Biologic medicines have transformed treatment for numerous chronic and life-threatening conditions such as cancer, auto-immune diseases, and diabetes. These therapies can offer significant benefits in efficacy, safety, and convenience, compared to conventional medicines. However, their high costs have limited accessibility for many patients globally. Biosimilar versions of biologic medicines are now helping to change this landscape by providing more affordable treatment options, particularly in low- and middle-income countries (LMICs) where the burden of disease is high, and healthcare budgets are constrained.
Understanding biosimilars
Biologics are complex medicines derived from living organisms. Their complex manufacturing processes have traditionally limited their availability, primarily serving high-income countries. In recent years, biopharmaceutical manufacturing capacity has grown faster in middle-income countries, increasing the potential for broader access.
Biosimilars are highly similar versions of biologic medicines, developed through comprehensive analytical studies and rigorous preclinical and clinical trials to ensure therapeutic equivalence. These products offer equally effective and safe alternatives thereby increasing market competition and reducing the costs of biologic therapies (1). Biosimilars are about 60 % cheaper than their originator counterparts (2).
Biosimilars offer significant cost savings, which can expand access to essential biologic therapies.
WHO's role in promoting biosimilars
The World Health Organization (WHO) recognizes biosimilars as key drivers for expanding global access to essential biological medicines. Through its Essential Medicines List (EML), WHO evaluates and includes quality-assured biosimilars, endorsing them as safe, effective, and cost-effective alternatives to originator biologics. The WHO prequalification of biosimilars builds confidence for their procurement by the United Nation (UN) agencies and countries, enhancing their availability and affordability. WHO also advocates for non-exclusive voluntary licensing to accelerate affordable biosimilar access and emphasizes the importance of regulatory harmonization, healthcare professional education, and stakeholder collaboration in promoting biosimilar use (3).
Standards for biological products
Since early 1950s' WHO has played a pivotal role in establishing norms and standards for biological products. These standards ensure the consistent quality, safety, and efficacy of biological medicines and related in vitro biological diagnostic tests worldwide. The WHO Expert Committee on Biological Standardization (ECBS) collaborates with international scientific and professional communities, regional and national regulatory authorities, manufacturers, and expert laboratories to develop these standards based on international consensus. WHO guidelines and recommendations for biological products cover various aspects, including production, control, and regulatory preparedness. This guidance is crucial for maintaining high standards in the development and use of biological products, including biosimilars. For instance, the guidelines on the quality, safety, and efficacy of biotherapeutic products provide a framework for evaluating biosimilars at country level, ensuring they meet the same rigorous standards as their reference products. WHO also establishes International Biological Reference Materials, which serve as benchmarks for the quality and potency of biological products (i.e. WHO International Reference Standards for Biological Products ). These reference materials are essential for standardizing assays and ensuring the comparability of biosimilar products across different regions and manufacturers. WHO emphasizes the importance of regulatory harmonization to facilitate the global adoption of biosimilars.
Biosimilars in the EML: bridging the gap
As of 2023, the WHO EML includes 81 biologic therapies, representing over 15% of all listed essential medicines. The inclusion of biosimilars on the EML helps bridge the gap in affordability and availability of these therapies. For example, following the EML recommendation and WHO prequalification of trastuzumab and rituximab biosimilars treatment costs for breast cancer and lymphoma have significantly reduced. Countries such as Brazil (4), India (5), and South Africa (6) have successfully expanded patient access through approved biosimilars, demonstrating the practical benefits of these inclusions.
Evolution of biologic medicines in the EML
WHO recognizes the importance of expanding access to essential biologic medicines globally. In 2013, bevacizumab (recommended for age-related macular degeneration, a disease of the eye) was the first monoclonal antibody added to the WHO EML, followed by trastuzumab and rituximab in 2015, both indicated against cancer.
