Matthew Kibby

More than 80 percent of patients say they are willing to participate in clinical research studies, but only around 10 percent actually do so.

  Meanwhile, from an investigative site perspective, it is realistic to assume that at least one-third of principal investigators and their staff for a given study will fail to randomize a single patient.

  These are just two factors that make more than 76 percent of all Phase II and III studies enroll more than 90 days late; how can we develop standard procedures to address these shortfalls proactively?

  More specifically, how can sponsors accurately measure the feasibility of a protocol and plan accordingly to achieve timely and cost-effective enrollment and the quality data to advance their pipelines?  

Study "feasibility" is a widely used term in the clinical trial industry among researchers, clinical operations executives, investigative sites, and patient recruitment specialists. However, it is defined differently from sponsor to sponsor—and even from individual to individual—within the same organization.  

"Recruitment feasibility is not as ambiguous as the broader term of clinical trial feasibility," said Mike Neidl, Vice President of Clinical Research at Genzyme Corporation. "Seems to me, five years ago feasibility meant sending out surveys. So formal, up-front feasibility is a relatively new concept, and this is an ideal time to address it." 

True clinical trial feasibility includes strategic, scientific, operational, and patient recruitment considerations—an exploration that is worthy of a series of articles. However, if we focus on establishing a platform for study feasibility through an acceptable definition and general parameters regarding the "enrollability" of a clinical trial—particularly a large-scale, multicenter, global trial—this will benefit sponsor companies and the clinical trial industry as a whole through supporting proactive, early, and efficient recruitment feasibility assessments.  

This article will focus on exploring the definitions and parameters of recruitment feasibility, touching on some key considerations for all trials, and propose a flexible formula to help sponsors be more proactive with regard to their specific protocol scenarios. The goal is to establish components of recruitment feasibility and lay the groundwork for the industry-at-large to collaborate and develop a standard set of best practices—and for each sponsor to modify the standards for their own benefit based on the unique demands of their individual research pipelines.  

Perhaps the best place to start is by establishing where sponsors are frequently misled and misinformed—both internally and through strategic partnerships. Whether recruitment feasibility is considered on its own or bundled in with operational feasibility, the current "standard" often consists of the following steps:  

Medical specialists confirm the protocol design. 

Sponsor/CRO assesses logistical considerations.  

Sponsor/CRO survey sites to determine potential patient numbers for recruitment success.

Unfortunately, from a recruitment point of view, these steps are very broad and can be defined differently by each sponsor. Likewise, each sponsor will vary in the number and type of processes they will then use within each step. Perhaps most importantly, there is no consistent application of a recruitment perspective, or "lens," to the steps. As such, these are all contributing factors that hinder up to 70 percent of trials from meeting their original recruitment targets. Ultimately sponsors pay for inaccurate forecasts either in additional time and/or money, not to mention the costliness of miscalculating the power of a study.

"Before, the feasibility result was mainly the number of patients and the number of sites that a country can commit to," said Jurek Bojanowski, International Clinical Trial Manager at sanofi-aventis. "But this is not real feasibility. Corporate management must do some validation to check not just how many patients and sites a country can provide, but also when and how fast this enrollment can be performed." 

While there are some general standard operating procedures (SOPs) available to research sites for guiding a feasibility assessment,

  sponsor companies have only just begun to define their own SOPs. 

"We consider strategic feasibility to be part of a global clinical development plan for a compound or protocol," Neidl said. "It's a high-level process taking into consideration the market strategy, disease incidence and prevalence, regulatory approach, and country selection, and maybe some preliminary idea for an investigator strategy, such as specialty selection and mix of generalists and specialists." 

Considering the infinite number of potential recruitment conundrums that varying protocols will create, it may seem an insurmountable task to gain a full understanding of how all of these considerations will factor into a successful study. By breaking feasibility into a few key phases, we can begin to prioritize and operationalize our efforts—a process that can be applied to any therapeutic indication or the scope of the research in question.  

"We divide feasibility into two phases, the first being protocol design, and the second operational planning," said Martin Lee, MD, Executive Director of Site and Patient Recruitment for Pharmaceutical Product Development (PPD), a leading global CRO. "It's in the latter process that we consider the regulatory time lines, drug supply, and other factors that ultimately determine whether recruitment will happen in a timely fashion."  

 Figure 1. Example of factors assessed in a site survey. 

Indeed, within the broader scope of operational feasibility for a clinical trial, recruitment feasibility is the process for determining the time frame and parameters necessary for successful recruitment.  

For the purposes of exploring new methods for improving clinical trial enrollment planning and execution, we propose the following definition of recruitment feasibility. 

 Recruitment feasibility is the process by which a clinical study sponsor can forecast and manage the probable randomization rate (number of patients per site per month) for a specific protocol and determine realistic parameters for site enrollment months (number of sites multiplied by number of open-to-enrollment months).

With this in mind, study planners must consider each of the following factors through a recruitment lens. 

