The Evolution of Medicine
Exploring Biopharmaceuticals and Biosimilars
Gillian Woollett, MA, DPhil, VP and Head of Regulatory Strategy and Policy, Samsung Bioepis
1. How is innovation driving the development of novel biopharmaceuticals and biosimilars?
Just like with any other industry, biotech relies on new products replacing old – the virtuous cycle. The competition from biosimilars nibbles at the heels of the originators, and they innovate to create novel options as biosimilars replace older biologics with competitive versions that improve access and affordability. Known as the Virtuous Cycle, this is demonstrated by the success of generics where some 80% of the doses of small molecule drugs consumed by patients around the world are generics. It will be a while before biosimilars achieve that level of success, but the savings that would represent allow for the next generation of medicines to be paid for at premium prices.
And all biologics also benefit from the advancements in technology. Biologics development technology has advanced significantly over the past few years, with biosimilars being able to benefit every bit as much as originator biologics. Better scientific tools are used to demonstrate high degree of similarity between the marketed originator biologics and biosimilars, as well as for any biologics pre- and post-manufacturing changes, and this allows sponsors and regulators to anticipate potential clinical significance if there are differences. Biosimilar developers can better characterize the originator biologics to establish the quality target product profile through advancement in such analytical technologies. Advances in manufacturing technologies also support consistent manufacturing of high-quality biosimilars, as well as their future reference products still under development. Further innovations in analytical tools such as the multi-attribute method (MAM) could improve the efficiency in development of biologics leading to faster patient access to valuable treatments.
2. How are advances in manufacturing processes and technologies improving the scalability and cost-effectiveness of biopharmaceutical production?
While advances in manufacturing processes and technologies are improving the scalability and cost-effectiveness of biopharmaceutical production, increasing costs of raw materials and maintaining quality manufacturing facilities are hurdles to sustainable biosimilar market that will always incur significant costs. Quality is important but can be expensive to maintain. Overall efficiency and reliable quality will always be important for biopharmaceutical manufacturing. There are also immediate opportunities to improving the efficiency of biosimilar development by reassessing the current regulatory requirements, and removing those expectations that do not contribute to the quality, safety and efficacy of the products finally approved. This is called regulatory streamlining. Further, harmonizing the regulatory requirements for different jurisdictions could provide a more feasible environment for biosimilar development.
More specifically:
• Biosimilar development has contributed to advancements in analytical methods and a better understanding of biologics and which variations are clinically relevant. This was often not available when the originator biologics used as reference products for biosimilars were first developed. A biosimilar sponsor first conducts an analysis of the refence originator biologic, sourced commercially, through extensive “characterization” of multiple samples of that reference. After quality features are defined, the biosimilar sponsor designs a manufacturing process to make that biosimilar which is controlled and reproducible, giving a product that meets those very specific quality specifications for each stage, from cell line production to mass scale production. The quality of the biosimilar is monitored and controlled throughout for every batch and throughout the whole lifecycle, just as is the case for any other biologic.
• The science of biosimilars and the use of biosimilars in real-world practice has led to a better knowledge and understanding of biologics in general, and is also enabling a reconsideration of whether comparative clinical efficacy studies contribute any new information of value (see FDA’s Virtual Workshop, Increasing the Efficiency of Biosimilar Development Programs--Reevaluating the Need for Comparative Clinical Efficacy Studies, 12-13 Sep 23). This raises fundamental scientific and ethical questions.
• There remains no ‘residual uncertainty’ discoverable by a clinical equivalence study because such studies are much less sensitive to compositional differences than are analytical comparisons
• Consequently, comparative clinical efficacy studies are not informative – MHRA has concluded that they will not routinely be required. Other regulators are reconsidering. WHO has revised their guidelines
• Regulatory certainty that no such comparative clinical studies will be expected by regulators can make future biosimilars eminently more feasible.
3. How do biopharmaceuticals and biosimilars contribute to improving patient access and outcomes?
Biologics have become mainstay treatments for many chronic and acute diseases, becoming increasingly fundamental in reducing mortality and managing multiple medical conditions. However, access to these treatments can be limited, often due to high cost of treatment or lack of necessary infrastructure to ensure appropriate care, e.g. timely diagnosis.
