Eligibility determination for clinical trials: development of a case review process at a chiropractic research center

Eligibility criteria for clinical trials are designed to ensure the safety of research participants [1] and reflect the scientific objectives of a study [2]. Automated eligibility determination systems help strengthen the enrollment process by standardizing decisions so that study personnel do not influence the selection process [3, 4]. However, in most clinical trials, investigators or their designees determine whether individual participants meet selection criteria, a process vulnerable to selection bias because of subjective interpretations [5] and the personal views of study personnel [6]. Thus, a challenge for clinical trial researchers is to render eligibility determination with procedures that facilitate consistent decision-making and avoid enrollment error, thereby reducing the opportunity for participant risk [1, 7, 8]. Determinations that lack a consistent and transparent process may lead to an unrepresentative sample [9] and influence the generalizability of study results [10, 11].

Although inclusion and exclusion criteria are reported routinely in scientific publications [12], the specific processes by which participant eligibility is determined and selection bias mitigated are often unclear. A 2010 systematic review studying interventions for improving adherence to eligibility criteria in randomized controlled trials did not find any primary publications describing such procedures [5]. Thus, there is a need to report eligibility determination procedures specifically designed to address potential limitations and to reduce the need for clinical trial managers to continually re-invent this process, which is necessary when established methods are not yet documented or disseminated broadly [13].

This article describes a multidisciplinary eligibility determination process developed and in use at a research center engaged in community-based recruitment for clinical trials of chiropractic care for non-surgical spinal pain. Our research teams developed this process to determine eligibility requiring clinical decision-making for three federally-funded randomized clinical trials in the United States: Trial 1 was a study of spinal manipulation with physiological and kinetic measurements for 221 adults aged 21 to 65 years with sub-acute or chronic low back pain [14]; Trial 2 was a study of collaborative care involving chiropractic and medical care for 131 participants with low back pain in adults aged over 64 years [15]; and Trial 3 was a study utilizing spinal traction mobilization for 48 adults aged 18 to 70 years with neck pain.

The novel case review process presented here is a systematic method to mitigate selection bias in clinical trials of spinal conditions for subjectively determined eligibility criteria such as clinical diagnosis, tolerance of study procedures, participant safety, need for referral, substance abuse, and compliance concerns. Our structured case review process creates an environment for collaborative discussion, which includes vital contributions from clinicians, coordinators, and investigators who fill fundamentally different yet synergistic roles in the eligibility determination process for participants enrolling in a clinical trial. Each panel member is solicited to voice their perspective so as to capitalize on their unique expertise and experience to: i) facilitate clinical and scientific interpretation of eligibility criteria; ii) ensure participant safety regarding the ability to perform and receive trial procedures; and iii) mitigate selection bias by providing an environment to challenge, and therefore encourage, justifiable decision making, consistent with established eligibility definitions.

Unfortunately, we cannot compare the effectiveness or efficiency of our case review process with other methods for eligibility determination as the biomedical literature is silent regarding standard or systematic procedures designed to accurately enroll participants into clinical trials, particularly where clinical decision making is required [5]. This article represents a first step in describing systematic methods that specifically incorporate steps to mitigate selection bias where it is known to occur.

Our case review process is designed with the awareness that clinicians and other healthcare professionals do not always make eligibility determinations consistent with study aims or established inclusion and exclusion criteria. For example, clinicians may avoid enrolling eligible patients into a clinical trial because of the perceived effect such participation could have on the current doctor-patient relationship and to avoid feelings of responsibility if treatments were found to be unequal [25]. Clinicians also may prefer one trial therapy over another [6, 25–27] or avoid enrolling participants due to the concerns that the patient might receive a placebo [28]. Clinicians have reported reluctance to enroll study participants due to the complexity of clinical trials [26], the practical difficulty in following procedures, dislike of discussions with patients regarding uncertainty [25], and excessive time commitment [28]. Interviews with hospital personnel involved in one clinical trial found personal judgments about patients possibly explains why more than 50% of eligible patients did not receive an explanation of a study they could have been involved with [27].

Healthcare professionals may experience conflict between what they understand as their clinical responsibility to the patient and the variables by which trial eligibility decisions should be made. Clinicians may not fully understand key components of clinical research and may lack time, motivation, or opportunity to become knowledgeable about study procedures. However, skilled clinical assessment is usually essential for eligibility determination. To address this issue, our process includes clinicians and other study personnel to confirm interpretation of clinical information and to serve as a quality control mechanism. Our case review procedures and the inclusion of at least one study investigator [29] in the eligibility determination process are intended to prevent selection drift [30] and may be beneficial during trials in which participant recruitment lasts several years, occurs in multiple sites, or when implementation occurs with changing staff.

