Bias in Biosimilar Use: Dr. Elif Çar on Reducing the Nocebo Effect

By 2030, patent protection will expire for many newer, effective, and important medicines, including several immunotherapies. Biosimilars will consequently become an increasingly important topic in oncology.

However, switching to biosimilar medicines may trigger the nocebo effect in some patients. Negative expectations may reduce treatment effectiveness or increase perceived side effects independently of the medicine's pharmacological properties.

Research suggests that nocebo effects develop faster than placebo effects and may have a stronger influence on clinical outcomes.

This article discusses a systematic review by Elif Çar and colleagues, published on November 29, 2024, in Pharmaceutical Medicine , which provides a systematic examination of strategies to reduce nocebo effects, considering how clinical practice can support patients and improve adherence to biosimilar treatments. Researchers identified 13 key approaches for these aims.

Before exploring these strategies, let us briefly consider what biosimilars are.

What Is a Biosimilar?

Biosimilars are biotechnology-produced medicines highly similar to an already approved reference biological medicine . They largely share its effectiveness, safety, and quality characteristics. Minor differences may occur, but these are not clinically meaningful.

How Do Biosimilars Differ From Biological Medicines?

• Biological medicines are molecules such as complex proteins or antibodies produced using living cells or organisms. They commonly treat diseases including cancer, rheumatoid arthritis, and diabetes.
• Biosimilars are developed to provide the same therapeutic effects as original biologics but use different manufacturing processes.

Why Are Biosimilars Important?

• Cost-Effectiveness: Their lower cost compared with biologics provides economic benefits to healthcare systems.
• Wider Access: More affordable options expand access to biological treatments.
• Similar Safety and Efficacy: Clinical studies demonstrate similar safety and efficacy profiles to reference medicines.

Biosimilars offer treatment of the same quality while reducing expenditure, benefiting both patients and healthcare systems.

What Is a Generic (Equivalent) Medicine?

An equivalent medicine , also called a generic medicine, is an alternative to an original (reference) medicine whose patent or exclusive protection has expired. Generics are small-molecule chemical medicines , such as paracetamol or ibuprofen. Their simpler structure is the main distinction from biologics and biosimilars.

Generics match the reference medicine in their active ingredient, dosage, safety, effectiveness, route of administration , and pharmacokinetic properties .

Differences Between Generic and Original Medicines

• Active Ingredient: The same active substance is used.
• Excipients: Minor differences may occur, such as coloring, sweeteners, or coatings.
• Price: Generally cheaper because research, development, and marketing costs are lower.
• Bioequivalence: Generics must be bioequivalent  to the original, meaning they are absorbed to the same extent and produce the same effect.

Why Are Generics Cheaper?

Original medicines require lengthy research and expensive trials. During patent protection, the manufacturer has exclusive marketing rights. After expiry, other companies can produce generic versions using the same active ingredient. Competition lowers prices.

Are Generics Reliable?

Yes. Health authorities such as WHO, the FDA, EMA, and Turkey's TİTCK have strict regulations ensuring that generics match reference products in effectiveness, safety, and quality . They can therefore be used with confidence.

Differences Between Generics and Biosimilars

• Generics are small-molecule chemical medicines , such as paracetamol or ibuprofen.
• Biosimilars are large, complex biotechnology medicines , such as insulin and monoclonal antibodies.
• Generics are exact copies, whereas biosimilars are highly similar to the original biologic  but not completely identical.

In summary, generics are equivalent, lower-cost alternatives that benefit healthcare systems economically.

What Is the Nocebo Effect?

The term comes from Latin meaning “I will harm.” It describes symptoms worsening because of negative expectations about treatment.

Research suggests that nocebo effects develop faster than placebo effects and produce stronger clinical effects.

Biosimilars play an important role in reducing expenditure and expanding access to safe biological therapies. Building trust and minimizing nocebo effects are therefore crucial.

A Belgian and Dutch research team published its review on November 29, 2024, in Pharmaceutical Medicine . It examined strategies to reduce nocebo effects and identified 13 approaches used clinically to support patients and improve adherence:

13 Key Strategies to Reduce the Nocebo Effect

1. Open, supportive body language: Make eye contact, nod, smile, use an open tone, and maintain relaxed body language.

2. Positive framing: Emphasize similarity to original biologics.

3. Empathetic communication: Ask open questions to understand treatment concerns.

4. Validation: Acknowledge concerns as valid and help patients feel taken seriously.

5. Shared decision-making: Actively involve patients in treatment choices.

6. Encourage self-reflection: Help patients consider their strengths and values.

7. Education about nocebo effects: Ensure patients and professionals understand their importance.

8. Information about biosimilars: Help patients and healthcare workers understand these medicines.

9. Health economics education: Inform professionals about biosimilar cost-effectiveness.

10. Personalized information: Tailor explanations to patient needs.

11. Additional resources: Provide further information to address concerns.

12. A multidisciplinary approach: Involve different healthcare professionals in patient support.

13. Proactive switching plans: Plan ahead to manage treatment changes smoothly.

Conclusion

Biosimilars offer reliable treatment and economic benefits. Minimizing nocebo effects is essential to improve adherence. An informed, supportive approach can strengthen trust. Applying these strategies will be crucial for improving biosimilar effectiveness and acceptance.