Biosimilars, as lower cost alternatives, play an important role in alleviating the financial burden faced by healthcare systems, as well as by increasing surety of supply. In the US, the past five years’ savings due to biosimilars has been estimated to be 40 billion USD (compared to the anticipated spending without biosimilar competition over the same period). Similarly, estimates suggest there is up to 180 billion USD of potential savings from biosimilars between 2023 and 2027. In Europe, the cumulative savings from biosimilars are estimated to be over 30 billion EUR since the introduction of the first biosimilar in 2006. Those savings become available for the next generation of originator biologics, as well as the infrastructure needed for the use of both biosimilars and originators.
Biosimilars also play an important role in improving the quality of life for patients through earlier access to optimal care. When patients do not have timely access to biologic medicines, it can significantly impact their disease progression in an irreversible manner. This is particularly important for the often debilitating, progressive, and fatal diseases treated by biologics. However, the introduction of biosimilars can cause higher utilization of the molecule as lower costs bring more patients within the window for feasible treatment (e.g., UK with filgrastim). Indeed, in some countries, the reference products are not available at all, and biosimilars allow essential therapies to become an option (e.g. Eastern EU as well as many low- and middle-income countries elsewhere).
4. What are the considerations for ensuring patient safety and efficacy in this rapidly evolving field?
As with any approved biologic, good pharmacovigilance practices are important to ensure patient safety and efficacy. Quality is not an issue specific to biosimilars, and good manufacturing practice are essential for all medicines. Pharmacovigilance systems vary between jurisdictions, and monitors not only the safety of medications but also the effectiveness of medications allowing healthcare professionals to identify and mitigate risk, avoid adverse drug reactions, and improve patient care. Through reliable pharmacovigilance, real-world evidence for biosimilars has been accumulated which has provided additional confidence in biosimilars by demonstrating the same clinical benefits as the originator products without differences in safety and efficacy.
As we move towards single global development of biosimilars, the availability of products that are the same across jurisdictions is a further assurance of regulatory consistency and quality, because a flag in one jurisdiction can alert others. Just as the branded biologics used as reference products for biosimilars are the same across the world, so having the biosimilars to them be the same will represent progress in the access and availability of quality-assured, safe and effective biologics for all the patients who need them.
5. How are patient support programs or initiatives positively impacting biosimilar adoption rates?
In general, biosimilars sponsors provide a range of support services to patients that are comparable to those of their reference products. However, by definition of being biosimilars to products that have been available to health care providers (HCPs) and their patients for many years, there is already significant understanding of the options available, within any given therapeutic area. However, biosimilars per se may be new to some HCPs so having policies to improve information availability, and affordability of biosimilars at the government/regulatory authority levels and having educational materials from theses trusted sources will significantly improve the confidence of patients and healthcare providers in biosimilars and increase patient access.
6. How do market dynamics, such as healthcare reforms or shifts in healthcare spending, influence investment and innovation in biopharmaceuticals and biosimilars?
Market dynamics represent, by definition of the term, a changing commercial environment. And commercial feasibility will always be an important question that is often product and therapeutic area specific. Consequently, market dynamics will always have an impact on the decision to invest in any biologic. Considerations will include whether to develop biosimilars or innovative biopharmaceuticals as the feasibility of either is highly dependent on the market success of already available biologics for that particular therapeutic area and with which any new entrants must compete, and development resources will always be finite.
Further, while the availability of biosimilars has led to increased patient access and a lowering of healthcare costs, a sustainable market for biosimilars that can continue to contribute to cost savings and provide broader access to biologics more quickly must still have some metrics of predictability. The rule of thumb for a biosimilar is a 7-10 years development time and hundreds of dollars of investments per candidate. Consequently, regulatory predictability and a fair market with some level of commercial certainty are crucial in pulling through the investment for any biologic. Progress is being made on regulatory streamlining but it is slow. Efficiency in biosimilar development could further influence investment and innovation in biopharmaceuticals and biosimilars – not least as fully 50% of originator biologics facing loss of exclusivity in the next ten years have no biosimilar candidates in development at an ll. By reevaluating the current requirements for biosimilar development and reducing unnecessary requirements based on the accumulated experience and knowledge, the cost of biosimilar development could be substantially reduced, which in turn makes the investment to develop biosimilars more feasible.
Author Bio
Gillian Woollett, MA, DPhil, is responsible for providing science-based regulatory strategy and policy expertise for biologics, including biosimilars, at Samsung Bioepis. She currently chairs the International Generic and Biosimilar Association’s (IGBA) Biosimilars Committee, working closely with World Health Organization (WHO) on access and affordability matters.