Eligibility assessment for clinical trials involving non-surgical spinal pain is challenging, in part because of the difficulties in establishing a definitive diagnosis [19, 31]. Other limitations include incongruent terminology among investigators, clinicians, and other study personnel with divergent areas of expertise involved in eligibility determination [32]. Without the use of consistent terminology it is easy to conceive of eligibility decisions that are inconsistent with criteria as envisioned by investigators. One example of inconsistent medical terminology is represented by the term lumbar spinal stenosis. Lumbar spinal stenosis is an imaging finding (a narrowed vertebral canal) whereas the clinical diagnosis of lumbar stenosis syndrome, with subtypes, is characterized by both imaging findings and distinctive symptoms. However, a variety of terms are used to describe the clinical condition [33, 34]. Without clear definitions of the clinical presentation, detailed examination procedures, and the specific factors indicating inclusion or exclusion, determining eligibility in a consistent manner can be difficult.

Because eligibility criteria can be unclearly defined [35] or interpreted inconsistently [27], we provide electronic access to study protocols and definitions during case review meetings. Real-time access to study protocols and definitions is designed to help prevent errant decisions due to complex study designs or protocols, and inadvertent misunderstanding [13]. We believe it is especially helpful when conducting simultaneous trials. We incorporate mandatory review of all eligibility criteria into our case presentations. To further prevent definition drift or systematic misunderstanding we include at least one investigator in case review meetings. The investigator also serves in the role of clarifying definitions, answering questions when they arise, and rendering final determination when consensus is not reached.

While our research center has automated the eligibility determination process for objective criteria, there remain eligibility decisions requiring clinical expertise that are more subjective in nature. The safety of participants when a manual therapy is delivered per the allocation scheme instead of tailored to an individual’s condition [36], the ability to tolerate and safely undergo challenging biomechanical tests without condition aggravation, the need to refer for further evaluation or treatment of a health condition, and the ability of a participant to comply with the study protocol [37] are eligibility considerations that might be swayed by misunderstanding or the personal biases of study personnel. The consensus-based case review process described here uses expertise from across the research team and a stepwise procedure to systematically render and support these decisions.

This eligibility determination process is not without its limitations. The diagnosis of spinal disorders is challenging [31, 38, 39]; participants often present with multiple overlapping conditions and a diagnosis is often based on the clinical interpretation of a wide range of information. We include multiple clinicians to aid this process. However, participants are not present during panel discussions of their case to provide clarifying information about their health history due to the challenges and costs of scheduling this additional visit. When the case review panel determines that additional information is needed, the eligibility decision is pended and the participant is re-contacted by a research clinician. Additional information is then presented to the panel at a future case review meeting for final eligibility determination. In addition, the act of verbally polling the opinions of panel members, necessary to confirm if reasons for individual eligibility decisions are consistent with study aims and operational definitions, can potentially hinder the free expression of thoughts and influence panel members.

This case review process is limited by personnel schedules and the amount of time and resources study teams allot to the process of eligibility determination. Our research center and personnel dedicate more time to the case review process than may be available elsewhere. We estimate that this case review process may work sufficiently with as few as three to four panel members. Further, key components of the case review process are transferrable to other research environments, including those that train students and clinicians to conduct clinical research [40]. We allocate extra time to case review at our research center to clarify procedures and to help educate graduate students serving as panel members on relevant topics such as clinical trial management [13], diagnostic reasoning, research ethics, and other critical aspects of clinical research. With experienced personnel and a developed process, the efficiency of case presentation and eligibility determination can be improved.

Exclusions during baseline visits conducted by a single study coordinator do not involve clinical decision making; rather, they are determined from objective measurements (e.g., weight, pain level). However, it is possible that enrollment error could occur due to incorrect data entry. While individual research clinicians also make eligibility determinations requiring clinical evaluation during the baseline process, these decisions are focused on facets of the participant’s health history that are similarly objective (e.g., surgical status in past year). Though procedures are designed to mitigate selection bias, subjective decisions are still made by personnel subject to unintentional bias and some decisions are made by a single individual when consensus is not reached.

Case review is based on the concept of providing a formally structured decision-making process that includes at least one person from each of four roles: the consenting coordinator, examining clinician, project manager, and an investigator. It also includes designated steps to facilitate thorough case presentations, incorporate user-friendly and secure access to operational definitions for eligibility across multiple trials conducted simultaneously, moderate structured member discussions, and provide a formalized decision-making process to render eligibility determinations that reflect the scientific objectives of a clinical trial.