Harold E. Glass, PhD

The COVID-19 pandemic has had devasting effects in a broad range of medical, economic and social areas in the United States and many other countries. Just what impact though has COVID-19 had on the volume of US pharma-sponsored clinical trial activity? Public statements have covered the spectrum, from minimal to devasting. However, the 

 actually enables us to answer the question directly; the affect on the total volume of US clinical trial activity has been quite limited. Total pharmaceutical industry spending, as measured by Open Payments, on US patient enrolllment and treatment activities did not decline in the years 2020 and 2021 from the baseline pre-COVID 2019 level.

Open Payments is the result of a federal law, the Sunshine Act. For each year since the end of 2013, pharmaceutical companies with at least one marketed product have had to report all payments, over a low threshold, to physicians and other medical professionals. These Open Payments include two types: general and research. General payments relate to pharmaceutical companies’ payments to medical professionals when marketed products are involved. Research payments though are more restricted, and can be broken down in what is often called clinical grant payments. These cover virtually all clinical investigators and their clinical trial experience across all indications. Other related payment activities, such as consulting, are reported separately and not included in the Open Payments data used for this analysis. All payments must be reported, but the publication of certain research payments may be withheld for up to four years. However, few companies withhold the public release of these data. We estimate that 97% of all US pharmaceutical clinical grant payments are reported, and eventually made public in the Open Payments database.* This report research data only for pharmaceutical company sponsored clinical trials. The Open Payments research (clinical grant) data shown below adjusts for any such delay, even if this reporting delay is minor.

The Open Payments database allows us to measure directly the impact of COVID-19 on US industry-sponsored clinical trial activity through the end of 2021, the most recent year for which these data are currently available. COVID-19 may have negatively affected the launch and execution of clinical trials in two ways. First, COVID-19 clinical trials may have displaced other clinical trial activity. But did this displace non-COVID-19 related clinical trials? Second, the COVID-19 pandemic itself presented major operational challenges to clinical trials of any sort. Recruiting patients, treating these patients, and validating source data are but a few areas where the pandemic must have made the conduct of clinical trials particularly difficult. Since we coded Open Payments data by individual study indication, we are able to answer both questions.

ClinicalTrials.gov shows virtually no decline in the number of US sites opened for Phase II and III clinical trials between 2019, 2020, and 2021. However, opening sites may not adequately capture the level of patient activity taking place. Sites may be opened, for instance, but lag in the recruitment and treatment of patients. There is no way to assess actual activity levels from the ClinicalTrials.gov database. However, Open Payments provides the appropriate data since the payments are predominately associated with patient enrollment and treatment activity.

Open Payments data show a constant, if undramatic, increase in US clinical trials between 2017 and 2021, a trend dating back to 2013 when the database first began. Even if we were to remove COVID-19 related spending from the 2020 and 2021 time period, there is no decline in non-COVID related study spending. Moreover, the total increase strongly rebounded in 2021. The COVID-19 pandemic did not reduce overall US industry-funded clinical trial activity. While COVID-19 studies themselves may have paused, but not due to reduced non-COVID clinical trial activity.

Pharmaceutical company US clinical research spending, reported in Open Payments ($billions)

Two related questions remain. How did COVID-19 affect commercially funded clinical research outside the United States? And, what will the 2022 data show? Open Payments does not address the question of ex-US clinical trial activity. The data for 2022 will become available in June of 2023.

*A separate analysis of these non-reported data showed that most of these studies were early phase studies from quite small pharmaceutical companies, constituting a very small total share of all commercially sponsored US clinical trial activity.

Articles

Research shows there was no decline in non-COVID related study spending during height of pandemic.

The Limited Impact of COVID-19 on US Clinical Trial Activity

	The Sunshine Act mandates that all payments by pharmaceutical and medical device companies to a range of healthcare providers be reported in the Open Payments database. One major consequence of this database is to make the investigator relationships with individual pharmaceutical companies transparent to others. An example can be found in the clinical trial payments captured in the research payments file of Open Payments. These data are providing a level of detail about the clinical investigator landscape not accessible until recently. For example, it is now possible to understand how individual pharmaceutical companies use their investigators. Pfizer data are illustrative.

