Number of global clinical PIs remains a mystery
Sunday, November 1, 2015
How many clinical trial investigators are there in the world? In fact, no one really knows.
Estimates about the number of global Principal Investigators (PIs) vary wildly, ranging from about 40,000 to nearly a half-million, and depend on the criteria used to define the landscape. Researchers disagree about the most accurate sources for estimating the PI landscape size. And while many different investigator databases have been created, they are not complete lists of all global investigators that cross-reference each other. In addition, questions remain about whether numbers are inflated when databases are used for marketing purposes.
“It’s a little like trying to estimate the size of a crowd on the National Mall in Washington in the dark. You might be able to do it during the daytime when you can count everybody, but we are really working in the dark,” said Greg Koski, Ph.D., M.D., who is CEO, president and co-founder of the Alliance for Clinical Research Excellence and Safety (ACRES), a nonprofit organization working to build a global network of accredited research sites. “I don’t think anybody has good information about what the actual numbers of sites and investigators are. The best we can do is look at the range.”
High turnover rates and the large number of investigators who quit research after conducting only one trial also make it difficult to calculate the PI landscape size. At the same time, there is no common agreement on how to define which investigators should be included in the total sum. Some databases keep the names of inactive investigators on file and include inexperienced physicians interested in future research opportunities. Other assessments only count active investigators.
“I’m not sure that it’s a useful number to get to,” said Paul Evans, Ph.D., global head of feasibility and enrollment solutions at Parexel. “Even getting to the number is a bit like nailing jelly to the wall. What is an investigator? Is it somebody who has done a study sometime? Is it an investigator who has done more than one study? Is it a doctor who would like to do a study and is registering to be an investigator? The definition is quite important, which is probably why you see such a wide range of estimates on the number of PIs.”
At the end of the day, the number matters for those trying to understand the capacity of the PI landscape. Is there a surplus of relatively inactive investigators available to conduct clinical trials? Or is it a much smaller community that sponsor companies and CROs can count on to get research done?
In the following, CenterWatch takes an in-depth look at a wide range of estimates about the number of global PIs and how different researchers and organizations define the landscape.
The Tufts Center for the Study of Drug Development (CSDD), which has the most frequently quoted data about the size of the PI landscape, has found there are nearly 40,000 unique active investigators worldwide conducting at least one FDA-regulated clinical trial. Tufts CSDD bases its conservative assessment largely on Form FDA 1572 information that is filed and captured on the Biomedical Research Monitoring Information System (BMIS), a public database maintained by the FDA’s Center for Drug Evaluation and Research (CDER). Tufts CSDD compiled and analyzed 1,309,392 records in December 2014 for its most recent global investigative site landscape analysis led by Ken Getz, director of sponsored research programs and associate professor, Tufts CSDD at Tufts University Medical School.
The Tufts CSDD researchers count only investigators conducting industry-sponsored interventional studies for medical treatments. Duplicate listings are identified and removed from the final tally.
Investigators are considered inactive if they fail to have a second 1572 form listed on the BMIS database within four years. Tufts CSDD found that half of all PIs listed in the 2009 BMIS database have yet to file another 1572 form, up from 40% four years ago. In addition, the least active investigators, defined as those who only filed a single 1572 per year, had the highest turnover rates in the study. The annual growth rate in the number of PIs fell to 3.3% between 2009 and 2013 compared with 4.1% during the previous four-year period, suggesting that a small number of PIs are overseeing more trials. Half of all investigators in 2013 were first-time filers and only 10% conduct five or more studies a year.
“Our research shows that the investigative site landscape is very fragmented and highly unstable given the turnover rates and the vast number of small, novice investigators conducting one or two clinical trials each year,” said Getz.
Tufts CSDD has acknowledged limitations to its BMIS data analysis. The 1572 forms only represent active investigators for FDA-regulated trials, which means researchers need to generalize findings across other mature markets to estimate the size of the global landscape. In addition, sponsor companies are required to collect a 1572 from each PI involved in a trial conducted for an Investigational New Drug (IND) application, but the sponsors are not required to submit the forms to the regulatory agency. Most sponsors, however, make it a practice to file 1572 forms with the FDA because it’s a convenient way to submit information the agency requires in some way about investigators. A previous Tufts CSDD survey of sponsor companies found that a high percentage of respondents typically submit 1572 forms to the agency, even though they are not always filed in a timely way.
