Challenges in Biosimilar Development

With patents expiring for many successful biologic drugs, researchers are focusing on developing drugs that are competitively priced and affordable to patients who require critical medications for managing chronic diseases.

A biosimilar medicinal product is a replica of the innovator medicinal product with similar safety and efficacy profiles. ^1,2

Some of the popular biosimilars are monoclonal antibody biosimilars for cancer therapeutics, erythropoietin biosimilars, insulin biosimilars, interferon biosimilars, granulocyte colony-stimulating factor biosimilars, and human growth hormone biosimilars.

Small Molecules Versus Large Molecules

Small molecules are chemically synthesized and are simple, well-defined molecules.

They can be characterized fully and have highly predictable functions.

On the other hand, biologics are large molecules, typically protein-based, synthesized from highly complex biological sources.

As living systems are used in the manufacturing of biologics, the process requires sound technological expertise.

Despite large molecules posing challenges such as extreme sensitivity to processing and handling, as well as immunogenicity, their proven efficacy and precision in targeted therapy are making biologics popular in the treatment of many non-communicable and chronic diseases, including blood disorders, cancer, inflammatory diseases, and diabetes. ⁴

Current Scenario of Biosimilars

Approximately 32 biologics will lose patent rights by 2019, the combined sales of which are estimated to be around $51 billion. ⁶

However, developing biologics is a tedious and complex process, with many products taking approximately 10 to 15 years to reach the market. ⁷

Studies have indicated that the market will continue to grow at a rate exceeding 20% due to an increase in the incidence of chronic conditions, resulting in increased utilization of biologics.

The patent expiration of several best-selling biologicals opens the door for the approval of biosimilar versions of the original products.

These biosimilars are typically 20-30% less expensive than the innovator product.

The European Union (EU) has approved more than 20 biosimilars since it first granted consent to use a biosimilar, somatropin, in 2006. ¹⁰

It is anticipated that the global biosimilars market will surpass $35 billion by 2025, with a compound annual growth rate (CAGR) of 33%.

Challenges in Developing Biosimilars

➔ Difference in Regulatory Approval Processes Between Countries:

In the EU, the interchangeability of biosimilars does not require additional regulatory evaluation if the biosimilars demonstrate similar activity as the original product with no additional risk to the patient.

However, this is not acceptable to the US regulatory body that mandates complex and costly trials to demonstrate the interchangeability of biosimilars.

In addition, the USFDA limits the use of data extrapolation.

The additional regulatory requirement not only increases the timeline for biosimilars development but also increases the cost and impedes the manufacturer’s enthusiasm in pursuing biosimilars in the long run. ^{3, 13, 14}

➔ Development and Timeline Challenges:

It is estimated that the cost of developing biosimilars can range from $100 million to $200 million, with a development time of 5-9 years, excluding the cost of failure. ¹⁵

The Pharmaceutical Research and Manufacturers of America (PhRMA) estimated the cost of developing a biosimilar to be approximately $ 375 million as compared to $1.2 billion to develop a new biologic.

However, the development timelines for biosimilars are relatively shorter than those of biologics.

The Phase I and Phase III stages for biosimilars can be shortened, while the Phase II stage can be skipped due to the established therapeutic efficacy and safety of the biologic.¹⁶

➔ Clinical Challenges:

Immunogenicity is a potential risk with biosimilars.

Hence, stringent risk management plans and post-marketing surveillance of the drug should be implemented to monitor any potential adverse events. ^13,17

Another challenge is patient acceptance of biosimilars, which is often hindered by limited knowledge or awareness about these products.

Concerted efforts must be made to ensure that patients understand the basic principles of biosimilars and their ability to exert therapeutic efficacy at significantly lower costs than their biological counterparts. ¹⁸

➔ Analytical Challenges:

The physicochemical and structural comparability of biosimilars with the original product is difficult due to their inherent heterogeneity.

Analytic techniques such as mass spectroscopy, chromatography, or electrophoresis can be used to address some of the hurdles by: ^13,17,19

• Comparing biosimilars lots against a reference product to assess the pharmacokinetics and pharmacodynamics of the biosimilars.
• Understanding multiple mechanisms of action involved in in vitro characterization
• Choosing a bioassay should be a case-by-case decision depending upon the specificity and sensitivity of the biosimilars.

➔ Commercialization and Marketing Challenges:

Major pharmaceutical companies sometimes block other small players from producing biosimilars by creating restricted distribution agreements, leading to the unavailability of the innovator product sample.

In addition, patents are abused to prolong the monopoly of a brand name, thereby delaying patient access to more affordable and life-saving biosimilars. ¹³

➔ Establishing Concrete Guidelines for Market Approval:

The US FDA and regulatory bodies of other countries have yet to establish streamlined guidelines for the marketing approval of biosimilars. ^3,13,14

The Way Forward

➔ Biosimilars manufacturers can promote optimization by: ⁵

• Building trust and confidence between payers and providers by reimbursing biosimilars and providing cost-saving alternative solutions for long-term treatment.
• Engage with regulatory authorities during the early stages of biosimilar development to capture their interest.

➔ Enabling the extrapolation of data by regulatory authorities in the country is one of the crucial steps that can accelerate the development of biosimilars. This, in turn, helps establish fair market trade. ⁵

➔ Contract research organizations (CROs) can lend expertise to sponsor companies:²⁰

• To develop a holistic, tailor-made, and optimal clinical development plan (CDP) without losing focus on the commercial aspect of the business
• By using therapeutic and regulatory expertise, real-world data, and market access strategies to influence access to biosimilars and to establish competitive pricing.

➔ By forging strategic global alliances and enhancing their expertise in biosimilars development.

Conclusion

Advanced manufacturing processes, limiting patent litigations, and changes in physicians’ and patients’ perceptions towards biosimilars can mitigate the current level of complexity and ambiguity involved in promoting biosimilars.¹⁰

In addition, the overall cost of biosimilars can also be reduced by involving a larger number of players; these measures will allow for safer and wider access to biosimilar products to patients around the globe.

Sources

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