Biosimilars and nocebo effects: Lessons for the field of rheumatology
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First, I want to thank our panel of experts, including Madelaine A. Feldman, MD; Allan Gibofsky, MD, JD; Robert W. Levin, MD; and John R. Tesser, MD; for their enlightened comments on the next phase of the biosimilar experience, which is to me quite alarming.
The substitution by pharmacies of biosimilars without additional approval from the rheumatology practitioner should raise concerns for numerous reasons, primarily the potential effects it may have on the patient experience and their response to a new, but similar, drug. To me, one of the biggest issues is the potential to induce nocebo effects in the patient, generating both signs and symptoms, which may influence quality of life and generate intervention by the care team.
So please let me digress on the field of placebo-nocebo biology and the field of rheumatology for a moment.
I am acutely aware that most of us, in the era before biosimilars, were neither with nor had even ever heard of the nocebo effect, which is a phenomenon that can simply be understood as the negative equivalent of the placebo effect. For that matter, I may also add that for too long “placebo effect” has been considered a dirty phrase in the vast majority of the rheumatology literature, where the primary focus and concern has pertained to its problematic presence in clinical trials and not how it can be harnessed in patient care.
The placebo effect in rheumatology is a different subject that I promise Healio Rheumatology intends to tackle later. Nocebo effects, meanwhile, are physiologic, psychologic and neurobiological phenomena associated with actual or perceived harm. These harmful effects are generally a consequence of a patient’s negative expectations, or some psychosocial contact, or even the therapeutic environment, but independent of the known actions of the therapy.
Regarding biosimilars, the case seems pretty clear, for by definition these agents must be “similar” and show no decrease in effectiveness and no increase in safety risk. As our discussants point out, however, numerous studies over the past decade have demonstrated a palpable increase in negative outcomes across clinical trials of biosimilars. To me, it appears that the vast majority of these events reflect nocebo effects, which do not diminish or trivialize the findings and should be of great concern to all of us.
Reflecting on why a person would react negatively to a drug that is essentially similar is an exercise in understanding the neurobiology and clinical underpinnings of the nocebo effect. I will cite a singular outstanding review on this subject written by one of the leading placebo-nocebo scientists, Luan Colloca, MD, PhD, MS, who with her colleagues summarized this effect and their impact on biosimilar use.
In their review, they point out the numerous factors that can contribute to such effects, including patients’ expectations, which are heavily influenced by verbal information in the practitioner-patient dyad — and now, it appears, in the pharmacist-patient dyad as well. In this seminal review, they also dissect the dos and don’ts of how to craft medical communication to minimize nocebo effects, which I believe not only pertains to biosimilars but also all clinical experiences associated with delivering informed consent.
I found it of particular interest that cost can be a negative factor and can be associated with placebo and nocebo effects. Previous experimental data have suggested that when patients are given a placebo for pain and informed they were receiving a more expensive medication, it was more effective than when patients were told they were receiving a less expensive medication.
So, when a patient hears, “This biosimilar is the same as your current drug but cheaper,” it may be associated with a greater nocebo effect than when they hear the subtlety different statement, “This new biosimilar is equally effective to your current drug but more affordable.” I think you can see how information and how we frame our treatments can have great power in the overall tolerability, and perhaps efficacy, of virtually all of our therapies, ranging from traditional DMARDs, to biologics and even non-pharmacologic therapeutics. Master clinicians do this naturally, but I will add there is much to learn from the placebo-nocebo academic community.
I have previously suggested in vain that the American College of Rheumatology include a scientific seminar at our annual meeting on the science of placebo and nocebo biology, and how to apply lessons from this field to the care of patients with rheumatic diseases. I feel strongly that this would be both of high interest to the field and of great value to the practitioner and clinical researcher alike. I am hopeful that, sooner or later, it will come out of the shadows and into the light in our field as an important area of science and a powerful force in healing.
That’s my take – what’s yours? Please share your thoughts with me at calabrl@ccf.org or at rheumatology@healio.com.
- Reference:
- Colloca L, et al. Front Pharmacol. 2019;doi:10.3389/fphar.2019.01372.
- For more information:
- Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.
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