Biosimilars or Follow-on Biologics: Scientific and Regulatory Considerations
Kadriye Ciftci, PhD • Senior Director, CMC Specialist, Regulatory Affairs, ICON Clinical Research
Biopharmaceuticals represent one of the most promising frontiers in pharmacotherapy and appear to be the way of the future as they have revolutionized health care with effective, targeted therapies designed to treat costly and complex diseases such as cancer, Parkinson’s, Alzheimer’s and rheumatoid arthritis. In 2008, the total biopharmaceuticals market generated approximately $108 billion in sales with $160 billion forecast by 2013 according to Datamonitor. Although global sales of biopharmaceuticals have steadily increased over the last decade, market growth of these products began to decline in 2006 (Figure 1), partly due to the entry of non-innovator versions of biopharmaceuticals called ‘biosimilars’ in the European Union (EU), and ‘follow-on biologics’ (FOBs) in the United States. Biosimilars or FOBs are defined as biological products similar to, but not the same as, the innovator products.
Figure 1. The biotech market size and growth
for 1998-2007 (Courtesy of IMS Health)
Key Scientific Issues and Challenges with Developing Biosimilars
Chemistry, Manufacturing and Control (CMC)
Biopharmaceuticals are usually protein molecules manufactured in living cells.1 Manufacturing processes for biopharmaceuticals, including biosimilars, are highly complex and require many specific isolation and purification steps.2 It is thus almost impossible to manufacture an exact copy of a biopharmaceutical, as changes to the structure of the molecule can occur during the production process3 and the changes may lead to differences in efficacy, safety and may trigger patient immune responses. Therefore, the most significant challenge for the development of biosimilars is proving similarity against the innovator product. In order to maximize comparability between batches, manufacturers of both innovator and biosimilar products must ensure consistency in the production processes and perform rigorous purity and potency profiling. Quality assurance assays for biopharmaceuticals are generally less sensitive and precise than tests for small-molecule drugs.4 For the above reasons, it is difficult to establish biopharmaceutical equivalence between a biosimilar and an innovator product.5, 6
In addition, biopharmaceuticals, including biosimilars, are not terminally sterilized so that adventitious agents (i.e., bacteria, fungi, mycoplasmas, and viruses) can be introduced during manufacturing, and therefore all steps of manufacturing should be performed under cGMP conditions.6
Due to the inherent complexities of biosimilar development, Quality by Design (QbD) principles should certainly be considered when designing the product development plan.7 Regulatory agencies are generally more likely to grant regulatory flexibility to manufacturers for subsequent process changes, provided that those changes still occur within the established quality attributes.
Biosimilarity and Comparability
Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the biosimilar and the innovator product. Physicochemical characteristics of biosimilars are compared with their innovator product in vitro. However, in vivo biological activity can not be predicted by in vitro tests and biological activity is difficult to assess in animals as few animal models are able to provide data that can be extrapolated for an accurate prediction of biological activity in a patient. Therefore, controlled clinical trials remain the most reliable ways of demonstrating similarity between a biosimilar and the originator products.8
The comparability exercises should include an assessment of characterization, physicochemical properties, biological activity, purity and impurities, and stability.9 The physicochemical comparison of the biosimilar with the reference product to prove comparability is an addition to, not a substitute for full characterizations as part of CMC development work. Regulatory authorities agree that non-clinical and clinical data are needed to demonstrate the safety and efficacy of a biosimilar. In addition, post marketing surveillance and Risk Management Plans should be in place for the approval of biosimilar products.8, 10
Interchangeability
FDA defines interchangeability as “the situation where scientific data convincingly demonstrate that two products with very similar molecular compositions or active ingredient(s) can be safely substituted for one another and have the same biologic response and not create adverse health outcomes.” The European Medicines Agency (EMA) does not assess the interchangeability or substitutability of a biosimilar when granting a marketing authorization application. Therefore, considering the inherent molecular complexity, and the associated safety concerns about biosimilars, automatic substitution or interchangeability will less likely occur in the US and Europe.11
Immunogenicity and Patient Safety
Biopharmaceuticals have the potential to provoke immune reactions and it is currently not possible to accurately predict immunogenicity in a patient. Several factors i.e., the presence of impurities, structural modifications as a result of the manufacturing process and/or storage conditions, administration route and patient factors can affect immunogenic potential and the safety and effectiveness of the product in patients.12 The currently available pre-clinical assays are not sufficiently predictive for the immunogenicity in humans; therefore the immunogenic potential of biosimilars can only be determined in appropriately designed clinical studies.
Will there be a Biosimilar Monoclonal Antibody (MAb)?
The development of MAb biosimilars is expected to pose several challenges to biosimilar manufacturers considering their complex structure and glycosylation characteristics.13 These issues also represent significant regulatory challenges and raise questions such as the extrapolation of efficacy and safety across therapeutic indications (i.e. can all of the indications for the innovator product be approved for the biosimilar product by extrapolation, if comparability is demonstrated in one model therapeutic indication?) and the selection of efficacy endpoints.14 Nevertheless, MAbs are the fastest growing segment within the biopharmaceutical industry (estimated $48 billion sales by 2013) and their initial patents are set to expire in 2014. They therefore represent a legitimate target for biosimilar manufacturers.15 A concept paper on the development of biosimilar MAbs was released for consultation by the EMA in October 2009.16 In this document the EMA confirmed that biosimilar MAbs were being developed.
