Professor Applied Physics and Instrumentation Faculty of Sciences, Kingston University, UK.
The differences between traditional generics and biosimilars are really quite fundamental. Biologicals are orders of magnitude more complex both in structure and in terms of impurity profile compared to small molecules. As a consequence of this increased complexity, it is more challenging to convince the regulatory authorities that the "biosimilar" is similar to the innovator product. Therefore, biologicals will not be treated as standard generics.
With standard generics, the primary concern of regulators relates to whether the formulated generic will behave similarly to the innovator formulation specifically with respect to the drug release and absorption profile. Therefore, there is the need for bioequivalence studies to demonstrate that peak and total plasma levels are equivalent, i.e. within 80 - 125% of each other at the 90% confidence level.
With biologicals, the situation is far more complex. In fact, there is a spectrum of complexity from simple peptides through to complex products such as live viruses. It follows that some biologicals are in fact so complex that they will not be suitable for development as biosimilars. For now, the biosimilar concept is generally applied to the simpler and highly purified recombinant proteins such as insulin, somatropin, GCSF, epoetin and interferon.
But, even with these products, the prevailing view is that they are too complex to enable similarity to be demonstrated using physico-chemical and biological testing alone. These proteins are comprised of long chains of often over a hundred or many hundreds of amino acids (the natural building blocks of proteins). This amino acid chain is intricately folded and correct folding is essential to ensure the desired
biological activity of the protein. The folded structures are held together by weak non-covalent bonds that are easily disrupted and dependant on the environment in which the protein is contained. Additionally, there is potential for the existence of a multitude of degradation products and contaminating impurities arising from the manufacturing process. These impurities can impact the activity of the protein and more importantly contribute to immunogenicity. Therefore, regulatory authorities will require a higher level of assurance that the similar biological medicinal product possesses a similar safety and efficacy profile as the originator product. This will require extensive bridging with non-clinical and clinical data to achieve regulatory approval, something which is not required for standard generics.
Therefore, biosimilars differ from traditional generics in two fundamental ways. First, they require greater expertise and infrastructure for their production and second, they will only be approved following successful completion of a costly non-clinical and clinical development program.
Clearly biological medicines are generally expensive and consequently may be somewhat unaffordable to many patients throughout the world. This is not just the case in emerging markets but even in established markets where budget limitations could mean that patients may not always receive the latest treatments. It might appear that the introduction of biosimilars could provide the "magic solution." In Europe, for instance, the environment for biosimilars is very complex. Biological medicines currently remain expensive to produce and with stringent regulatory requirements for biosimilars in Europe, development costs will most likely remain high. Thus, there may be relatively limited scope for price reductions at least for some products. In this respect, it is interesting to note that one pharmaceutical company announced discontinuation of their epoetin development program, since epoetin was unlikely to be a good return on investment.
A number of factors, which vary between regions, influence the market. First and foremost is the affordability of the originator product and the extent of price saving on switching to a biosimilar. In Europe a 25% reduction has had little sway in persuading the prescribers to switch to biosimilars or other cheaper brands. There are many reasons for this, including a number of hurdles that need to be surmounted in order to persuade prescribers and patients to change to cheaper brands. If a patient is doing well, for instance, there will be a reluctance to switch to a different medicine, which might lead to or more likely be falsely implicated with adverse effects. Furthermore, the innovator companies have developed a symbiotic relationship with the prescribers, providing them with support that may include research fellow funding, educational support, and associated materials, such as pen delivery devices. This may make it difficult for biosimilar companies to break into the market initially.
However, as the cost of medicines increases, health economics is becoming more and more of a driving factor in prescribing decisions and this should swing the market towards greater usage of biosimilars. In parts of the Asia region, affordability of medicines is a challenge. For instance, a driving force behind increasing biopharmaceutical industry activity in India appears to be the need to deliver affordable healthcare to the domestic market. In South-East Asia, for example, regulators are determining how to best deal with biosimilars. This also points towards a potentially sizeable market in this region.
The biosimilar market is complex. Unlike standard generics prescribers and purchasers will need to be educated directly, and also indirectly, for instance through journal articles. Innovator companies are making efforts to protect their market, and biosimilar manufacturers will need to do the same. Ultimately, existing perceptions will need to be changed, reinforcing that biosimilars are not of inferior quality and utilise the latest technology to ensure quality. Furthermore, the latest analytical technology is being employed together with confirmatory testing so that biosimilars are as safe and effective as the innovator products.
Biosimilars will eventually bring down the cost of biological medicines and in doing so will expand the market.
In the US there is only one example of a biogeneric approval, for Omnitrope, which was approved after years of prevarication by the FDA. When Omnitrope was finally approved in the US, the FDA advised that this approval should not be seen as a precedent for other follow-on biologicals. Omnitrope was approved under Section 505(b)(2) of the Food Drug and Cosmetic (FD&C) Act, which essentially allows a bibliographic / hybrid type of application.