Trastuzumab has revolutionized breast cancer treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Since its introduction almost 25 years ago, trastuzumab has significantly improved outcomes for patients with this type of cancer. It is a monoclonal antibody that targets the HER2 protein, which is overexpressed in some breast cancers, and it has been pivotal in reducing recurrence and improving survival rates. Trastuzumab's impact is reflected in the shift from conventional chemotherapy to targeted therapies, offering more effective and less toxic treatment options. However, with an average annual cost exceeding $20,000 USD, many LMICs faced severe budget constraints, leading to limited use of trastuzumab and poor survival rates for patients. In response, WHO prequalified the first trastuzumab biosimilar in 2019. These biosimilars, offering the same efficacy and safety at approximately 65% lower cost, had the potential to transform breast cancer treatment in LMICs.
Since then, several trastuzumab biosimilars have been approved or are in development by various companies. These biosimilars have been launched in all WHO regions. The inclusion of these biosimilars on the EML facilitated initiatives such as the Cancer Access Partnership, led by the Clinton Health Access Initiative (CHAI) and the American Cancer Society (ACS), which included biological medicines for the first time.
Today, equitable global access to trastuzumab biosimilars is gradually being realized. Countries like India and Brazil have swiftly integrated these biosimilars into their national healthcare systems. India, for example, has approved multiple trastuzumab biosimilars, significantly reducing treatment costs and broadening patient access nationwide. Similarly, South Africa has adopted trastuzumab biosimilars into its treatment protocols, enhancing accessibility to essential breast cancer medications for patients. Overall, trastuzumab biosimilars have received market authorization and approval in at least 65 countries, signaling a major step forward in global cancer care (7).
As of 2019, trastuzumab biosimilars have received market authorization and approval in over 65 countries (8).
The 2019 inclusion of adalimumab (recommended for rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis and Crohn's disease) further underscored WHO's commitment to improving access and affordability through biosimilars. Over the next few years, WHO has built on this biosimilar precedent by continuing to add further important biologic medicines to the EML and explicitly listing their quality-assured biosimilars as alternatives.
Removing barriers to adoption
While biosimilars have made promising inroads into the Model List, concerns have persisted regarding interchangeability and switching between reference biologics and their biosimilar versions. In 2021, after reviewing substantial evidence confirming the safety and efficacy of transitioning patients from original biologics to biosimilars, the WHO recommended that quality-assured biosimilars of listed biologic medicines should also be viewed as interchangeable and considered for national selection and procurement. This recommendation was pivotal for improving real-world access and use, positioning biosimilars as equal to their reference counterparts and affirming confidence in transitioning patients to save costs without compromising care. The committee reinforced this support by recommending the expansion of WHO prequalification to include biosimilars and advocating for their regular evaluation alongside originators (9).
WHO recommends that quality-assured biosimilars of EML-listed biologic medicines should be viewed as interchangeable and eligible for selection and procurement at the country level for national essential medicines lists.
Despite their potential, challenges remain in integrating biosimilars in clinical practice across countries and clinical areas. Issues such as concerns about switching between biosimilars and reference products, regulatory complexities, and educational gaps among healthcare professionals necessitate careful consideration (10).
Current landscape of essential biologic and biosimilar medicines
The 2023 Model List includes multiple biologics and their biosimilar alternatives across different therapeutic areas:
Table 1: Biologic medicines and therapeutic alternatives (including quality-assured biosimilars) on the WHO Model Lists .