“Sometimes the reports of the 1572 filings come in late,” said Getz. “But the FDA eventually puts them in the database. We then update our figures to align our analyses with the agency’s data. We would like to be regularly interrogating the ClinicalTrials.gov database, but there are still a number of issues with its integrity.”
University of the Sciences
Researchers at the University of the Sciences in Philadelphia, who calculate the size of the PI landscape using data from ClinicalTrials.gov, estimate there are 50,000 global PIs conducting studies for pharmaceutical companies. Harold Glass, a dean’s professor at the university, believes cross-tabulating the number of sites in ClinicalTrials.gov with the sponsoring organizations—whether industry or government—can give a more accurate view of the number of global PIs than other sources, since federal law requires that all FDA-regulated studies be registered with the database. It’s reasonable to expect that the database is a good representation of all phase II-III global trials, according to Glass, since it is unlikely that companies would want to exclude the branded prescription market in the U.S.
Glass believes estimates of the PI landscape based on BMIS data are too low, since sponsor companies are not required to submit 1572 forms to the regulatory agency, while the numbers in the largest investigator databases are inflated by organizations that have a financial interest in selling a related product or service.
“These claims are not reviewable by a third party. No one has ever audited them,” said Glass. “I don’t know the actual number. I do feel, though, that the high numbers we see are largely marketing numbers, numbers derived erroneously from databases such as BMIS or wishful thinking.”
The 50,000 global PI number was calculated with data from ClinicalTrials.gov and independent research as follows: Pharmaceutical companies open about 30,000 sites annually, which means that over a three-year period, about 90,000 sites initiate new studies. Glass said ClinicalTrials.gov defines a site as “one study at one place,” so the terms “site” and “Principal Investigator” are used somewhat interchangeably. During the three-year period, the university researchers found investigators conduct a median of three studies per year: 90,000 study sites, divided by three studies, yields 30,000 investigators. Another 20,000 investigators were added to take into account investigators who do fewer than the median number of studies each year and might have been less likely to report their study activity.
In the ClinicalTrials.gov database, however, it can be difficult to distinguish trials that are just starting up, which leads to a timing issue with the data. Another shortcoming of the ClinicalTrials.gov database, which Glass believes will be resolved in time, is that many large sponsor companies don’t list specific information about their sites. For example, in some cases, the study listings will not include information about any of the countries involved in the study, the number of sites involved or the names of investigators.
“Sometimes they just give you the ZIP code. So if you want to come up with a number of Principal Investigators from ClinicalTrials.gov, you still have to triangulate it. But one of the reasons ClinicalTrials.gov came into existence was so that people could look up the number of investigators,” said Glass.
Investigator Databank hosted by DrugDev
The Investigator Databank, a collaboration between Janssen Research & Development, Lilly, Merck, Pfizer and Novartis to share investigator information governed by data-sharing and privacy rules in a global database, has amassed a list of about 150,000 PIs worldwide. The largest percentage of investigators is from Europe (40%), followed by North America (32%), Asia-Pacific (18%), Central/South America (9%) and Africa (1%). As additional pharmaceutical companies join the service hosted by technology company DrugDev, participants expect the number of investigator listings in the databank to rise.
The service contains investigator names, key site information and operational site metrics from interventional studies conducted by the five pharmaceutical companies from 2008 to the present, including trials overseen by the FDA and other global regulatory agencies. Member companies send DrugDev copies of Clinical Trial Management System (CTMS) data each month to keep the data updated. A unique number is assigned to each person and facility that touches the platform and DrugDev uses sophisticated tools to identify and remove duplicate investigator or site information across the sources.
The Investigator Databank also includes listings from DrugDev’s own network of 80,000 active investigators across 115 countries. The DrugDev Network, which began in 2009, was built with investigators who self-register through a website and peer referrals. Participants are contacted every six months to confirm they are still interested in conducting industry-sponsored research. A recent survey of DrugDev network investigators found that 75% of the 572 respondents have conducted more than five studies in the past five years, while 4% have done zero or one study during the same timeframe.
