The Future is Biosimilar . . .
The development and commercialization of novel biologic therapies for serious unmet medical needs has mushroomed in the last decade. They accounted for approximately $100 billion in worldwide sales in 2009, and may increase by 30% per year for the near future. Dozens of compounds are approved in the US, and many more are in development. The therapeutic possibilities with biologics are enormous, but so are the development costs and market prices. Thus, the promise of ‘generic’ biologics that could bring lessen the financial burden to society of biologic treatment, analogous to what generic drugs have done for small molecules, is enticing.
Unfortunately, it is not that simple. A "generic" biologic is really an oxymoron, since the structural complexity of a large protein therapeutic cannot be precisely replicated by a separate manufacturing process: Hence, the term 'biosimilar'. A biosimilar is a follow-on biologic that is highly similar to an innovator (original licensed) biologic. The devil is in the establishment of what "highly similar" means for drug developers and regulators: the compound must have physicochemical and biological equivalence to the reference compound. Since the reference compound itself is likely to be heterogeneous, the range of variation for a parameter, e.g., degree of glycosylation, has to be established. Then the biosimilar must show bioanalytical properties and PK/PD characteristics that match the reference compound. Finally, it is likely that some demonstration of clinical equivalence in the target population may be required, which would likely entail a head-to-head non-inferiority trial in one or more indications. In the US, FDA is currently in the process of defining these requirements for the drug development industry.
But there is yet another level of complexity. The requirements for validating a biosimilar listed above are only a rough sketch. The details will depend on a number of factors that may lead to individualized regulatory pathways for different compounds. The nature of the agent being copied will play a great role, as a relatively small biologic like erythropoietin is easier to replicate structurally than a larger molecule, like a monoclonal antibody. The clinical uses must be considered, in terms of unmet need and the degrees of risk that would be tolerable in a patient population. Immunogenicity is a particular concern with biologics, and the likelihood of an immune response and the seriousness of its consequences will be quite different for different compounds. If a clinical trial indeed proves non-inferiority for one indication, does that mean that other indications can be permitted for the biosimilar (by extrapolation), or must separate trials be required, as they were for the innovator biologic? Could a biosimilar ever be so “highly” similar that a pharmacist could be permitted to make a substitution at her own discretion; or conversely, would any physician be able to prescribe a biosimilar without a thorough knowledge of the evidence that lead to its approval? The ambiguities and uncertainties of the requirements for biosimilars will likely create important financial and regulatory hurdles that developers will need to overcome.
The issues surrounding biosimilars are sufficiently difficult that disparate regulatory bodies may reach different conclusions regarding the standards required for approval. Biosimilars for erythropoietin, G-CSF, and somatotropin have been approved in the EU, but the European Medicines Agency (EMA) is still grappling with the proper approach to regulating biosimilars for more complex agents. FDA’s position has evolved recently, in part under the Biologic Price Competition and Innovation Act passed last year. This proposes an abbreviated biologic licensing application (aBLA), which is intended to streamline the development of biosimilars. However, the act requires full data disclosure from the biosimilar developer, which combined with certain aspects of defined time-frames, actually facilitates legal action by the innovator for IP infringement. Thus, the developers could successfully complete all the steps required to be ready to launch their biosimilar, and then be denied because of patent violations. This legal hurdle, combined with the scientific data-requirement uncertainties discussed above, and the projected modest price differential between innovator product and follow-on, will together tend to discourage development of biosimilars.
What will the impact be of biosimilars? It is certainly less expensive and entails less risk to produce a biosimilar, which can benefit from the clinical experience, both within and outside trials, of the innovator compound, than it would be to produce a novel molecule which may have the same target as an existing biologic. Given the complexity of manufacture and approval of these agents, the cost savings will likely be much less dramatic than what has been possible with small molecule generics. Nevertheless, the cost of biologics has been such a major limiting factor in their use worldwide, that any significant price reductions will extend their use to many patients who would otherwise be excluded. From the other side of the fence, some smaller biotech companies have a majority of their revenues coming from biologics, so that the advent of direct competition will likely necessitate a redirection of their efforts. Many large pharma companies have already hedged their bets by participating in the development of biosimilars in addition to the development of novel compounds.
All these issues are being discussed at various levels, and biosimilars will become more and more a part of our pharmacopoeia in the coming years, as patents expire on existing biologics, follow-on biologics progress through the relatively long developmental process, and regulatory agencies and developers become more comfortable with the requirements of licensing. Some countries with less strict intellectual property protection, and greater unmet clinical needs, have moved faster than the US or Western Europe; although it is unlikely that many of the agents that they produce will meet the stricter standards required for approval in the US and Western Europe. There will continue to be a level of uncertainty about the long-term risks that the inevitable variations in follow-on biologics might create, such that ongoing pharmacovigilance and post-marketing surveillance will be essential. Hopefully, better structured systems will be developed to keep track of serious adverse events for every patient who receives a biologic (including the exact source of the agent), so that important variations in risk or clinical efficacy of biosimilars (as well as new agents) can be efficiently detected. But the successes of targeted biologics have been so impressive, and their future promise of more is so great, that they should be made available to as many people worldwide as possible. Hopefully, ongoing discussions and experience will help achieve the right balance that will encourage development of biosimilars and satisfy critical regulatory needs.
For futher reading:
- Kozlowski S, Woodcock, J., Midthun, K., Sherman, R.B. Developing the Nation's Biosimilars Program. The New England Journal of Medicine. [perspective]. 2011 August 4, 2011;365(5):385-8.
- Blackstone EA, Fuhr JP, Jr. Biosimilars and innovation: an analysis of the possibility of increased competition in biopharmaceuticals. Future Med Chem. 2010 Nov;2(11):1641-9.
- Kay J. Biosimilars: a regulatory perspective from America. Arthritis Res Ther. 2011 May 12;13(3):112.
- Doloresco F, Fominaya C, Schumock GT, Vermeulen LC, Matusiak L, Hunkler RJ, et al. Projecting future drug expenditures: 2011. Am J Health Syst Pharm. 2011 May 15;68(10):921-32.
- McCamish M, Woollett G. Worldwide experience with biosimilar development. MAbs. 2011 Mar-Apr;3(2):209-17.
- Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol. 2011 Apr;86(4):277-88.