Summary:
What if the majority of new, trans-formative discoveries in clinical research have nothing to do with devices, pharmaceuticals or behavioral interventions? Answering the question, 'Is clinical research relational?', sets the stage for a wave of new and innovative tools in research execution and subject engagement. This article examines this new opportunity space and the work that needs to be done.
The Genesis of Questions
It is universally recognized, but often neglected, that asking the right question has profound implications not only on the end-result answer, but also the entire framework used to perceive and understand the problem. As Albert Einstein said,
“If I had an hour to solve a problem and my life depended on it, I would use the first 55 minutes determining the proper question to ask, for once I know the proper question, I could solve the problem in less than five minutes.”
It is mentally challenging and often disorienting to work within the space one step prior to the question. However, this 'no-where' space is precisely where the separation between what 'could be' and 'what is' happens. It’s the place that holds the entirety of the problem and demands the hard, visionary work of an artisan to carve out the question. It’s hard precisely because it's more natural to remain grounded in the realm of known answers, thankfully so since this natural state facilitates organized navigation through the world by keeping the overwhelming chaos of 'no-where' at bay. Adding to the difficulty, this natural state also tends to mold the questions that do arise into mere refinements of existing questions and answers. Despite the tremendous upside to this adaptive natural state, an awareness of its grip, risks and limitations is critical for continued advancement in any field. Most notably, the complete expanse of the problem, and possible solutions, is no longer fully comprehended.
The Clinical Research Trap
In clinical research, this natural state manifests as scientific questions being reflexively framed through a singular focus on the independent variable, which in turn is assessed through known outcomes. Clearly, this commonly accepted approach to scientific inquiry has resulted in an amazing set of discoveries and insights. However, as with all beliefs or practices that are widely adopted, what gets pushed out of awareness are the circumstances surrounding their adoption, the separations of 'no-where' space into the definitions used, the expanse of possibilities, and the full range implications.
To get a sense of its grip over investigators, consider the following question. What if a significant proportion of the forthcoming new, disruptive and trans-formative discoveries in clinical research have nothing to do with devices, pharmaceuticals, interventions or any other to-be-dreamed-up independent variable? Notice this hypothetical immediately throws clinical research back into the pre-emergent chaos of 'no-where', and calls forth the great separations used to define research, its methods, aims, practices, etc. Questions that re-imagine the principles and methods of clinical research will be the mechanism that uncovers these new discoveries. To clarify, this is NOT advocating for questioning the scientific method (e.g., random assignment, objectivity, staff blind to condition, etc.) in the manner of a naïve post-modern nihilist. Instead, it’s a call for questions that re-draw the definitional lines of clinical research.
What type of questions will emerge? Their characteristics are easy to spot since the scope always applies across therapeutic domains and designs, as opposed to being centered around an independent variable. There are many such questions, but one of the cornerstone questions will be: Is Clinical Research Relational?
The Traditional Answer
By definition, clinical research involves people and where people are found, relationships exist. Thus, there is an obvious side to the answer. Yes, there is some type of relationship between subjects and investigative staff in all clinical research. Relationship as used here is not meant to include exchange between investigative staff and subjects that would jeopardize or influence the results (e.g., a discussion of the study rationale). Instead, relationship is meant to be mechanisms through which the investigator engages subjects in the research process.
The well-schooled empiricists would argue any relationship isn’t worth the risks and hail the virtues of "objectivity", maintaining distance between subjects and investigators so-as-to minimize potential confounds and/or interaction effects with the object of study. This is a reasonable assertion and in line with the tradition of leaning heavily on the importance of internal validity (i.e., the extent to which changes in the independent variable [e.g., a drug], can be attributed to changes in the dependent variable [e.g., blood pressure]). Certainly, Hawthorne effects and other investigator / subject confounds (e.g., trial effects, secondary observer effects, etc.) have been well documented, so the position of objective detachment is well supported. However, the grounding in objectivity doesn't deny the existence of a relationship, but instead forms the arena of constraints and liberties within which the research relationship game is played. Stepping back, however, into the 'no-where' space of clinical research reveals that the current game as one of many possible instances with its own inherent risks, limitations, compromises and trade-offs that may be ameliorated, in part, through the building of a different arena.
Theoretical vs. Practical Rationale
In attempting to build a new arena, a re-examination of the original building materials is in order. The theoretical rationale behind relationship objectivity has been acknowledged, but to what extent was this merely the result of practical circumstances? Historically, relational exchange between investigative staff and subjects largely involved social pleasantries, scheduling discussions, words of encouragement (phone or face-to-face), and conversations about study events (i.e., discussion of consent documents, descriptions of procedures, etc.). The options available for staff / subject interactions have dramatically increased and changed with advances in information technologies. Is it reasonable to take the same detached, minimal engagement stance with these new technologies or may these new building materials offer considerable benefit? The answer requires weighing the limitations/strengths of the current vs. new ways to engage subjects, as well as an examination of whether the proposed levels of engagement introduce possible confounds (e.g., If so, under what conditions, etc.).
