\"Follow-on\" proteins pose complex questions for patients, biopharmaceutical companies, and regulators. Understanding the challenges in the development of biosimilars by the industry and regulators and addressing them could pave the way for delivering affordable and better biological medicines to patients throughout the world.
Many of the blockbuster biological products that currently dominate the markets are coming to the end of their patent protection. The opportunity to provide more affordable "generic" versions is now attracting the interest of both generic and research-based pharmaceutical companies. The development of "generic" biological medicines referred to as "biosimilars" in Europe and increasingly in the rest of the world and as follow-on-proteins in the US, could well expand their availability and usage creating new markets, new opportunities and wider availability of life saving treatments.
However, those developing biosimilars face major challenges; first and foremost of these is that regulators do not accept that generic biological products can be the same as the innovator product, but only nearly the same or "similar." The use of the word "similar" rather than "same" may seem pedantic, but it has major repercussions and obligates the generic manufacturer to embark on a complex development programme in order to gain regulatory approval. This programme involves generating non-clinical and clinical data to demonstrate equivalent safety and efficacy to the original product. This raises the questions as to what and how much data is required for the regulatory approval. For the simpler products regulatory precedence now exists; but for the more complex proteins such as monoclonals, the jury is still to come out. The problem is that like any jury, every member has their own view, and this does not bode well for establishing a global programme for the development of a biosimilar. The complexity and uncertainty is exacerbated by the fact that regulations for market approval of biosimilars are still evolving around the world and at different rates. The European Union (EU) has led the way in establishing regulations for follow-on proteins and several biosimilar products have already been approved in the EU; these include somatropin, filgrastim and epoetin. Elsewhere, the regulatory landscape varies dramatically. In parts of Asia, such as India, although biosimilar products have been on the market for many years regulatory thinking is still evolving. In the United States, Congress has yet to establish regulations for follow-on proteins. Other major markets, such as Canada and Japan, have issued draft guidelines. In this maelstrom of views, industry has the opportunity to guide rational thinking with cogent scientifically robust arguments through comments to guidelines, participating at international meetings, regulatory scientific advice submissions and other such forums.
Even as regulations begin to appear, new questions are being raised: How should follow-on products for monoclonals and other complex proteins be handled? How much clinical data should be required to demonstrate equivalence? How similar does a biosimilar product need to be? The challenge for both regulators and the biopharmaceutical industry in this constantly changing environment is to maintain a reasoned approach and resolve the issues in a way that keeps the science of biosimilars moving forward for the benefit of patients around the world.
How "similar" is biosimilar?
One of the most basic issues surrounding follow-on proteins is determining what types of proteins can be considered biosimilar. One viewpoint is that only proteins that can be fully characterised, with no discernible differences in either the structure or impurity profile, can be considered biosimilar. However, this narrow view is not shared within the EU, where guidelines and precedence allow a degree of difference-provided this can be justified. For example, one approved biosimilar product is expressed from yeast, whereas its reference product is expressed from E coli. Although this variation in production method creates differences in the follow-on protein's impurity profile, those differences have been demonstrated not to impact safety or efficacy and the product has been accepted as biosimilar. Similarly differences in glycosylation profile have been justified and accepted by the EU regulators.
If lower-cost therapeutic proteins are to reach the market, more innovative and efficient production technologies, including transgenic production, must be introduced. Although these technologies may create differences in impurities or post-translational modifications, it should still be scientifically possible to demonstrate that the biosimilar product provides equivalent safety and efficacy to the reference product. While, there is no regulatory precedent for this approach today, this seems scientifically sound and hopefully common sense science will prevail.
On the other hand, if differences in primary structure or profound post-translational modifications are detected, then, according to current views such a product would need to be treated as a novel compound. Yet, such a clear-cut position may not be necessary or scientifically justified. As experience with biosimilars grows, regulators may become more comfortable in allowing greater flexibility and may approve less similar follow-on proteins based on an abridged "Biosimilar" approach. This approach can even be taken where significant differences from the reference product exist, although always equivalent safety and efficacy will need to be proven. However, we have not yet reached this point.
Can the biosimilar concept be applied to complex proteins?
The biosimilars approved under the current EU process represent just the beginning of a global biosimilar revolution. A host of other products, including follow-on monoclonal antibodies, exist or are in development and will probably be submitted to regulatory agencies in the years ahead.
The EU's "Guideline on Similar Biological Medical Products" (CHMP / 437 / 04) states that, in principle, the biosimilar concept applies to any biological medicine. However, the guideline notes that this will depend on a number of factors-including the ability to characterise the product. Clearly technology is moving forward apace and the power to characterise complex proteins down to the last atom is now a reality whereas a decade ago it was a dream. Methods such as MS-MS, 2D-NMR, and chemi-luminescence are but a few of the powerful tools available today that enable resolution to atomic levels, generation of high fidelity information on protein folding and detection of impurities even to picogram levels. Science allows full understanding as to how the protein binds to its ligand and the type of bonds involved. Biological testing using methods such as surface plasmon resonance, Fluorescence-Activated Cell Sorting (FACS) and other cell-based assays can provide a thorough insight into biological effects compared with the reference product. Thus, strong evidence of similar therapeutic effect can be available well before the biosimilar ever enters a patient.