	We examined how often Pfizer used their individual investigators between 2014 and 2016, the three full years for which data are currently available to the public. To do this we first identified investigators used by Pfizer in 2014 and followed their usage through the end of 2016. Of course these investigators could have been used by Pfizer during time frames not covered by the analysis.

	With Open Payments it is possible for Pfizer to better understand its own investigator usage pattern and how that pattern may differ from the practices of other pharmaceutical companies. A case in point is the one time investigator. Pfizer does a much better job than the rest of the industry avoiding the use of investigators who never do a second clinical trial for any pharmaceutical company. At the overall US industry level, 30% of all investigators who conducted any clinical trial for any pharmaceutical company in 2014 failed to do a second clinical trial between 2014-2016. For Pfizer, thirty five percent of 2014 sites are not used a second time. A more detailed review in Open Payments of these one-time Pfizer investigators highlights Pfizer’s success in avoiding true one-time investigators. Pfizer used 1,214 investigators only once between 2014-2016. However, most of these investigators, 891 worked on clinical studies for other sponsor companies. Only 323 never did a second clinical trial for any other company, a percentage much lower than the industry average. 

	Pfizer’s Use of US Investigators, 2014-2016

With Open Payments it is possible for Pfizer to better understand its own investigator usage pattern and how that pattern may differ from the practices of other pharmaceutical companies.

Understanding the Investigator Usage of Individual Pharmaceutical Companies; the Pfizer Case

	ClinicalTrials.gov has become a widely used operational and research tool. ClinicalTrials.gov has now reached the credibility level that almost all major medical journals require clinical trials discussed in that specific journal be available in ClinicalTrials.gov. The level of missing data for these mandatory variables, with one major exception, rarely exceed 2-3%. This exception is investigator detail. Not all sites are included or updated in ClinicalTrials.gov. Moreover, the data are rarely complete for the sites which are entered. For the sites in ClinicalTrials.gov, the country is almost always given. For US sites, the relevant zip code is frequently given.  Usually no other information is given, although the database does require that the name and address of the investigator be indicated.

	Open Payments helps fill this information gap for US sites. Open Payments, mandated by the Sunshine Act, contains all the payments by pharmaceutical and medical devices manufacturers to certain healthcare professionals, including physicians. The payments are of two types, research payments and all other general transfers of value. With the research payments, it is possible to identify the specific clinical trial for which the respective research payments were made to the clinical investigators.

	A Sanofi study illustrates the data available from Open Payments. Sanofi conducted a phase 3 study between 2013 and 2014 with US sites, with a study title:

	An Open-label, Randomized, Parallel Group Study Assessing the Immunogenicity and Safety of Sarilumab Administered as Monotherapy in Patients with Rheumatoid Arthritis.

	Sanofi provided a listing of sites with zip codes to ClinicalTrials.gov, but no other public investigator identification information. Open Payments provided that detail for each investigator and identified three more physicians not listed in CT.gov. From Open Payments for each investigator we have the institutional or practice name, the physician’s name, exact address and specialty. The Sanofi detail can be replicated for a near census of US clinical trials. With Open Payments US investigator names and experience will become public knowledge.

With Open Payments US investigator names and experience will become public knowledge.

Investigator Detail in Open Payments

	For a number of years there has been discussion about the relative levels of clinical trial activity in the United States and Western Europe, on the one hand, and in the emerging countries, on the other. This seems to be one of the more popular topics at drug development professional conferences. A previous column (Applied Clinical Trials Dec 5, 2016) with ClinicalTrials.gov data indicated that the absolute and relative amount of commercially sponsored clinical activity in North America and Europe remained unchanged between 2008 and 2013. More recent ClinicalTrials.gov data indicate that the United States remains the central location for clinical trial activity.

	Clinical trials are conducted to gather patient data, the most critical element in the new drug approval process. But the placement of clinical trials is a function of a number of elements, not the least of which is a country’s market attractiveness. Through clinical trials a sponsor company learns more about how the new drug might be used by medical professionals in a particular country. Clinical trials gather information, but they also signal information to a market about a sponsor company’s longer term new drug launch priorities. On a cost per patient basis some of the newer geographies are frequently lower than more established areas like the United States and Europe. However, many companies have found that the costs of conducting clinical trials in these newer geographies to be sometimes higher than originally anticipated when all the site operational costs are taken into account. The United States despite the higher costs of investigator payments remains the most attractive market for new drugs.

