Kenneth A. Getz

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.

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.

"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."