These technologies should make it possible to demonstrate biosimilarity at the physico-chemical and biological level for virtually any highly purified protein. The next step in demonstrating biosimilarity requires leveraging current knowledge and filling the gaps by conducting appropriate non-clinical and clinical studies.
Even for small molecule generics, bioequivalence in terms of absorption needs to be demonstrated in clinical studies and so it is no surprise that this applies to biosimilars as well. However, for biosimilars, the EU regulators require more data to be convinced of similarity; for example, they will want evidence for equivalent efficacy and adequate safety, which will require clinical trials. The requisite clinical programme will vary and will require detailed thought and justification from the sponsor, who is well advised to work with external expertise and seek scientific advice from the regulatory agencies. In the EU it is incumbent on the sponsor to submit a scientifically robust justification in support of their programme and such submissions will play a significant role in shaping future thinking.
The size and complexity of the clinical programme will depend on the level of understanding and interactions of the protein structure, the impurity profile, and other characteristics, as well as the relative difficulty of demonstrating therapeutic equivalence. In some cases, a biosimilar development programme may require the study of more patients than were included in the innovator programme!
Can biosimilar development be globalised?
Key to the success of a biosimilar programme is accessing markets throughout the world, but regulations and experience around the globe differ dramatically. The adoption of a biosimilar approval pathway in the US and other major markets will certainly ignite new thinking that will influence current strategies for development of biosimilars and set new precedents for their approval.
For now, fundamental challenges confront the establishment of a global biosimilar programme. Foremost, there is currently no way of confirming that the reference product sold in one region is identical to that in another region even when they are sold under the same brand name, which indeed is not always the case. Until this problem is resolved, a worldwide biosimilar development programme cannot be a reality. Currently to achieve EU approval, the reference product must be sourced from within the EU. If similar demands are set in other regions, then development programmes will need to be replicated in each region, resulting in duplication of effort and unsustainable costs.
There is obviously an urgent need to establish some level of international harmonisation to allow mutual recognition of reference products and data for approved biosimilars.
Yet another challenge is regulatory concern about the impact of ethnicity. In reality, this should not be an issue for biosimilars where the reference product will have already been approved and marketed in the target region, and there would seem to be no rational reason why a biosimilar product would display a different ethnicity profile; however regulators may not always share this view.
Even if the above barriers are crossed, regional differences in data requirements may still dictate the need to replicate certain aspects of a biosimilar development programme, tailored to the requirements of specific regions. This is another area where global harmonisation of biosimilar guidelines would greatly benefit the development of global biosimilar products.
Can the obstacles be overcome?
Despite the progress in the EU, much uncertainty remains as to which products will qualify as biosimilars, and what degree of similarity will be required for follow-on and subsequent-entry proteins. Furthermore, the level of supporting clinical data that will be required for the more complex proteins has yet to be fully defined-which is not surprising, given that it is a multidimensional issue, influenced by the complexity of the protein, the potential for differences between the reference product and the biosimilar, and the challenges of demonstrating therapeutic equivalence.
The uncertainty and variability of the biosimilar environment increase in proportion to the complexity of protein. The level of clinical and non-clinical data required to bridge the gap between the reference protein and the follow-on protein needs to be based on risk analysis, with the amount of data being proportionate to the level of uncertainty and risk. In fact, the idea of a risk-based approach could be applied even to improved intentionally modified proteins or "biosuperiors" where receptor interactions, pharmacokinetics, and pharmacodynamics mirror those of the reference biological entity. Extension of the biosimilar concept to "biosuperiors" does not align with current regulatory views but its future adoption could serve to nurture innovations such as novel and more efficient manufacturing technologies that will enable the generation of more affordable protein-based medicines.
The ability of biosimilars to access global markets based on a single development programme that meets the requirement of all markets is clearly an important factor driving the success of biosimilars. Although, World Health Organization has issued guidelines which establish a base standard, the regulatory framework for the approval of biosimilars in major markets is very much still in flux and relies on the generic and biotechnology industry to guide regulatory thinking towards a harmonised approach.
Biosimilarity is still in its early stage of evolution and the industry and regulators together now need to drive the concept so that it becomes a powerful vehicle for delivering affordable and better biological medicines to patients throughout the world.
Cecil Nick, Vice President - Biotechnology at PAREXEL Consulting, is a trained biochemist and has over twenty years of experience in the development of biological medicinal products. He now 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.