The Evolving Landscape of Biosimilars
Challenges, Opportunities, and the Future of Biopharmaceutical Access
Gillian Woollett, MA, DPhil, VP and Head of Regulatory Strategy and Policy, Samsung Bioepis
1. What are the unique challenges and opportunities in the biosimilars market compared to traditional pharmaceuticals?
The commercial environment is critical to our business. In some markets complex reimbursement systems have perverse incentives that can actually encourage the use of the most expensive product. This situation needs to be rectified if biosimilars are to offer a sustainable business. A good start is more transparency so that the use of the most cost-effective medicine is visibly encouraged, and also that biosimilars are used in a manner that the patients can afford and so improve access.
Today, way too many patients don’t have timely access to these biologic medicines, either brand or biosimilar, as these are not saturated markets. In progressive diseases that means greater pain and disability for patients. This occurs even in rich countries like in US and EU. Using available science and technology to make biosimilars efficiently and cost effectively would help and can change so many lives.
Improving the efficiency of development, in terms of reduced cost and time, can have a significant impact in the biosimilar products that become available, especially the variety of products that they reference (see IQVIA report “Assessing the Biosimilar Void – Achieving Sustainable Levels of Biosimilar Competition in Europe”). The science to support this is available and published in the peer-reviewed literature. But old habits die hard and reducing regulatory burdens are tough. However, regulatory certainty is essential for sponsors given development times of up to a decade. Both streamlining (through reducing unnecessary clinical studies) and global comparator product (if the reference is global then a biosimilar to it should be too) will not change the quality, safety and efficacy of the biosimilars approved, and needs to be possible to expand the biosimilars available.
WHO updated their Biosimilar Guidelines in 2022 and the implementation of these by incorporating state-of-the-art science, recognizing the experience to date with biosimilars, could significantly change the feasibility of biosimilars to many more reference products. There is no sound scientific case for continuing the extensive routine clinical comparative efficacy studies, nor even for the 3-way pharmacokinetics (PK) studies still expected in many instances. To change access and affordability for patients, allowing this fully state-of-the-art science-based approach that will not change the nature of the approved product would make a huge difference to the biosimilar community and will open up more opportunities for all stakeholders. It may even help fill the void identified by Medicines for Europe in the biosimilars pipeline.
According to IQVIA, 70% of biologics face loss of exclusivity in the future but 47% have no biosimilars being made to them at all. And biosimilars take 8-10 years to develop and up to $500 million for development. The market has to be sustainable – tough, especially in the US, where pricing is obtuse. Bottom line – Brand development costs and generic pricing will not build a sustainable biologics market anywhere in the world.
2. What role does advocacy and education play in increasing acceptance and adoption of biosimilars?
We have seen tremendous improvement in the acceptance of biosimilars over the years, helped by various advocacy and education efforts by the regulators and the industry. Biosimilars are behaving just like their reference products in every indication of that reference. Initially, physicians were very skeptical about using a biosimilar for the indications of the reference product in which the biosimilar itself was not directly studied clinically. However, based on the totality of evidence generated throughout the biosimilar development, it is widely accepted that well-established safety and efficacy information from the reference product can be bridged to the biosimilar for all indications. This makes sense as the extrapolation is actually between the active molecules in the reference and the biosimilar, and they must do the same thing in a clinical setting – they have no choice. Through continuous advocacy and education activities, the concept of extrapolation of indications is now widely accepted by healthcare providers and their patients.
The market is better informed today about biosimilars than 10 years ago, but the level of understanding and acceptance still various across different therapeutic categories. As a biosimilar become available in each new therapeutic area, new education efforts are needed. Similarly, as different health care systems and jurisdictions gain access to biosimilars, some with little or no experience with the reference product, so education of health care providers becomes essential. This allows more rapid adoption and patient access to occur.
In the US, when the first infliximab biosimilar was launched in 2016, there was only gradual acceptance of the new treatment options. As experience with biosimilars has grown over the years, rheumatologists became more comfortable prescribing biosimilars. In oncology, there was a more rapid uptake (partly incented by the payment system), but the rate of adoption in other therapeutic categories such as insulin and adalimumab remains slow. If anything is to be learnt from the past several years of experience with biosimilars, it is that a concerted efforts across stakeholders to accelerate biosimilar use, in order to achieve lower systemwide healthcare costs.
Multiple factors come into play in increasing acceptance and adoption of biosimilars, but one of the most critical factors, alongside reimbursement being appropriate, is health care provider’s willingness and confidence in prescribing biosimilars in real-world clinical practice. And that can be facilitated through education on biosimilars from trusted sources, such as the US FDA. Healthcare providers and patients that may be new to the concepts of biosimilars need an understanding of what exactly a biosimilar is, what is the experience to date with these products, and not just in the US, but globally.
Biosimilars have been in Europe for more than 18 years and in the US for more than 9 years, but there is still room for improvement if biosimilars are going to grow beyond initial success.
3. What are the challenges in educating healthcare providers and patients about the safety and efficacy of biosimilars?
Challenges in educating healthcare providers and patients can be their relatively limited clinical experience with biologics, even before biosimilars become available. This varies by jurisdiction and therapeutic area. However, we now have accumulated data on various biosimilar products developed to many reference products, and the biosimilars have been shown to work exactly as expected. Even switching established patients creates no safety or efficacy issues (documented in a large meta data study published by FDA - Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis).
The lack of knowledge or confidence regarding biosimilars among some healthcare providers continues to serve as a barrier to adoption, and creates access delays for patients that it is important to address. More trusted sources of educational materials, such as FDA (FDA Multimedia Educational Materials), and involvement by professional societies is helping.
For instance, in the US, interchangeability is often misunderstood and misportrayed. Prescribers may delay access by some patients to biosimilars that are already available because those prescribers are waiting on an FDA interchangeability designation that is only relevant to dispensing and not prescribing (see the peer-reviewed paper Interchangeability for Biologics is a Legal Distinction in the USA, Not a Clinical One). The FDA designation of interchangeability is not relevant to physician-administered biologics, but can allow substitution by a pharmacist for those biosimilars that are dispensed by a pharmacist for self-administration. The existence of a legal statute and an additional regulatory designation for interchangeability triggered misunderstanding around interchangeable biologics as representing a "higher" standard and this is not the case. In order to combat this kind of misinformation, education by regulators especially, but also by healthcare institutions/associations and individual companies will continue to be important.
We need everyone involved in the healthcare space to pay attention to where the market is now and where it is going for biologics and biosimilars. The pipeline for originator biologics offers tremendous opportunities, but these products need to be paid for by the savings biosimilars offers for the older biologics that are off patent. If these biosimilars are not prescribed routinely in clinical practice, then the goal to realize the potential of biosimilars will not happen, but even more importantly the promise of future originator biologics cannot be achieved either. The financial challenges to healthcare systems, especially the US where some 60% by value of the biologics market resides, will not change and patients will continue to suffer through lack of access. The more stakeholders learn about the value biosimilars offer as lower cost alternatives to high-priced originator biologics (after exclusivity and patents expire), the sooner we will see real momentum in their adoption, greater access by patients and drug cost savings to our healthcare system.
4. 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, 12-13Sep23). 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 reconsidering5. 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.
5. Can you discuss the role of artificial intelligence and data analytics in drug discovery and development for biopharmaceuticals and biosimilars?
Any progress in the efficiency of research and development of medicinal biologics that AI can offer will be most welcome, but as a highly regulated industry there are special considerations that apply. The methodologies would likely have to be transparent and evaluatable by regulators and that will entail significant extra steps and likely delays.
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.
