Biosimilars-RIGHT is a set of evidence-based guidance that aims to help HCPs with the transition of patients from reference products to biosimilars.  Biosimilars are susceptible to nocebo effects unrelated to the product characteristics.  Speaking the right language consistently during the transition has shown to reduce these factors.

Speaking with "One Voice"
Glossary of positive language
The evidence
The Parker Institute

One Voice

How we speak with patients about medications can have a measurable impact on how they do. It is therefore essential that we all speak with one voice when transitioning a patient from a reference product to its biosimilar.

Manuscript + References

Ensuring that everyone speaks with one voice is essential when transitioning patients to a biosimilar. Biosimilars-RIGHT provides guidance on language that can be used by everyone a patient may interact with. From the receptionist to the physician, standardised and unified communications around biosimilars are of key importance.

This principle ensures that no divergent opinions are being expressed to patients regarding the agreed treatment strategies, and preferably that all healthcare providers involved in their management ‘speak the same language’. 

Recommended verbal and written language has been discussed in several peer reviewed articles. (1,2,3)

In addition to the words you use, you should ensure that all stakeholders who interact with patients pay attention to any non-verbal communications that may undermine the transition. 

REFERENCES:

  1. Häuser W, Sarzi-Puttini P, Tölle TR, Wolfe F. Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Clin Exp Rheumatol. 2012;30(Suppl. 74):78–87.
  2. Jørgensen TS et al. Communication strategies are highly important to avoid nocebo effect when performing non-medical switch from originator product to biosimilar product: Danish results from applying the Parker Model a qualitative 3-step research model (Abstract 2260 /Accessed 7th of November 2017).
  3. Tweehuysen L, Huiskes VJB, van den Bemt BJF, van den Hoogen FHJ, den Broeder AA. FRI0200 Higher acceptance and persistence rates after biosimilar transitioning in patients with a rheumatic disease after employing an enhanced communication strategy. Annals of the Rheumatic Diseases. 2017;76:557.

BIO-BBU-0026h - Date of preparation: April 2018

What is Speaking with "One Voice"?

Ensuring that everyone speaks with one voice is essential when transitioning patients to a biosimilar. From the receptionist to the physician, standardised and unified communications around biosimilars are of key importance.

Glossary of Positive Language

Encouraging language instead of discouraging language

It is crucial that we are mindful of our word choice and tone when communicating. One word can change the entire perception of an experience.

The negative impact verbal and/or body language may have on the experience with a medication may result in a nocebo effect, i.e., adverse events and/or lack of efficacy triggered by negative expectations.

Such a nocebo effect is an important factor that may ultimately lead to a lack of acceptance and non-adherence to a medication.

This nocebo effect may occur with any switch from a medication to another but the problem has mainly been observed when patients were switched from an originator medication to a generic or a biosimilar.   Adoption of enhanced communication techniques may be useful in mitigating the nocebo effect. Effective healthcare professional–patient dialogue is key to transferring confidence to the patient, and has been shown to reduce nocebo effects in patients when switching from an originator to a biosimilar.

 

Stay attuned to questioning style and non-verbal messages.

Often, it’s not what you say but how you say it that makes the difference. Both verbal and non-verbal behaviors can either facilitate or inhibit the acquisition of data from the patient and help develop clinical rapport and engagement. For example, methods that engage the patient in the care process include: good eye contact, affirmative nods and gestures, a partner-like relationship, closer interpersonal distance, and a gentle tone of voice. These items improve clinical outcome, treatment adherence, reduce symptoms and need for pain medication, and shortened hospital stay.

Reference; Drossman, DA. 2012 David Sun lecture: helping your patient by helping yourself-how to improve the patient-physician relationship by optimizing communication skills. Am J Gastroenterol. 2013. 108(4):521-8)

 



Below are some examples on different language on the same topic:

Might be perceived as discouraging Language Might be perceived as encouraging Language
“This is a similar, cheaper XYZ molecule” “This is a similar, more affordable XYZ molecule, that will be as efficacious and as safe as the one you were used to take”
“82% of patients reach a 20% improvement” “To date many patients with similar signs and symptoms achieved a significant improvement”
“This is the first choice of treatment. If it doesn’t work than contact me again”
“I must follow the guidelines and give you this medication first. There are other choices if it doesn’t work”
“This medication may help.”
“Let’s try this drug.”
 “I have very good experience of this effective treatment, and as before I will continuously follow up on your progress”
“I need to switch your current XYZ molecule to a biosimilar to save money “ “I suggest substituting your current XYZ molecule by a new XYZ molecule to ensure sustainable healthcare costs for all patients who need this treatment“

