The Breakthrough of Biosimilars: a promise to foster unprecedented life-saving biologics
Global acceptance of biologic drugs has witnessed several challenges, which have been addressed with significant effort, but the number of products has grown since the approval of the first biopharmaceutical in 1982.
What is a biosimilar medicine?
Within the past three decades, nearly 300 recombinant biopharmaceuticals have been patented and approved; as the older ones come off-patent, companies are developing and selling copies commonly referred to as biosimilars. While most patients have a limited understanding of the risks and benefits of biosimilars, they generally trust their physician when prescribing them; however, education programs directed to healthcare providers on biosimilars have had a limited impact, and the need to grow more familiar with the benefits has become a priority.
If the goal is global biosimilar adoption as alternative treatment options, the development of such products needs to be augmented with product trust, predictable regulatory frameworks and sustainable policies.
In addition, establishing robust biosimilar pharmacovigilance systems could ensure continuous feedback on their therapeutic success and maintain a patient-centred approach to biosimilar availability.
- Biological Products are used to diagnose, prevent, treat and cure diseases and medical conditions. They are generally large and complex molecules produced through biotechnology in a living system (a microorganism, plant cell or animal cell). They present challenges in characterising and manufacturing. Slight differences between manufactured lots are typical and expected (a specific strategy must be in place to control product variations); however, such procedures must ensure consistent clinical performance.
- Reference Product. It is the single biological product already approved by the regulatory authority after presenting full safety and effectiveness data and against which a proposed biosimilar product is compared.
- Biosimilar Product. It is a biological product that is highly similar to and has no clinically meaningful differences from an existing approved reference product.
- What does “Highly Similar” means? The manufacturer has to demonstrate that the proposed biosimilar is highly similar to the reference product by extensively characterising (analysing) the structure and function of both (reference and proposed biosimilar) by state-of-the-art technology, including purity, chemical identity, and bioactivity. Minor differences in clinically inactive components are acceptable, and the regulatory authority carefully evaluates such differences. The manufacturer must also demonstrate that the proposed biosimilar has no clinically meaningful differences, shown through human pharmacokinetic and pharmacodynamic studies, an assessment of clinical immunogenicity, and other clinical studies if needed.
- What is an interchangeable product? It is a biosimilar product that meets additional requirements. Let us consider the FDA definition: “supplementary information provided to show the product is expected to produce the same clinical result as the reference product in any given patient; also, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable and a reference product will have been evaluated”. So, according to the FDA, an interchangeable product is a biosimilar that meets additional evaluation and testing (see below). Other regulatory agencies and the WHO have or are updating their guidelines to provide more flexibility and clarity for further reducing the need for non-clinical and clinical data to streamline the clinical development of biosimilars. Current data suggests that the state of the art analytical and functional testing and robust pharmacokinetic (PK) and pharmacodynamic (PD) studies are sufficient to demonstrate biosimilarity, whereas in vivo animal studies and large confirmatory efficacy and safety clinical trials are generally not needed. The FDA guidelines require analytical and PK/PD “bridging” studies by default, whereas the European Authority (EMA) and Health Canada guidelines require analytical bridging, but only PK/PD bridging if analytical bridging alone is insufficient. In addition, naming and labelling are crucial for the identification of products and also for pharmacovigilance and prescribing.
- What is the difference between Biosimilars and Generic drugs? Both are approved through different abbreviated pathways that avoid duplicating costly clinical trials. However, biosimilars are not generics, and there are significant differences: a generic has to be bioequivalent to the original branded drug, and the biosimilar manufacturer has to demonstrate that the product is highly similar to the reference product except for minor differences in clinically inactive components and that there are no clinically meaningful differences in terms of safety and effectiveness.
The critical point is that independent scientific and medical societies should play a more active role in providing prescribers and patients with objective information on biosimilars because many clinicians are not fully aware of the nature, structure, function, immunogenicity and efficacy/safety profile of biosimilars.
In a study reported by Cook, JW. et al. (2019), when asked to define a biosimilar, 74% of surveyed oncologists could not provide a satisfactory definition and 40% considered a biosimilar to be the same as a generic drug.
EMA and the FDA have developed a free Continuing Education Course for healthcare professionals to strengthen their knowledge and understanding of biosimilars and interchangeable products. The course is available on FDA’s website (www.fda.gov/CDERLearn) and provides levels 1 and 2 and videos.
We must make an important distinction: we must keep in mind that the FDA interchangeability designation, as described above, is a “legal distinction”; it allows the substitution by a USA pharmacist (biosimilar for reference product) without consulting the original prescriber. European Union regulators (EMA) have stated they consider all their approved biosimilars to be interchangeable; while not a legal designation in Europe, this is a scientific one with clinical ramifications.
Why biosimilars are important
The rationale for biosimilar use.
Physicians may be vulnerable to misinformation, especially when a new brand name appears, however, according to a recent analysis by Park, JP. et. al. (2022) https://doi.org/10.1007/s40259-022-00538-6
“all biosimilars approved in the highly regulated markets using the scientific standard of comparability are interchangeable with their reference products as a clinical matter; analytical differences understood and known do not alter the clinical outcome”. In the USA, a valuable tool, the Purple Book, lists licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations.
Another problem to consider is “the nocebo” effect, which negatively impacts the patient’s perceived treatment outcome resulting from the patient’s negative expectation about the change in therapy. Hence, the treating clinician and specialised nurses must mitigate the nocebo effect.
Consequently, despite the potential of biosimilars to positively impact expenditure (cost reduction) and patient access (particularly in emerging markets), they may be hampered by reluctance on the part of both healthcare professionals (HCPs) and patients to use them because of a lack of trust and understanding; also, prescribers may lack a clear motivation to use biosimilars. So, education and dissemination of clinical switch data and sharing positive switch experiences creating stakeholders’ confidence are essential.
Experienced HCPs advocate for a pragmatic approach when deciding whether to switch, initiating only bio-naïve patients with a biosimilar regardless of the treatment setting (acute or chronic) and, after evaluating outcomes in a certain number, deciding to switch patients from the reference product based on individual patient characteristics giving them the option to return to the reference product. This reassures patients that their physician controls treatment decisions as well as themselves.
Abundant information exists on the abovementioned matters triggered by an increasing number of affordable and efficacious biosimilars entering the marketplace.
Disparagement and misinformation about biosimilars can be countered by educational efforts (balanced educational materials about biosimilars should be made easily accessible), appropriate oversight and regulatory activities. Physicians, nurses, pharmacists and patient advocacy groups should work together to provide patients with consistent information about the value of biosimilars.
The above should include practical aspects of interchangeability and the clinical guidelines to address the concept of switching from one biosimilar to another biosimilar of the same biologic reference, which has emerged as a new practical option.
Increasing patient access to life-saving pharmaceuticals is central to the goal of Masters Speciality Pharma, a global pharmaceutical company. We collaborate with skilled pharmaceutical drug suppliers to the healthcare sector as well as life science partners. Our main objective is to provide vital medications to people in developing markets.