 How would each group of study community members respond to this protocol—regulators, investigators, coordinators, project managers, monitors and patients? In what ways might the protocol design be off-putting to one or more of these groups, and can that be changed, or must it be mitigated? Can we afford to prioritize one group over another? 

 While there may be many business reasons to include a specific country—such as market importance, regulatory barriers affecting speed to market, existing relationships with investigators, cost of conducting—none of these exempts a country from a recruitment feasibility assessment. From a recruitment perspective, the goal is not merely to determine which countries should be included, but what will it take within each country under consideration to succeed? What level of recruitment support may be required to offset protocol design challenges?  

 What types of investigators are most likely to be high enrollers for this study? Will that vary by country? Do we have a platform for contracting specific sites in each selected country? What are the likely enrollment rates for sites in each country? Site surveys play an important role in assessing recruitment, however most current models co-mingle recruitment feasibility with site selection—a near guarantee for collecting misleading information.  

While it may seem obvious to include patient perspectives in the recruitment feasibility process, it is a rare sponsor that consistently asks patients for their input. More often than not, investigators, key opinion leaders, or country managers are used as surrogates for patients. 

Brendan O'Neill, Manager in the Patient Recruitment Specialist Group at Merck and Co., agreed with this sequence, "We approach recruitment feasibility in that order—country, site, and patient. It's great to consider the patient level, but if the protocol won't be approved in a country, you're wasting everyone's time." 

Indeed, from a patient recruitment perspective, these four key considerations are the root of most enrollment barriers and certainly a thorough analysis of a given protocol will provide the necessary insight regarding ideal study countries, sites, and ways and means to reach the patients most likely to value study participation. Assuming that we know our protocol and our patients well, let's focus on some key considerations for country and site assessment and selection and how qualitative data collection strategies can be applied universally for all studies, and ultimately applied to a feasibility formula to generate quantitative insights for successful study planning.  

By focusing on business drivers, study planners often prevent a careful examination of recruitment barriers when deciding which countries to select for a global trial. Our recommendation here is to develop a method for a comprehensive assessment of countries that includes business drivers but also many other recruitment-related criteria. 

"We work with the clinical teams as they're designing the protocols to add our recruitment knowledge before it gets out to the field," O'Neill said. "We then work with our international affiliates to make sure, first, that the procedures align with the standard of care so we can assure approval in the country, and second, that the patient populations are available. We take it a step further and work with some of our experienced investigators to determine the likelihood for successful execution of the protocol." 

. Assess recruitment suitability of 25 countries for a Phase III study seeking to enroll 800+ treatment-naïve stage III non-small cell lung cancer (NSCLC) patients. 

We began by conducting research in the 25 potential countries to understand the environment for a study with an active comparator investigating concurrent radiotherapy followed by consolidation therapy. Variables identified as important to recruitment included incidence, healthcare system, attitudes toward the comparator, and the number of competing clinical trials. Once the key variables were in place, we weighted them according to their significance to impact recruitment (Table 1). Using the results of the market research, we rated each of the countries and ranked them from most to least likely to deliver recruitment success.  

Table 1. Each factor is weighted for importance in affecting recruitment and a consistent scoring system designed. 

The research revealed that many physicians in the countries targeted for participation rarely used the active comparator for first-line treatment and in the majority of countries, only some sites had the infrastructure necessary to conduct concurrent radiotherapy. 

For this study, we recommended that the sponsor reconsider the choice of active comparator to align with current standards-of-care in the majority of countries and to focus country and site selection on physicians who continue to practice consolidation therapy. 

Perhaps the most flawed element in the current standard for selecting investigators is the expectation that sites can provide accurate estimates without enough time, information, or compensation for their efforts. Lee referred to an analysis conducted by PPD on site estimates, and he concluded, "We've looked at whether site surveys predict enrollment rates. We don't think they do, if you simply ask them how many patients they can enroll in 12 months. Our data shows that there's almost no correlation between site predictions and their actual enrollment performance." 

Many voices in the industry advocate for a more robust assessment of site enrollment capabilities, including provisions for more detailed protocol criteria and payment for time spent. "I do think sites should be compensated for the time they spend on feasibility estimates," said Neidl, "but it's also important to have some sort of quality assessment on the value of the data returned."  

Even assuming such support, the site selection process is still in need of a broader, more consistent process that can be applied across trials and companies.  

To start, it is important to throw the widest net when considering sites for running a trial. Because every protocol is unique, even choosing sites with prior experience may not ensure enrollment success. Thus, expanding the pool of sites to include some the sponsor or CRO has not worked with can be strategically important.  

In addition, as in country selection, the list of criteria for site assessment must be expanded for truly effective selection. These factors should be weighted by their potential impact on patient recruitment performance for the particular protocol (Figure 2). The results of the analysis will reveal each site's overall recruitment aptitude.  

Figure 2. The benefits of defining recruitment feasibility and developing standard procedures are varied, but they must accommodate the needs and goals that are unique to each study and sponsor. 

Identify 80 sites for a Phase III study of a treatment for immune thrombocytopenic purpura (ITP). 

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