| Medicine | Indication(s) |
|---|---|
| Adalimumab (therapeutic alternatives: certolizumab pegol, etanercept, golimumab, infliximab) |
Ankylosing spondylitis, Crohn disease, juvenile idiopathic arthritis and rheumatoid arthritis |
| Anti-rabies virus monoclonal antibodies | Rabies post-exposure prophylaxis |
| Asparaginase | Acute lymphoblastic leukemia |
| Bevacizumab | Age-related macular degeneration |
| Enoxaparin (therapeutic alternatives: dalteparin, nadroparin) |
Acute coronary syndromes Venous thromboembolism |
| Erythorpoiesis-stimulating agents (therapeutic alternatives: epoetin alfa, beta, and theta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta) |
Anaemia of chronic renal disease |
| Filgrastim | Primary and secondary prophylaxis of febrile neutropenia associated with myelotoxic chemotherapy. |
| Insulin (human) (soluble and intermediate-acting) |
Diabetes |
| Long-acting Insulin analogues (therapeutic alternatives: insulin degludec, insulin detemir, insulin glargine) |
Diabetes |
| Nivolumab (therapeutic alternative: pembrolizumab) |
Metastatic melanoma |
| Pegaspargase | Acute lymphoblastic leukemia |
| Pegfilgrastim | Primary and secondary prophylaxis of febrile neutropenia associated with myelotoxic chemotherapy. |
| Rituximab | Burkitt lymphoma, chronic lymphocytic leukaemia, diffuse large B-cell lymphomas, follicular lymphoma, multiple sclerosis |
| Trastuzumab | HER2-positive breast cancer |
Economic benefits and WHO recommendations for biosimilar medicines
The WHO guideline on country pharmaceutical pricing policies includes a strong recommendation for promoting the use of quality-assured generic and biosimilar medicines.
WHO recommends that countries enable early market entry of generic and biosimilar medicines through legislative and administrative measures, with a view to encouraging early submission of regulatory applications, allowing for prompt and effective review, and ensuring these products are safe, efficacious, and quality-assured (9)
The WHO guideline also emphasizes the importance of cost-effective procurement strategies to enhance accessibility and sustainability of healthcare systems, particularly in LMICs.
Challenges and future directions
Despite the demonstrated benefits, several challenges remain in the broader adoption of biosimilars. Regulatory barriers, lack of awareness among healthcare professionals, and limited manufacturing capabilities in certain regions can hinder the widespread acceptance and utilization of biosimilars. Addressing these challenges requires coordinated efforts among governments, healthcare providers, and the pharmaceutical industry to promote education, streamline regulatory processes, and invest in local manufacturing infrastructure.
WHO continues to play a pivotal role in promoting the adoption of biosimilars through its strategic initiatives. WHO emphasizes the importance of regulatory harmonization and supports countries in building robust regulatory frameworks to ensure the quality, safety, and efficacy of biosimilars. Additionally, WHO collaborates with various stakeholders to enhance healthcare professional education and public awareness about the benefits of biosimilars, fostering a more receptive environment for their adoption.
References
- Agency EM. European Medicines Agency [Internet]. [cited 2024]. Available from: https://www.ema.europa.eu/en/human-regulatory-overview/biosimilar-medicines-overview .
- Calleja MA, Albanell J, Aranda E, García-Foncillas J, Feliu A, Rivera F, et al. Budget impact analysis of bevacizumab biosimilars for cancer treatment in adult patients in Spain. European Journal of Hospital Pharmacy. 2023;30(e1):e40.
- Burrone E, Gotham D, Gray A, de Joncheere K, Magrini N, Martei YM, et al. Patent pooling to increase access to essential medicines. Bull World Health Organ. 2019;97(8):575-7.
- Celltrion. Biosimilar Development [Internet]2019. [cited 2024]. Available from: https://www.biosimilardevelopment.com/doc/celltrion-announces-approval-of-herzuma-trastuzumab-pkrb-in-brazil-0001 .
- Lopes G. American Society of Clinical Oncology (ASCO) Connection [Internet]2016. [cited 2024]. Available from: https://connection.asco.org/blogs/biosimilars-emerging-markets-india-and-russia .
- Pategou J. Biosimilar Development [Internet]2020. [cited 2024]. Available from: https://www.biosimilardevelopment.com/doc/africa-s-biosimilar-landscape-outlook-current-challenges-0001 .
- CHAI and ACS announce agreement to expand Cancer Access Partnership [press release]. 2021.
- Biocon. Biocon [Internet]2019. [cited 2024]. Available from: https://www.biocon.com/mylan-and-biocon-launch-first-trastuzumab-biosimilar-ogivri-in-australia/ .
- World Health Organization. WHO guideline on country pharmaceutical pricing policies. World Health Organization; 2020. Available from: https://iris.who.int/handle/10665/335692