By design, inactive investigators are not removed from the cross-pharmaceutical Investigator Databank, which became operational in 2012. For consenting investigators, sponsors share data including investigator/site contact details, an inventory of site infrastructure and training records, past trial participation and site-level recruitment metrics. Keeping that data in a central repository can help reduce the administrative burden related to conducting clinical trials, which is a major reason investigators drop out of research, and allows sponsor companies to better match investigators to future protocols.
“The idea is that investigators will become more of a shared resource than a competitive resource,” said Elisa Cascade, president of data solutions at DrugDev. “Because of that, we have been very careful not to prescribe how one should evaluate an individual investigator because that could be seen as antitrust or collusion. Instead, what we do is make the contact details and the enrollment metrics of investigators visible and then each individual company can choose who they wish to contact for potential participation in specific clinical trials.”
About half of the PIs listed in the Investigator Databank have conducted only one study for a member company since 2008, which is consistent with investigator turnover rates cited by other sources. About 15%, or roughly 22,000 investigators, have conducted five or more studies; 85% of investigators in that group work for multiple member companies, which suggests that only a few professional sites are doing the vast majority of clinical trials for the databank’s members. Overall, about 25% of the investigators work with more than one participating company. As more sponsors join, and more data becomes available, Cascade expects the exact picture of the investigator landscape will become clearer.
In a similar industry collaboration, TransCelerate BioPharma, a nonprofit organization that brings together some 20 biopharmaceutical companies to share resources and work toward improving the overall efficiency of the R&D process, soon will launch its own global registry of qualified investigators, which also will be hosted by DrugDev. Cascade said once the TransCelerate BioPharma initiative becomes operational, the industry will have an even better view of the size of the global investigator landscape.
“Once the project has been launched, we will have even more investigator information coming through the platform and likely a higher estimate of what the unduplicated number of PIs will be. As these collaborations grow, eventually we will get to the point where we have a solid base. Every data source you add should contribute fewer new investigators because of the overlap, but we have technology to be able to look at the aggregate numbers across the platform to get a good sense of what the entire pool will be with permission from the members contributing data,” she said.
Investigator Location Services
Investigator Location Services (ILS), one of the largest study brokers in the U.S., has built a database of 27,000 experienced investigators across the country and 1,200 in Canada during the past 14 years. ILS President Joe Bollert, Ph.D., who has more than 40 years of experience in the drug development industry, believes his databank covers most of the active investigators in the U.S. today. The database includes about 12,000 site profiles; some sites represent a single investigator conducting studies, while others represent multiple investigators.
Investigators can submit a profile to join the ILS database, but only those with experience are accepted. The company also uses ClinicalTrials.gov to identify active investigators and help build the database. Investigators in ILS’s proprietary database typically have 10 or more years of clinical research experience; physicians who have conducted only one study many years ago or who haven’t yet conducted any clinical research are not included.
ILS investigator recruiting services are free to sponsors and CROs. Investigators pay ILS a commission after they are chosen for a study.
“We want to have a live, up-to-date database,” said Bollert. “I want investigators who are showing five or more years of experience so I can present good credentials to clients for consideration. I am not interested in a physician who did one study in 2010. In my mind, that person is not a player. Their CV will not look particularly good. I want to present people who will look good and have the highest chance of being used by the sponsor to generate revenue for our business,” he said.
Once an investigator meets ILS’ screening requirements, the company doesn’t track how many studies he or she conducts, or remove inactive investigators. Names are taken off the list upon request from the investigator or, in rare instances, if the FDA disqualifies an investigator.
CRO investigator databases: Quintiles and Parexel
Global CROs also maintain their own databases of investigators, which are typically built with data about PIs they have worked with in the past and those who sign up through websites to be considered for study opportunities. The databases are used not only to identify potential investigators for research opportunities, but also to assess study feasibility and inform long-term planning.
Quintiles, the world’s largest CRO, has a global database with more than 260,000 clinical investigators listed in its CTMS. More than 60% of the sites are outside of the U.S. The CRO began to compile its official investigator database almost 20 years ago with the introduction of a new CTMS that could help identify investigators with the right population and performance metrics to meet the needs of a particular project.
The database includes profiles of investigators who have worked with Quintiles on a previous clinical trial, data from public databases and information from questionnaires completed by other physicians—both experienced investigators and those new to research—who register to join the network for clinical trial opportunities.