Poor Engagement Risks
The traditional objective, detached, minimalist relational approach between staff and subjects works in many cases. Indeed, it may be preferable given staff’s often pressing time demands. That is, subjects are minimally engaged by investigative staff and experience little beyond the burden of scheduling and completing forms, visits, procedures, etc. Thus, to say the current approach 'works' has a practical answer that seeks to minimize the effort by clinical staff.
But what if the impulse to minimize effort also holds true on the subject side? Consideration along these lines exposes the two main risks and limitations of this approach. The detrimental effects of dropouts and poor data quality (e.g., incomplete forms, missed study visits, procedure and/or data item refusal) has been well documented in the literature, often leading to desperate analytical attempts to correct for the problem, but in the end significantly reduces confidence in the findings. Here in lies the gem in redefining the game of clinical research in a manner the centers around engaging subjects in the process, building relationships, and thereby maximizing retention and data quality.
Countering Objections
The traditional empiricist may argue, “Yes, these negative consequences of the current approach may be more likely in some cases, but these effects are the same across groups, and thus do not confound results.” Against this rationale, consider designs or interventions with characteristics that may be differentially affected by limited engagement (e.g., long-term studies with wait-list control, or those involving: a multi-step subject requirement, a heavy subject burden, painful procedures, etc.). Seems reasonable to assert the possibility of interaction effects abound using the current methods. That is, to the extent there there are any subject burden differences between empirical groups, the risks of confounding detrimental effects due to limited engagement increase.
Moreover, what if higher levels of engagement significantly increases retention rates and/or data quality across groups? If so, adverse interventions are stopped earlier and conversely, positive results are confirmed faster. For instance, consider studies whereby negative or positive effects in the interventional arm (i.e., active group) is associated with increased dropouts vs. control (e.g., studies of obesity, smoking cessation, diabetes control, pain, etc.). In such cases, increased engagement would minimize this dropout bias.
The empiricist may continue, “Yes, but these new methods may interact with the object of study (i.e., introduce a confound). Said differently, there may be an admission of benefit from increased relational interactions with subjects, but the observed effects may be different between the intervention vs. control group, and thus influence results in an unknown manner. This is an empirical question and worthy of further exploration.
As seen in the figure below, ideally the level of engagement has no affect on outcome (blue line), and thus the benefits of higher levels of engagement could be leveraged. But research is needed to determine if results diverge across groups merely due to differing levels of engagement (red lines). It will be important to examine potential design, population, and outcome related characteristics at risk for such an effect. Relatedly, it will also be important to explore engagement level as a potential mediator and moderator on the outcomes of interest.
Potential Interaction Effects with Subject Engagement Level
Certainly, study design characteristics that increase the risk of subject engagement interaction effects will be important to explore to learn how best to minimize this possibility. Although a full discussion is well beyond the scope of this article, consider two brief examples, the Data Collection Schedule and Subject Burden.
Data Collection Schedule
Each interaction with a subject that a study contains increases the opportunity for potential engagement confounds to emerge. Thus, the more planned data collection points a study contains, the greater the risk of engagement interaction effects. Relatedly, designs that vary the data collection schedule between groups may also be at increased risk, such as non-parallel designs or those with a wait-list control arm.
Subject Burden
If motivation-level is one mechanism through which subject engagement mediates results (e.g., retention rates), then confounding factors that interact with engagement level may have a greater influence in designs with a high subject burden. For example, studies with painful procedures or a high base-rate of significant adverse effects, etc. Between group differences in burden would also be at increased risk.
What’s Next?
Noting the need for further investigation in the example areas of Subject Burden and Data Collection Schedule it is not being put forth as a rationale to prohibit moving forward with leveraging increase subject engagement in clinical research. There is simply too much potential benefits across studies and therapeutic domains to ignore. Also, I’m not aware of research exploring the equally important downsides to the currently accepted levels of subject engagement which, in turn, hasn’t kept investigators from its adoption.
This is simply an amazing time to be in clinical research! Investigators and information technology are coming together to explore not only new and exciting interventions (e.g., devices, pharmaceutical, behavioral treatments), but also transform the way clinical research is conducted, particularly from the subject’s perspective and their level of engagement in the research process. There are opportunities for many inventive pioneers in this area!