From the introduction of the Guidelines for Biosimilars in the EU in 2004, Europe has been pressing hard for the introduction of these money-saving options into the marketplace. The initial guidelines of 2004 were followed very rapidly with further guidances on comparability (2005), preclinical and clinical requirements (2005), recognition of the changing landscape (2010) and in 2011, further recommendations for studies and statement of the recognition of the issues surrounding licensure. To aid developers they even issued product specific guidances, recognizing that each molecule would have specific challenges to overcome. From the issuance of the first two in 2005 for granulocyte colony stimulating factor (GCSF) and human somatotropin, to interferon beta, follicle stimulating hormone and insulin in 2011, we have seen others in the intermediate period including epoietin, heparin, interferon alpha, and monoclonal antibodies (MoAbs).
The activity has not been simply issuance of guidances and guidelines, but actual approval of products, with them well-established in the market place. The first approval for human somatotropin was for Sandoz’s and BioPartners’ versions with the latter withdrawn by the manufacturer later. We have seen various epoetins, filgrastims (GCSF) and follicle stimulating hormones with a total of 18 approvals with 2 withdrawals through 2012.
June 2013 saw the issuance of further guidance documents including a draft “Concept paper on comparing quality in biologicals and biosimilars.” In this document they describe in more detail than before the challenges and issues in comparing the potential biosimilar to the innovator biological. It is still in its review period but the results should be forthcoming very soon.
The document hopes to address the adequacy of the statistical approaches on comparing quality attributes of the potential drug to the innovator especially in the context of manufacturing process changes. The agency recognizes that in the comparison, there is often limited data available to make clear definitive comparison. This is because often only a few batches are made thus lending little statistical power to the investigation and because of the less than complete characterisation of the molecule that is available. Basically these concepts should be addressed in comparability discussions.
In spite of further guidances, the agency has been pushing forward with approval of two further biosimilars. Both are copies of J&J Remicade (Inflizimab) and made by the South Korean company, Celltrion. Celltrion has its Remsima and also makes Inflictra for Hospira, who holds the license for the latter. Both were licensed in September 2013, with the Celltrion version gaining approval in South Korea in 2012. The approval of the product was also associated with gaining the same indications as the originator, Remicade, in rheumatoid arthritis, Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis and ankylosing spondylitis.
How did these companies gain approval? As expected there was a comprehensive characterisation of the biosimilar and a comparison with the innovator. Also two clinical trials in humans were required. It was a single Phase 1 short-term safety trial followed by a single Phase 3 type double blind study in rheumatoid arthritis involving a comparison of efficacy and safety in 874 patients over two arms (biosimilar versus innovator) lasting 1.5 years of treatment. It involved 20 countries and 115 sites.
As expected there are other biosimilars in review at present including Merck/Serono’s follitropin alpha, and Sanofi-Pasteur’s insulin glargine. The insulin biosimilar is welcomed after Marvel LifeSciences withdrew their insulin application late in 2012.
At present characterisation work is proceeding as new technologies are developed to evaluate and compare biosimilars to innovators. But the age-old question of “What changes are significant and concerning and what are clinically irrelevant” still needs to be addressed. This is particularly true for the monoclonal antibody approvals this year. Their complexity versus filgrastims, insulins and somatotropins are challenging analytical capabilities. The major risks are immunogenicity and safety. Even subtle changes introduced might give rise to the risk of immunogenicity. While we do know that certain elements contribute to immunogenicity (changes in primary sequence, aggregation, foreign carbohydrates and non-human domains), we are not confident we can predict whether a molecule will elicit a clinically relevant response and be problematic or not.
Clearly, with the introduction of the first two the risk has been taken – the 437 patients treated with the biosimilar (874-patient clinical trial on two arms) might not be sensitive enough to detect subtle reaction in the patient pool chosen. However, one of the MoAbs was introduced into South Korea a year ago in 2012 and no significant issues have surfaced so far. That said, the companies and regulators are surely viewing the adverse events profiles as these products are gaining popularity in the market place. Only with experience in a real life setting will the question of their safety be fully addressed.
On the US front, things have been moving slowly and the FDA is clearly 5-7 years behind the EMA with no approvals as of writing this article. However, the pathway laid out by the FDA is very similar to that of the EMA and as such, look to Europe to predict the US path and timelines. That said, we can expect to see approvals in the next 3-5 years. Now FDA, prove me wrong and approve one earlier!
Note: The views expressed in this article are those of the author and do not necessarily represent those of his or her employer, GxP Lifeline, its editor or MasterControl Inc.
Peter Calcott, Ph.D., is president and CEO of Calcott Consulting, which is focused on delivering solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He is also an academic program developer for the University of California-Berkeley’s Biotechnology and Pharmaceutics Postgraduate Programs. Prior to this he was VP at PDL BioPharma where he was responsible for development and implementation of quality and compliance strategy across the corporation. Previous to that he was chief quality officer and led the quality and compliance function at Chiron and Immunex Corporations and was director of quality assurance for SmithKline Beecham and for Bayer for their biotechnology and biologics businesses. He has also held positions in research and development, regulatory affairs, process development, and manufacturing at other major pharmaceutical companies. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Dr. Calcott holds a doctorate degree in microbial physiology and biochemistry from the University of Sussex in England and completed his post-doctoral work at McGill. University in Montreal, Canada. Recently, he was chair of the regulatory affairs committee of BIO and presently serves on the board of BayBio, a biotechnology industry association in San Francisco. He has been a consultant for 17+ years to various governments, industries, and academic institutions during his career. Dr. Calcott has authored more than 80 original research papers, reviews, and books. He may be reached at email@example.com.