 

 

Bibliography of nocebo vs placebo effect

 

  • Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017. 24;389(10088):2473-2481
  • Häuser W, Sarzi-Puttini P, Tölle TR, Wolfe F. Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Clin Exp Rheumatol. 2012;30(Suppl. 74):78–87.
  • Mitsikostas DD, Mantonakis LI, Chalarakis NG. Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. CephalalgiaInt J Headache. 2011;31:550–61.
  • Rezk M, Pieper B. Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect. Rheumatol Ther (2017) 4:209–218 DOI 10.1007/s40744-017-0085-z 
  • Jørgensen TS et al. Communication strategies are highly important to avoid nocebo effect when performing non-medical switch from originator product to biosimilar product: Danish results from applying the Parker Model a qualitative 3-step research model (Abstract 2260 /Accessed 7th of November 2017).
  • Voelker R, Nocebos contribute to host of ills. JAMA. 1996;275:345–7.
  • Colloca L & Miller F G. The nocebo effect and its relevance for clinical practice. Psychosom Med 73, 598–603, doi: 10.1097/PSY.0b013e3182294a50 (2011).
  • Data-Franco J & Berk M. The nocebo effect: a clinicians guide. Aust N Z J Psychiatry 47, 617–623, doi: 10.1177/0004867412464717 (2013).
  • Faasse K. & Petrie K J. The nocebo effect: patient expectations and medication side effects. Postgrad Med J 89, 540–546, doi: 10.1136/postgradmedj-2012-131730 (2013).
  • Häuser W, Hansen E, Enck P. Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int 2012; 109(26): 459–65. DOI: 10.3238/arztebl.2012.0459

 

 

The Evidence

Recent studies demonstrating the possible impact of the nocebo effect

Reference biologic/ biosimilar biologic

Study design (Phase)

Indications

Time of assessment after transition

Evidence of a possible nocebo effect

1

Observational, single-centre study (n=39)

RA, SpA, PsA, JIA, and chronic reactive arthritis

11 months

Of 39 Patients in Study, 11 patients (28.2%) discontinued CT-P13 treatment, with six patients discontinuing due to subjective reasons with no objective deterioration of disease.*

Author conclusion:
“Subjective reasons (negative expectations) may play a role among discontinuations of biosimilars”.

2

 

Observational registry** (n=802)

RA, SpA, and PsA

3 months

Of 802 patients, 132 patients (16%) discontinued CT-P13 treatment after 1 year, mainly due to perceived lack of effect (n=71/54%) or AEs (n=37/28%), although disease activity was largely unaffected in the majority of patients -/+ 3 months of the time of transition

Author conclusion:
“A nationwide non-medical switch from INX to CT-P13 had no apparent negative impact on disease activity”.

3 

Observational, multicentre, prospective cohort study (n=192)

RA, SpA, and PsA

6 months

Of 192 patients, 44 patients (23%) discontinued CT-P13 treatment, mainly due to perceived loss of efficacy (n=35) and AEs (n=23), although, in the majority of patients, no changes in efficacy, safety, or immunogenicity were observed.

Author conclusion:
“Patients discontinued biosimilar infliximab mainly due to a subjective increase in BASDAI score and/or AEs, possibly explained by nocebo and/or attribution effects rather than pharmacological differences”.

4

Observational registry* (n=1548)

RA, PsA, and SpA 

5 months

Of 1548 patients, ~9% stopped treatment during 5 months’ follow up, with reasons for withdrawal reported as lack of effect (n=59), AEs (n=42), remission (n=2), cancer (n=4), death (n=1), and other/unknown (n=21).

Author conclusion:
“Disease activity was largely unaffected in the majority of patients 3 months after switch to SB4 and comparable to the fluctuations observed in the 3 months prior to the switch. Longer follow-up will offer additional understanding of the potential efficacy and safety consequences of the non-medical switch”.

5

Observational register study (n=642)***

RA, SpA, and PsA

6 months

635 of 642 (99%) patients agreed to transition of whom 625 patients (433 RA, 128 PsA, 64 AS) were included in the study. 600 patients were included in the historical cohort.