Largely for historical reasons, most biological medicines are regulated not by the FD&C but instead by the Public Health Service Act (PHSA). The PHSA arises from legislation that is over 100 years old and defines a biological medicine as "any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, or blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment or cure of a disease of human beings." It seems that most recombinant proteins, which were not even conceivable when the legislation was drafted, now fall under this definition. At the time when the PHSA was passed, the analytical tools available today did not exist, so that the only way of ensuring product consistency was by relying on an established and consistent process. Consequently, a similar product from a new manufacturer was perceived as a novel product and there was therefore no need for a mechanism for filing of truncated submissions for biological medicines. Today the manufacture of similar biologicals is possible but there remains no legal basis for their approval in the US until the current legislation is changed.
In fact, not all proteins are covered by the PHSA. Included in these exceptions are hormones such as insulin and somatropin which when they were introduced were regulated under the FD&C and therefore do qualify for truncated marketing application procedures, specifically under Section 505(b)(2) of the FD&C Act. It was under this legislation that Omnitope was approved as a biosimilar in the US.
There is now the need to clarify the legislation in the US to bring practices in line with current thinking to allow the FDA to regulate biosimilars as it can for generic drugs. Several bills have been prepared but so far none have made it into legislation.
As far as the EU is concerned, when Omnitrope was filed the EU found itself in the same position as the US with no appropriate regulatory framework to deal with biosimilars. So, while in the EU Omnitrope was granted a positive opinion by the assessment committee (Committee for Medicinal Products for Human Use, or CHMP), approval was blocked by the European Commission because there was no appropriate legal basis for such an approval. However, unlike the US, European regulators promptly amended the legislation, which conveniently happened to be under revision at the time. In Europe, there is as a result now a very clear legal pathway for the approval of biosimilars.
Subsequent to revision of the EU legislation, a raft of guidelines has been produced to provide further direction to companies intending to bring biosimilars to the EU market. Despite this, regulatory data requirements are relatively extensive and the guidelines are not fully transparent. To date only four products have been approved in Europe (two somatropins and two epoetins) and one product has been rejected (an interferon alpha). Therefore, approval cannot be considered as a forgone conclusion.
There is the need to give careful consideration to the development program and to go to the European regulators for scientific advice. In fact, getting the biosimilar program right requires considerable skill and the fusion of expertise from regulatory professionals, clinicians, statisticians, pharmacologists, toxicologists, analytical biochemists and others.
Some innovator companies see biosimilars as an opportunity to enter new markets themselves. However, others see their entry as a significant threat and are exerting effort to keep biosimilars out of the market. For example, some innovator companies are engaging in political lobbying to make regulatory requirements as arduous as possible and to block substitution. They are also priming the market against biosimilars through articles and sales and marketing activities. These companies which have been working closely with their customers for years often have strong relationships with the prescribing community. Also, list prices are not necessarily the prices hospitals pay and innovator companies may well meet the challenge of biosimilars with targeted discounting. These activities will present formidable hurdles to the biosimilar companies which will need to approach the sales and marketing of a biosimilar more like a branded medicine and not in the same way as traditional generics. Of course, innovator companies will need to continue to be innovative, since additional innovation is their key protection against biosimilars.
New and better patent protected products have and will supplant the older products which are the focus of attention for the biosimilar companies. On the other hand, by making medicines more affordable, biosimilar companies will naturally expand the market. Furthermore, healthcare payers, such as national healthcare systems, are becoming more and more influential and biosimilars will be perceived as good value, which is what purchasers are looking at and insist on buying.
Overall, there is room for both innovators and biosimilar manufacturers but clearly both are in competition, and only the skillful companies will endure. The innovators will need to innovate and the biosimilar manufacturers will need to keep production and development costs as low as possible. Above all, there is a need to appreciate that marketing a biosimilar involves trail blazing new approaches that are different from those applied to traditional generics.
While there is a need to apply the latest technologies to make manufacturing as efficient as possible and thereby keep the cost base as low as possible, there is no reason why biosimilar manufacturers should not be innovative themselves. Customers will pay extra for innovation and thereby provide for increased profits for the biosimilar manufacturers. And innovation does not need to always produce altered proteins (which are not strictly biosimilars), although that is certainly worth considering. With respect to biosimilars innovation could involve novel formulations, presentations, delivery systems and packaging. With biosimilars the world of generics and innovation merge to generate a new breed of medicinal products entirely.
Cecil Nick Principal Consultant, PAREXEL Consulting provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. He has been involved in the development and regulatory approval of a number of innovative and biosimilar medicinal products in Europe. He also has extensive experience in the development and EU registration of biotechnology and blood products, devices, new chemical entities, CMC, orphan drugs, health economics, and scientific advice.