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Sponsors have been addressing the problem with initiatives designed to find, attract, and retain patients in clinical trials more effectively.
Sponsors in drug development face several complex barriers to success, yet one of the most intractable challenges is patient enrollment. In fact, the issue of delayed enrollment not only impacts trial timelines, but more critically, trials are being canceled because of it, preventing investigators from determining the safety and/or efficacy of what could be promising new therapies. Specifically, in a review of more than 8,000 trials on clinicaltrials.gov, 12% of trials were terminated, and of those, nearly 40% were terminated because of insufficient enrollment.
Many sponsors have long been addressing this problem with initiatives designed to find, attract, and retain patients in clinical trials more effectively. These approaches, however, may only scratch the surface of a much deeper-rooted problem: the dearth of available, experienced, and knowledgeable investigators who know how to navigate the increased complexities of today’s clinical trials and efficiently recruit patients.
Sponsors are in crisis mode
Sponsors want their studies to succeed, and most believe their trials will operate in an efficient, streamlined manner. Unfortunately, according to the Tufts Center for the Study of Drug Development (CSDD), the enrollment numbers are stacked against them: 37% of investigative sites under-enroll and 11% fail to enroll a single patient.
These numbers come with a financial cost. A study from Covance found that between 2006 and 2010, the global pharmaceutical industry wasted nearly $2 billion on startup costs for non-performing sites.
Furthermore, changes in trial protocols and development practices that aim to improve the success rate of clinical trials can actually make patient recruitment more difficult for investigators. As sponsors adopt innovative trial designs, such as adaptive designs that incorporate a number of different cohorts, it has become more difficult to meet enrollment targets. This is because in the era of precision medicine, in which clinical trials focus on narrower indications, investigators must be more selective in their recruitment efforts, leaving a smaller pool of patients that fit the eligibility criteria for a given study.
Investigators are being left out of the equation
As clinical trials become more complex and varied, it is becoming harder for sponsors to find appropriate investigators that have relevant experience. Sponsors were once able to screen potential investigators for their experience in a specific disease. Now, in pursuit of precision medicine, sponsors are embracing so-called basket trials, wherein a drug is tested on a specific genetic mutation, rather than a disease. This requires that they find investigators who have deep experience in narrower indications; however, it’s challenging to identify an investigator’s area of expertise as it relates to mutations, as these data have not traditionally been tracked.
The One-and-Done syndrome
The number of investigators involved in clinical trials is dropping precipitously. In fact, many investigators are dropping out after only one trial, fueling what’s being called the “one-and-done” syndrome. A survey on this subject, funded by the Food and Drug Administration (FDA) and the Clinical Trials Transformation Initiative, showed that 54.2% of respondents were classified as one-and-done. Likewise, a study conducted by the CSDD found that the principal investigator (PI) landscape remains highly fragmented, with heavy turnover, particularly among inexperienced investigators. This conclusion resulted from a CSDD analysis of information from the Bioresearch Monitoring Information Database from 2008–2015, which revealed that half of all PIs who filed a single Statement of Investigator form 1572 each year chose not to file again in subsequent years.
Our internal data sources show a similar decline in the number of investigators. In the last three years, the percentage of investigators experienced in conducting Phase 3 trials has dropped from 46% to about 22%, leading to increased competition to recruit the same experienced investigators. This problem will escalate as older investigators retire and new investigators attempt one trial, and then quickly drop out.
When it comes to patient enrollment, investigator experience matters. According to our data, investigators with at least four studies under their belts had non-enrollment rates of about 13%, while those who had conducted three or fewer studies had non-enrollment rates of 25%. Consequently, as the pool of experienced investigators shrinks, enrollment rates in clinical trials will only continue to falter, applying greater pressure on an already fragile clinical trial infrastructure.
A potential solution: support young investigators
To replenish the investigator pool, sponsors need to identify and invest in new investigators who may start as sub-investigators while being mentored by the PI, and who may possess a tier-2 or 3 track record of enrollment. Their only hurdles to becoming top-tier investigators are a need for clinical research support, and training with respect to their responsibilities. Support could entail:
Sponsors also need to do a better job tracking investigator experience, taking into account factors such as how many patients an investigator has previously enrolled, and the number of studies they’ve completed. They must also start tracking and capturing an investigator’s experience using factors not historically captured, such as experience on trials focused on specific gene mutations, the number of patients screened for previous studies, and/or the number of study coordinators at the site. Finally, a sponsor’s profile should contain data that can help sponsors evaluate protocol feasibility, contract research organizations, investigative sites, study designs, relationships between investigators, and performance data on FDA-regulated investigators.
Sponsors often gather these data from databases such as Citeline, the Shared Investigator Platform, and clinicaltrials.gov. However, none of the information housed in these databases is independently verified and, therefore, may be subject to inaccuracy caused by sponsors who may be misremembering or forgetting critical information. On the other hand, WCG Clinical’s Knowledge Base is composed exclusively of FDA-verified information. Their FDA-verified information consists of experimental protocols.
Just as precision medicine’s aim is to develop the right drugs for the right people, a sponsor’s aim should be to find the right investigators for the right trial-not necessarily the most experienced investigators, but the ones who are familiar with the appropriate techniques and disease areas for a study. With a little training and support, these investigators are better positioned to deliver the results sponsors need, including an efficient recruitment program that can save a trial from likely failure.
Suzanne Caruso is Vice President of Clinical Solutions, WCG