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Bioanalytical requirements and biosimilars: How does the molecule stack up?

When the patent on a previously ground-breaking blockbuster chemical expires, biosimilar versions of this medication could enter the market. Biosimilars, which are frequently a more cost-effective alternative, can increase access to crucial treatments.

But, in order to beat the competition, developers must work swiftly to get their biosimilar to market. To effectively launch a novel biosimilar product, researchers must demonstrate that their product is clearly similar to the innovator product, which necessitates both pharmacokinetic (PK) and immunogenicity comparability studies.

Jim McNally, Chief Scientific Officer, and Lynn Kamen, Scientific Officer at BioAgilytix, analyze the developing biosimilars market in this article, outlining the hurdles that developers beginning the road from preclinical to commercial can expect to face.

The biosimilars market is expanding.

The success of blockbuster therapies can be due to the drug's unique properties as well as the protective patent that prevents others from developing similar, competing goods. As a result, these blockbuster molecules tend to dominate the market, limiting access to other potential alternatives and, as a result, limiting competition, which might effect prices.

• Yet, once the blockbuster drug's patent expires, new, biosimilar treatments with comparable efficacy, safety, and immunogenicity may enter a previously forbidden market. 
• Biosimilars can help to increase patient access to essential medicines, particularly in developing countries, by making them more affordable.
• This is an appealing prospect for medication makers, as evidenced by the global biosimilars market growth between 2015 and 2020 as a result of a wave of expired patents for blockbuster compounds. 
• Throughout this time, the value of biosimilars increased at a compound annual growth rate (CAGR) of 78%, reaching roughly $17.9 billion in 20201. With 26 blockbuster compounds projected to go off patent in the next five years2 and medications like 
• Humira expected to have up to 11 biosimilars by 20233, this rise is expected to continue, reaching an estimated $75 billion by 20301.
• Recognizing the need for patients to have greater access to vital treatments, government bodies and agencies are assisting in the expansion of the biosimilars industry. 
• The World Health Organization is currently modifying its biosimilar development standards to address the requirement for frequently lengthy and costly comparative efficacy trials. 
• The federal government of the United States has also made policy adjustments that allow select hospitals that use biosimilars to be reimbursed at a higher rate.

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Bioanalysis is a critical step in bringing biosimilars to market.

With so many medication companies focusing on the biosimilars sector, acquiring a market share can be difficult. Not only will they have to overcome the challenges of developing a medicine that can be proved to have equal efficacy and safety to the originator, but they will also have to pass the important milestones on the route to market at a rapid pace in order to compete. Developers must therefore grasp what is required of their biosimilar at each milestone before beginning their journey from preclinical to commercial in order to prepare and accelerate timescales.

• In terms of regulatory standards, the FDA will only approve a biosimilar if the developer can demonstrate that it is highly comparable to an already approved innovator reference product (RP). 
• This includes establishing that there are no clinically significant changes in the biosimilar's safety, purity, and potency.
•  Analytical data must demonstrate structural and functional similarities. Pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) studies will also be required during the clinical phases.
• As a result, having robust and reliable PK and immunogenicity assays in place is crucial to ensuring that biosimilar clinical studies reach critical schedules and stay within budget.

Testing for pharmacokinetic comparability

When comparing the biosimilar to the RP, it is necessary to understand how the human body interacts with each medicine, from administration to absorption, distribution, metabolism, and excretion. Several clinical trial patient samples (for example, plasma, urine, and saliva) can be tested to determine the biosimilar's interaction with the body, as well as the strength and duration of its efficacy.

• When compared to immunogenicity testing, showing PK comparability between the biosimilar and RP poses fewer hurdles. Previously, PK tests were developed with two standard curves, one for the reference product and one for the biosimilar. 
• Recent trends, however, have oriented the assay design to a one assay method, demonstrating the comparability of standard curves of the RP and biosimilar in development, and using only one standard curve with assay QCs from both originator and biosimilar products. 
• As a result, samples from clinical trial participants receiving the biosimilar as well as those on the RP will be analyzed using the same assay.
• Although the construction of PK assays is frequently uncomplicated, bioanalytical developers must address the inherent variability that will arise as a result of minor changes in manufacturing methods. 
• Even when making an innovative medicine, there will always be tiny little changes across batches, influencing the drug's behaviour in some minor way.

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Testing for immunogenicity comparability

Unlike PK testing, methodologies for determining if the immunogenicity of the RP and the biosimilar is comparable are generally established utilising a two-assay methodology with a single positive control. The critical reagent in the RP anti-drug antibody (ADA) assay will be RP material, whereas the critical reagent in the biosimilar ADA assay will be biosimilar material.

• Although some have suggested that the single assay approach to immunogenicity technique development is more time-efficient and cost-effective, it can cause problems. 
• Because immunogenicity assays are dependent on the individual drug being examined, slight variations between the biosimilar and RP may result in large differences in antidrug antibody detection. 
• It is more difficult to identify whether the difference in immunogencity is due to process variances or if the two molecules are significantly different without separate assays to assess the potential differences.

Platform enhancements for immunogenicity assessment present new issues.

In addition to the need to design, develop, and validate two assays rather than one, there are a number of hurdles that bioanalytical scientists should expect to experience while bringing a biosimilar to market.

• Several of the initial innovative anti-drug antibody (ADA) assays for assessing immunogenicity were developed many years ago, under older regulatory guidance. The technologies utilised to conduct these tests have improved significantly since then. 
• As a result, some previously prepared assays may no longer meet today's standards. 
• This means that bioanalytical developers are fundamentally required to improve on current assays and, in essence, build an entirely new test that is compliant with the standards regulations.
• Yet, as sensitivity improves, it is inevitable that more individuals who would not have been identified as having an immune response using the old testing method are found with this new assay. 
• As a result, the number of people who responded to the RP may differ from what was previously reported or mentioned on the RP's label. 
• Although this disparity may raise concerns about the applicability and accuracy of the test, developers should be aware that regulators are generally aware of this common issue.
• Another consideration for makers of biosimilar comparability assays investigating immunogenicity is that clinical trial participants will likely have had limited access to medications other than the RP to treat their condition. 
• This indicates that many of these participants may have previously been exposed to the RP, increasing the possibility of pre-existing immunogenicity to both the RP and the biosimilar. Again, developers should be aware that this is a regular issue that regulators perceive to be a likely occurrence.

Bioanalytical knowledge can hasten the path to market.

When a biosimilar reaches the point when PK and immunogenicity comparability testing is underway, a significant financial commitment has already been made. If these assays are not suitable for purpose and the biosimilar fails the comparability trials, the developer and others who invested in the research could suffer severe consequences.

As a result, it is critical that these assays be robust, requiring skill and experience to overcome the hurdles involved and accomplish rapid development and validation. Robust PK and immunogenicity assays can be established fast by relying on people with the appropriate bioanalytical skills as well as the most recent analytical platforms available for support, potentially allowing a biosimilar to be delivered to the market before competition drugs.

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Looking forward

As more biosimilars enter the development pipeline and begin their trip to market, developers must be mindful of the problems that can occur during the important clinical testing period. Developers can prepare for success by studying the impact of variance, the advancement of technology since the RP's approval, and major regulatory changes. Therefore, developing robust and reliable PK and immunogenicity assays will ultimately be on on experience and skill. Biosimilar developers can overcome the hurdles involved and increase their speed to market with the help of professional bioanalytical partners.