Crude 6-months persistence rates of SB4 and [ENBREL] were: 90% (95%[confidence interval] 88%-93%) versus 92% (95%[confidence interval]90%-94%). The transition cohort had a statistically significantly higher relative risk of discontinuation (adjusted [Hazard Ratio] 1.57, 95%[confidence interval] 1.05-2.36) and smaller decreases in [C-Reactive Protein] (adjusted diff 1.8 (95%[confidence interval] 0.3-3.2)) and [Disease Activity Score-28]-[C-Reactive Protein] (adjusted diff 0.15 (95%[confidence interval] 0.05-0.25)) over six months compared with the historical cohort.

Author conclusion: 
“Non-mandatory transitioning from ENBREL to SB4 using a specifically-designed communication strategy showed a slightly lower persistence rate and smaller decreases in disease activity compared with a historical cohort, but these differences were considered as not being clinically relevant”.

 

*
CT-P13 is not licensed in chronic reactive arthritis and juvenile idiopathic arthritis

**
Data from observational data is limited by the lack of suitable control data.
AE, adverse event; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SpA, axial spondyloarthritis.

***
A prospective controlled cohort study (using a historical cohort as control)

REFERENCES

  1. Nikiphorou E, Kautiainen H, Hannonen P, Asikainen J, Kokko et al. Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opinion on Biological Therapy. 2015;15(12):1677–83.
  2. Glintborg B et al. A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis. 2017 Aug;76(8):1426-1431. doi: 10.1136/annrheumdis-2016-210742. Epub 2017 May 4.
  3. Tweehuysen L, van den Bemt BJF, van Ingen IL, de Jong AJL, van der Laan WH, van den Hoogen FHJ et al. Clinical and Immunogenicity Outcomes after Switching Treatment from Innovator Infliximab to Biosimilar Infliximab in Rheumatic Diseases in Daily Clinical Practice. (Abstract 627). Arthirtis & Theumatoloygy 2016;68 (suppl 10). Available from:http://acrabstracts.org/abstract/clinical-and-immunogenicity-outcomes-after-switching-treatment-from-innovator-infliximab-to-biosimilar-infliximab-in-rheumatic-diseases-in-daily-clinical-practice/ [Accessed 13 November 2016].
  4. Glintborg B et al. FRI0190 linical outcomes from a nationwide non-medical switch from originator to biosimilar etanercept in patients with inflammatory arthritis after 5 months follow-up. results from the danbio registry. Annals of the Rheumatic Diseases 2017;76:553–554.
  5. Tweehuysen L, Huiskes V, van den Bemt B, Vriezekolk J et al. Open-label non-mandatory transitioning from originator Etanercept to Biosimilar SB4: 6-month results from a controlled cohort study. Arthritis Rheumatol. 2018 Apr 2. doi: 10.1002/art.40516. [Epub ahead of print]

The Parker Institute

The Parker Story

The Parker Institute is part of Copenhagen University Hospital at Bispebjerg and Frederiksberg. The Parker Institute was founded in 1999 and has since then strived, through patient centered research with focus on locomotory and related disorders, to improve the status of health in the population via prevention at all levels, increasing knowledge of disease mechanisms and diagnostics, and by creating evidence-based treatments. The activities include observations and register based research, qualitative research, analysis of literature, and diagnostic studies of patient-reported outcome measures, clinical tests, imaging with ultrasound and MRI, biomechanical evaluation, as well as randomised clinical and population based interventions.

Since 2015 biosimilars have been adopted quickly and has been generally received well by health care providers and patients, as is the case for the rest of Denmark 1,2. Importantly, the Parker Institute has conducted qualitative research on transition from originator products to biosimilar products, and thus gained important insights in the potential risks for generating a nocebo effect 3.

REFERENCES

  1. Glintborg B et al. A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis. 2017 Aug;76(8):1426-1431. doi: 10.1136/annrheumdis-2016-210742. Epub 2017 May 4. 
  2. Glintborg B et al. FRI0190 Clinical outcomes from a nationwide non-medical switch from originator to biosimilar etanercept in patients with inflammatory arthritis after 5 months follow-up. results from the danbio registry. Annals of the Rheumatic Diseases 2017;76:553–554. 
  3. Jørgensen TS et al. Communication strategies are highly important to avoid nocebo effect when performing non-medical switch from originator product to biosimilar product: Danish results from applying the Parker Model a qualitative 3-step research model (Abstract 2260 /Accessed 7th of November 2017).

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