“At Quintiles, we have a really large pool of investigators we can pull from. But we continue to do outreach to physicians to support their interest to become investigators,” said Jeanne Hecht, senior vice president and global head of site and patient networks at Quintiles. “Because of the various niche populations, rare diseases and even biosimilar development, there is a need to access physicians who want to be part of the research environment. We invest in those resources.”
Duplicate entries are removed from the investigator database and sites are contacted routinely to update data. Investigators are not removed from the network, however, if they are inactive for a number of years.
Parexel has a database of more than 250,000 investigators who either previously have worked with the CRO on a trial or have registered an interest to participate in clinical research. The CRO’s site intelligence team regularly monitors and cleans the database. Inactive investigators are not removed, but they are flagged; some of them have been inactive with Parexel, but data sources show they have been involved with studies at other organizations. A total of 34% of its investigators have conducted at least three clinical trials and 20% have conducted at least five trials.
Executives at both Quintiles and Parexel said that rather than focus on building the overall number of investigators in their databases, they work to develop strategic relationships with a core group of experienced investigators and high-performing sites.
Quintiles has formed strategic partnerships with about 38,000 investigators, who have all participated in five or more Quintiles studies globally, through its Prime and Partner Site programs; the 24 Prime Sites are large hospital systems, academic institutions and healthcare provider networks, while the 1,200 Partner Sites include a network of investigators from smaller clinics and hospitals. Parexel’s Site Alliance network consists of more than 300 sites, which provide access to 8,000 investigators worldwide.
“Most people have the perception that you need a very large investigator base. That is because we tend, as an industry, to have a build-and-break mentality, so we rarely develop long-term strategic relationships with sites. We tend to go from one study to the next and use a different set of sites every time. That is what we are trying to get away from with our Site Alliance network. Those are long-term strategic relationships, not short-term tactical ones,” said Parexel’s Evans.
IMS Health database
IMS Health, which recently acquired ViS Research and its global site selection platform, has a database of 492,000 investigators from 183 countries as part of its Clinical Trial Optimization System (CTOS) offerings. The platform, which combines information collected during the past 10 years from both public registries and private sources, maps where clinical research is conducted down to the institution level and provides investigator profiles, multidimensional analytics on clinical trial infrastructure and patient demographics.
Investigators included in the database have been active in clinical research during the past 10 years. The platform, which is being integrated with other IMS offerings, allows investigators and site administrators to update their own information about qualifications and infrastructure elements. About 32% of the database’s investigators have conducted only one trial during the past five years, which is comparable to industry averages; only 6% of the investigators conducted more than 10 trials in the same timeframe.
The IMS platform also uses healthcare mapping and advanced analytics to identify new potential investigators with the appropriate medical expertise who work at medical institutions that already have the experience and infrastructure to support clinical trials. Fabio Thiers, M.D., Ph.D., director of offerings management, clinical trial optimization solutions at IMS Health and founder of ViS Research, said that because of high turnover rates and the small percentage of experienced investigators involved in research, the “elephant in the room” is that sponsors need to employ research-naïve physicians in order to have enough investigators to conduct large trials.
“You are talking about millions of doctors and hundreds of thousands of institutions that could potential be in clinical research,” Thiers said.
Other commercial databases also have compiled a large number of investigators worldwide. Citeline has 372,000 investigators in its Sitetrove database. Infinata’s BioPharm Clinical database includes 400,000 global investigators; the data was compiled with information from 17 international registries, publications, websites and newswires.
Evaluating landscape capacity
Ultimately, the discussion about the number of global PIs comes down to the question of whether the landscape has the capacity to meet industry demand for research sites. High turnover rates and the number of investigators who leave research after conducting only one trial, however, skew database numbers and make it difficult to determine how many investigators can be counted on for industry-sponsored research. Many of the largest databases include names of inactive investigators or those who have yet to conduct clinical research. Looking at the overall size of a database also doesn’t show if there is an adequate number of investigators to meet demand in specific therapeutic areas.
“The total size of the investigator base isn’t particularly important,” said Evans. “What is important is the experience and performance of investigators and the competition for investigators either in a given therapeutic area or around a specific study. If you are a sponsor and are going to start a study, are there good investigators for what you want to do?”
Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from Columbia University. Email firstname.lastname@example.org.
This article was reprinted from Volume 22, Issue 11, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>