Global Regulatory Challenges for Biosimilars
The EU is currently the most advanced region in terms of having a developed regulatory pathway for biosimilar products. Medicines legislation creating the regulatory pathway for biosimilars was introduced in Europe in 2004. The EMA / Committee for Human Medicinal Products (CHMP) issued an overarching biosimilars guideline17 for the development of biosimilars covering quality issues9, non-clinical and clinical issues18 and immunogenicity for both biosimilars and innovator products.12 In addition, the EMA/ CHMP released four product-class-specific guidelines.19-22 In 2009, health care payers, physicians and patients in the EU have the choice of multiple biosimilar medicines spanning several classes of biologic therapy, including hGH, erythropoietin (EPO) and filgrastim (G-CSF) (Table 1).
Table 1: Biosimilar Approval in EU
Currently there is no regulatory framework in place for approving follow-on biologics in the United States, although appropriate legislation has been under discussion in Congress since 2007. Most biopharmaceuticals are defined and approved under Section 351 of the Public Health Services (PHS) Act23 and in March 2009, the ‘Pathway for Biosimilars Act’ was introduced in the U.S. House of Representatives as an amendment to the PHS Act. In March 2009, three new bills on biosimilar legislation were introduced to the US Congress and in July 2009, committees in both the Senate and the House approved bills that would authorize the FDA to create an approval pathway for biosimilar products that would guarantee manufacturers 12 years of market exclusivity for a new biologic agent before any biosimilar product could be approved, even in the absence of a valid patent. If the 12-year period of data exclusivity is included in the impending biosimilar legislation, biosimilars will be unlikely to appear in the US market until 2020. Inclusion of the 12-year period of data exclusivity in final biosimilar legislation will not only delay approval, it will allow American biosimilar manufacturers to develop similar biosimilars which will then compete with foreign biosimilars for U.S. regulatory approval.
Omnitrope® (Sandoz GmbH) was the first biosimilar on the U.S. market. FDA approval was granted because the drug is relatively simple, well characterized, and shown to be comparable to Pfizer’s innovator Genotropin®. It was not approved as a generic under 505(j) regulations because it could not be scientifically proven to be bioequivalent, but was approved as a new biologic drug product under the FD&C Act (21 CFR Parts 600-680). In 2007, Valtropin, also a recombinant human growth hormone and biosimilar of Eli Lily’s Humatrope, was developed by LG Life Sciences and approved by the FDA. Other examples of biopharmaceuticals approved under provisions in section 505(b)(2) are: Hylenex (hyaluronidase recombinant human), Hydase (hyaluronidase), Fortical (calcitonin salmon recombinant) Nasal Spray, Amphadase (hyaluronidase), GlucaGen (glucagon recombinant for injection).
Approval of biosimilars in the US will likely be on a case-by-case basis and will depend on the complexity of the molecule and knowledge of its mode of action.
There is no harmonized worldwide regulatory framework for biosimilars yet. Many of the Asia-Pacific countries (India, Singapore, N. Korea and China) do not yet have regulatory approval pathways for biosimilars, although these countries are supportive of an approval scheme and many follow the WHO guidelines. Countries in Asia-Pac with specific guidelines are Australia, Malaysia, Taiwan, Japan, S. Korea and Singapore. The Japanese Ministry of Health, Labor and Welfare (MHLW) published a draft guideline in September 2008 and in October 2009, Sandoz announced the launch of its recombinant human growth hormone somatropin in Japan, the first-ever biosimilar to be approved and launched in the world’s second largest pharmaceutical market. In 2009, S. Korea released a draft guidance on biosimilars and in the same year Singapore’s drug regulation agency, the Health Sciences Authority (HSA), issued guidelines on the regulatory registration of biosimilars, which was mainly adapted from EMA biosimilar guidelines.24
Are Biosimilars on the horizon for the U.S.?
Many biopharmaceuticals are expensive, for example, a year’s worth of Genentech’s cancer drug Avastin® can cost upwards of $100,000. An estimated $10 billion worth of biologic drugs are expected to come off patent by 2010, with an additional $10 billion by 2015. Medco Health Solutions, Inc. estimates that biosimilar versions of biotech medicines could reach the U.S. market by 2013, creating a $34 billion opportunity through 2017.15 However, without the biosimilar regulatory pathway, biotechnology companies will continue to have a monopoly and competition will not exist in the U.S. market.
Conclusion
Biopharmaceuticals are complex molecules and, therefore, biosimilars cannot be treated in the same way as conventional generic drugs. The regulatory approval of biosimilars will require much more than the demonstration of pharmaceutical equivalence and pharmacokinetic bioequivalence associated with conventional generics. Only clinical and pharmacovigilance studies to monitor potential immunogenicity will provide definitive evidence for product comparability to the innovator product with respect to safety and efficacy. Based on the experience with the first biosimilars, existing guidelines for the market approval of biosimilars will be revised to include the latest developments and new guidelines will be developed for other biosimilar products.
In addition, entry of biosimilars onto the market will require transparent, unbiased distribution of information to physicians and other healthcare professionals.
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