Both Views of Each Patient Must be Captured During Drug Development.

The mission of the US Food and Drug Administration is to protect the public health, in part, “…by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices…”1It ensures real effects, ones directly attributable to the drug, product or device, are measured and reported. For example, placebo effects are controlled in clinical trials. Findings from behavioral economics research may now help control another flaw—over-reliance on virtual reality.

According to how questions are framed, answers from patients about drug effects differ. Because of this, adverse drug effects reported from within clinical trials are categorized as “spontaneous,” volunteered without prompting the patient, or “solicited” by asking the patient about specific effects. The point of this article is to suggest that regulatory agencies also consider another difference, each of our “two points of view,” when evaluating the safety and efficacy of products and devices. Differences between these views may be greater than the differences observed between spontaneous and solicited reports.

The behavioral economics literature suggests that each of us judges value, like severity of pain or happiness, from two different points of view. For one of these views, terms like “rational-cognitive,” “remembering,” or “conceptual” have been used because it relies on cognitive processes that use concepts and memory. For the other, terms like “experiential,” “experiencing,” and “sensory-perceptual” have been used because it relies only on immediate sensory perceptual experience to make assessments. Broadly, they appear to arise from the mental processing of either: a. Concepts, or b. Percepts2,3, likely done by the left and right-brain hemispheres, respectively. The importance of our perceptual view, information obtained directly by the processing sensory-perceptual experience and then reported on without the use of concepts, has been under appreciated and gone unnoticed. It has been co-opted by our reliance on language. Because percepts are non-conceptual, no one can convey them through words. It rose to fame when Daniel Kahneman won the 2002 Nobel Prize in economics by relying on it to make sense of predictable, but seemingly irrational, human decision-making.

It is important to realize that we fundamentally interact with a perceptual world. When asked, most people mistakenly believe they can express the color red. They do so by offering comparisons (e.g., to fire trucks, stop signs) but not saying what it is. But, no one can do so. The best test for this is that no one can say (i.e., conceptualize) what red is to someone who has never seen. Further, concepts can only describe the world down to the level of a category; my desk lamp desk is a unique object that defies being described by words. Percepts, however, know uniqueness. What’s truer, that it’s a “desk lamp” (i.e., a member of a category) or that one can perceive its uniqueness but cannot communicate that fact through words?

At first blush, use of language to answer questions about health appears to require the transformation of percepts into concepts and then reliance on the concept as an adequate substitute for the experience. But is the concept an adequate substitute? Likely not. Here’s an example of research done about happiness. College students rated their vacation on a daily basis6. At its end, they also evaluated its entirety and whether they wanted to repeat it. Results showed that students based their intention to repeat it mainly on their rating at the time of the last assessment, “even if the final evaluation did not accurately represent the quality of the experience that was described in the diaries.”2The findings suggest that the conceptually-oriented ratings are not equivalent to the experientially-oriented, daily ratings.

Types of questions that force someone to answer from a conceptual view often include use of memory, like “How was your pain during the past month?” or forced choices, like ratings on a 5 point scale. Behavioral economics research points the way to obtaining responses from our perceptual view. Use of questions having a present moment orientation like, “How is your pain now?” seem to do so. A response format where the respondent makes a mark across a 10 cm line indicating level of pain intensity may also help minimize categorization. Other methods for tapping into the experiential view are available. The experience sampling method4and the day reconstruction method5are two among them. Even if questions about health status are designed specifically to capture either one view or the other, no method is fool proof or controllable. Yet, the effort appears worthwhile.

If research participants inadvertently shift between views their reported health may change. It has been proposed that shifting between views may be one possible cause of the placebo effect3. Placebo responders may be those who initially report from the memory/conceptual view and then shift to the experiential/ perceptual view. By dropping the conceptual component they may report feeling better.

Inclusion of each patients two views (the perceptual as well as the experiential) during the assessment of drug effects is important and should not remain trivialized. Though conceptual, thought-based, reports of drug effects dominate patient questionnaires, these answers reflect a virtual reality. Reality is not what we think it is. What we think is virtual, an idea, an abstraction. What we experience is real.

Dictionary.com shows the philosophically-oriented definition of the word “reality” as “something that exists independently of ideas concerning it.” It also shows the definition of “perceive” as “ to become aware of, know, or identify by means of the senses.” This suggests that reports from a patient about his or her pain are real only when they originate from sensory-perceptual experience.

By contrast, the definition of “virtual” is “being something in essence though not in name.” The definition of “concept” is “a general notion or an idea,” while the related word “conceive” means “to form a notion, opinion, purpose, etc.” As applied to patient reports about the efficacy and safety of drugs, when a patient uses concepts to report the severity of his or her pain those answers do not represent reality. Because they represent virtual reality, they should not carry as much weight in the regulatory decision-making process about a drug’s safety and efficacy as answers that do reflect reality.

Earlier this year, JAMA published Guidelines for Inclusion of Patient-Reported Outcomes in Clinical Trial Protocols7, which addressed conditions for the appropriate use of subjective patient-reported outcome (PRO assessments during clinical research studies. Though the guidelines advanced many points, like the need to specify, “…concepts/ domains used to evaluate the symptom,” “…a schedule of PRO assessments,” etc., they do not consider our two points of view or suggest their inclusion as an important variable. Such discussion would have been beneficial. It’s my belief the guidance missed an excellent opportunity to move the field forward. It’s my wish that when FDA updates its guidance on the use of patient-reported outcomes measures, full consideration will be given to inclusion of our two views. I further hope that when subjective patient reports are required, researchers and clinicians will consider inclusion of both views and conduct analyses of the different results produced by each. Health economic appraisals related to the cost-effectiveness of drugs may especially benefit by incorporation of our two views within those analyses.

Cite as – Pashko, S. (2018). Patient-Centered Drug Effects: Their Reality is Perceived Not Conceived. Comment on the Food and Drug Administration (FDA) Notice: Patient-Focused DrugDevelopment: Developing and Submitting Proposed Draft Guidance Relating to Patient Experience Data; Public Workshop.

References

  1. Food and Drug Administration. Mission. https://www.fda.gov/aboutfda/whatwedo/default.htm. Accessed March 9, 2018.
  2. Kahneman, D. Thinking, Fast and Slow. New York, NY: Farrar, Straus & Giroux; 2012.
  3. Pashko, S. Conceptual versus perceptual information processing: Implications for subjective reporting. Journal of Neuroscience, Psychology, and Economics.2014;7:219–226.
  4. Hektner, J, Schmidt, J, Csikszentmihalyi, M Experience Sampling Method: Measuring the Quality of Everyday Life.Thousand Oaks: CA, Sage Pubs; 2007.
  5. Kahneman, D, Krueger, A, Schkade, D, Schwarz, N. Stone, AA Survey Method for Characterizing Daily Life Experience: The Day Reconstruction Method. 2004:306(5702):1776-1780. doi: 10.1126/science.1103572
  6. Wirtz, D, Kruger, J, Scollon, C N, Diener, E. (2003). What to do on spring break? The role of predicted, on-line, and remembered experience in future choice. Psychological Science. 2003;14:520–524.
  7. Calvert, M, Kyte, D, Mercieca-Bebber, R, et al. Guidelines for Inclusion of patient-Reported Outcomes in Clinical Trial Protocols: The SPIRIT-PRO Extenstion. JAMA. 2018;319(5):483-494. doi:10.1001/jama.2017.21903

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