In general medicine, there's not a great deal of viable work out there," he said. "But PIs get into clinical research expecting a big opportunity and then find that they can't get the number of trials that they think they can. We're all competing for that brass ring and it's not easy. And the new investigator also has to get up this steep learning curve to comply with the guidelines and manage the patients."

Other pressures

Indemnification clauses in study contracts are adding to investigators' malpractice risk. Quality performance often goes unnoticed except, remarkably, as a cue for an FDA or sponsor audit. Even the best sites report finding themselves on the receiving end of a 483 for violating a little-known aspect of federal regulations. The Federal Aviation Administration has been known to surprise sites with fines of $50,000 or more, using its authority over the shipment of lab specimens.

Investigators also report that insurance premiums continue to climb, regulatory paperwork grows more cumbersome, and sites' best coordinators are being lured away by study sponsors and CROs offering more competitive compensation packages. The research work itself is being outsourced to sites abroad with large treatment-naïve patient populations and investigators able to do the work for a fraction of the cost in the United States.

"It's hard enough to compete domestically. Sponsors treat experienced sites the same way that they do the novice ones," lamented a PI with a large Midwestern site. "Yet experience has shown these thrifty sites underenroll, produce unreliable data that can't be used, and cost the sponsor in more frequent monitoring visits per patient enrolled than do experienced sites."

A role for sponsors and CROs

Clinical investigators are quick to point out ways that sponsors and CROs could improve the situation. In my interviews and discussions, several investigators suggested that sponsors do a better job of screening prospective sites in order to identify more experienced candidates. Investigators also recommended revisiting contracts and budgets, shortening payment cycles, offering higher startup payments, and providing support to help sites better manage regulatory requirements. Investigators are also hopeful that the adoption of new technologies will eventually streamline the data collection process, result in more rapid payment for work performed, and replace some of the time-consuming face-to-face meetings.

"The best hope for investigators is to play it smarter," said one investigator. "They have to advocate for themselves. Yet most sites are too immature to know how. Only one in four investigators are in research greater than four years. That keeps the industry in an infantile position."

"Recognizing the problem is half the battle. If you're underpaid, you're under-valued," said another investigator. "Investigators need to acknowledge that clinical research has to be run like a business. We've been saying it for years, but we have to do it."

"Sponsors and CROs want to place trials at sites that are financially viable. Anything less places the patients at risk and jeopardizes the integrity of the data," commented an investigator from Florida. "But they're unlikely to listen to sites that can't substantiate their costs—and most sites can't. Sponsors aren't listening and they consider investigators as complainers. Solid, site-specific performance and financial metrics may be the only way to gain an audible voice at the negotiating table," she said.

"At the root of the problem are contracts, budgets and payment schedules. They need to be overhauled," said a Chicago-based investigator. "The majority of sites in my network feel that the terms and structure of research agreements are not reasonable any more. Sponsors need to revisit the conditions under which they're holding investigators accountable. I think they would see that they are pushing the PI too far in many cases," he said.

At a critical stage

An increasing proportion of active clinical projects have now entered into later stages of drug development. At the same time, R&D costs, cycle times, and the scope and complexity of clinical trials are rising. An unstable clinical investigator community will not serve growing sponsor and CRO demand for strong and sustainable study conduct performance while ensuring patient safety. Sponsors and CROs need to play a more active role in understanding and addressing where their efforts to manage clinical investigators have undermined relationship effectiveness.

"Investigators are not purely vendors—they are the bridge to the patient, and ultimately to the public," concluded a New York-based investigator. "Right now, principal investigators are coming in and out of a revolving door. This doesn't benefit anyone. It's not just the investigator's problem. Sponsors and CROs need to understand that there are things that they can do to improve the situation too," he said.

Kenneth A. Getz MS, MBA is a Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: kengetz@ciscrp.org

References

1. Tufts Center for the Study of Drug Development Impact Report, 7 (3) 2005.

2. FDA 2005 report on inspection results, www.fda.gov.

3. Western Institutional Review Board, 2005.

4. Tufts Center for the Study of Drug Development Impact Report, 7 (3) 2005.