	Over time it has become clear that there is a reporting lag of about six months to a year in ClinicalTrials.gov, a lag which increases to about a year for ex-US data. Over time as additional data appear the 2015 and 2016 will most likely resemble the 2014 figures. Nonetheless, the current ClinicalTrials.gov data show no trend away from the United States as a place to locate clinical trial sites. Discussions about conducting clinical trials in new geographies should remain an important topic at professional meetings, particularly for the more exotic locations.   

					Total Sites in Industry Sponsored Phase 3 Studies

					Percentage of Sites in the United States

More recent ClinicalTrials.gov data indicate that the United States remains the central location for clinical trial activity.

The US and the Location of Clinical Sites

	Open Payments, a database mandated by the Sunshine Act, requires that all pharmaceutical and medical device companies report all their payments to certain medical professionals, including doctors. The reason for that payment must also be given. Any payment associated with a clinical trial must be associated with a specific protocol and be covered by a written agreement. The first year’s data, 2013 only covered a partial year. The releases for 2014, 2015, and 2016 cover the respective full year. Since 2013, 48443 US clinical investigators took part in industry sponsored clinical trials conducted in the United States and its territories. About 29.5% of these investigators did only one study between 2013 and 2016. So the number of active investigators is very close to 34,000. Nonetheless, the pharmaceutical industry is constantly looking for new investigators. 

	A potential source may be the investigators who conduct clinical trials for non-commercial organizations such as the NIH and universities. There are a large number of clinical trials, especially phase 2, sponsored by non-commercial organizations. At one end of a continuum, many of these experienced investigators may not wish to take part in commercially sponsored clinical trials. At the other end of the continuum, many of these investigators may already participate in the commercially sponsored studies. But given the size of this particular investigator pool, pharmaceutical companies may benefit from understanding this group of physicians, and by developing sustained programs to reach these physicians.

	Non-commercial clinical trial activity is especially concentrated at phase 2. ClinicalTrials.gov data indicates that non-commercial sponsor organizations such as universities and hospitals concentrate their activity in phase 2 studies. Larger more expensive phase 3 clinical trials are done more often by pharmaceutical companies and probably large public organizations such as the NIH. Commercial phase 3 studies are generally larger, with over twice as many sites as non-commercially sponsored studies. Critically though, almost all the sites in non-commercial studies are located in the United States in contrast to commercially run phase 3 clinical trials. There may be a potentially rich pool of underutilized investigators working on clinical trials sponsored by organizations besides pharmaceutical companies. 

With the pharmaceutical industry looking for new investigators, a non-commercial clinical trial has become an under appreciated source.

Non-Commercial Clinical Trial: An Underappreciated Source of Clinical Investigators

	Clinical trial sites in many countries are often heavily concentrated in hospitals and similar institutions. Even within the United States many health care professionals probably think that is the case for the United States as well. Data from Open Payments, the database mandated by the Sunshine Act, definitely show that a large proportion of clinical trial work is done in physicians’ practices rather than hospitals. 

	As of 2015 there were 5,564 registered US hospitals, and only 22% of these participate in commercially funded clinical trials. Open Payments refers to these hospitals as teaching hospitals. A teaching hospital is broadly defined to include any hospital anywhere in the United States or its territories receiving Medicare, as well as indirect or direct graduate medical education payments.

	There are any number of reasons a study may be done at an institution rather than a private practice. The study indication of course leaps out as an explanation. In-patient indications, for instance, must usually be done in hospitals. In addition there might be particular expertise or a specific opinion leader on staff at a particular hospital. In addition study conduct costs and overheads at hospitals often exceed comparable private practice costs. Open Payments indicates 80% of all investigator payments go to physicians working in private practice. Few doctors conduct clinical trials in teaching hospitals alone. The large majority do all their clinical trial work in private practice settings. Slightly over one in ten work at both teaching hospitals and private practice.

	Where US Investigators Conduct Clinical Trials, 2016

A data analysis focusing on where US investigators conduct clinical trials.