Outsourcing for Biosimilars
Achieve regulatory compliance & gain competitive edge
PharmaNet Development Group
Growth opportunities for the biosimilars market are immense, with as much as $25 billion in biologics facing patent expiration by 2016. According to a recent report published by Markets and Markets, the global biosimilars market is expected to be worth $19.4 billion by 2014, growing at an expected CAGR of 89.1% between 2009 and 20141. In response to this impressive market growth, legislative bodies have introduced guidelines to ensure the safety and efficacy of biosimilars. We shall review the current regulations governing the approval of biosimilars in Europe, the U.S. and globally, and provide a detailed insight into the benefits of outsourcing the production of biosimilars to expert CMOs and CROs.
The European Medicines Agency (EMA)2 defines biosimilars as medicines that are similar but not identical to a biological medicine that has already been authorized (the so-called ‘biological reference medicine’). Also known as ‘follow-on proteins,’ ‘follow-on biologic proteins’ or ‘follow-on biologics’, biosimilars are developed following patent and exclusivity expiry on the original innovator product. The active substance of a biosimilar is similar to the one of the biological reference medicine and the two products are used in the same dosage regimen for the same indications.
Biosimilars should not be confused with generic drugs, which according to the FDA are identical or within an acceptable bioequivalent range to the small molecule innovator drug with equal dose, strength, safety, efficacy, intended use and method of administration. Generic drugs are generally fairly simple small molecules produced by chemical synthesis and offering high levels of stability. On the contrary, biosimilars are large and complex molecules produced by living organisms and can be very sensitive to even the slightest manufacturing process changes.
Manufacturers of biosimilars do not have access to the cell bank, molecular clone, active drug substance and the exact manufacturing processes used to develop the biological reference medicine. This means that identical replication of the original innovator product is not possible. Since differences, among other things, in impurities, breakdown products and molecular conformation of the active ingredient can have significant health implications, there are concerns that biosimilars might perform differently than the original branded version of the product and negatively impact human health. In response, regulations have been introduced in Europe, Canada and the U.S. to ensure that the efficacy and safety profile of each biosimilar are the same as its originator.
The European Legislative Framework
Having recognized the importance of patient safety and the need to minimize the risk to the patient, the EMA has established a regulatory framework that requires extensive preclinical and clinical testing of biosimilars before approval3. Such testing ensures that the quality, safety and efficacy of biosimilars are comparable to those of the biological reference medicine. The EMA takes an innovative approach, according to which any differences between the biosimilar product and the innovator medicinal product must be justified by appropriate studies on a case-by-case basis. Both efficacy and safety data must be gathered since a biosimilar product may have a different safety profile from the reference medicine even if their efficacy is comparable.
The EU regulator recognizes that biosimilars are different from existing biological therapies in terms of their raw materials and manufacturing processes and that even slight differences can significantly alter a biological therapy's safety and effectiveness. In particular, the EMA recognizes the potential for a biosimilar to exhibit immunogenicity problems that were not detected in clinical trials and do not occur with the innovator product. To address this problem, the agency requires that biosimilars undergo the same post-marketing monitoring as new biologics.
Biosimilars are approved by the European Commission based on the positive scientific opinion issued by the EMA following testing and assessment. The first biosimilar medicines were approved by the European Commission in 20064, with the endorsement that each one of them has been compared to and matches the reference medicine in terms of quality, safety and effectiveness.
The U.S. Legislative Framework
In March 2010, U.S. President Obama signed into law the Patient Protection and Affordable Care Act5. This Act provides an approval pathway for biosimilar biological products. According to the Act, a biosimilar is a product that is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and which exhibits no clinically meaningful differences with the reference product in terms of safety, purity and potency. The Act requires that clinical studies be performed to assess immunogenicity, pharmacokinetics and pharmacodynamics of biosimilars, which are expected to produce the same clinical result as the reference products in any given patient.
With the signing of the Patient Protection and Affordable Care Act, the Biologics Price Competition and Innovation Act of 20096 also became law. This Act creates what is intended to be a streamlined development and FDA approval pathwayfor competing versions of already-marketed biologic drug products. Its goal is to lower prices through increased competition in this rapidly growing segment of the healthcareindustry. The Act has two main sections. The first deals with the regulatory standards and procedures for approval of
follow-on biologic products, including a 12-year regulatory exclusivity period for the innovator. It also provides forthe interchangeability or substitution of biosimilars for
their innovator counterparts if they are able to demonstrate a high degree of similarity according to stringent criteria. The second section specifies complex rules and procedures for identifying and resolving patent disputes involving proposed follow-on products.
The new legislation paves the way to establish a regulatory framework by which the manufacturers of biosimilars can gain marketing approval from the FDA. On considering similar biological legislation in 2008, the Congressional Budget Office estimated that, over 10 years, as much as $25 billion could be saved through its provisions for FDA approval of biosimilars by significantly driving reductions in the prices of biological drugs.
Global Regulatory Outlook
Across the globe, pharmaceutical companies are making headway in the field of biosimilars. Although a number of countries have for the last few years approved the marketing of biosimilars through their general existing regulatory requirements (e.g., India), several countries, including the U.S., Europe and Canada, are the only regions to have established specific regulatory approval systems for biosimilars. In Japan, Sandoz, the generic drug subsidiary of Swiss innovator Novartis, has gained marketing approval of Japan’s first therapeutic biosimilar, Somatropin BD, the recombinant human growth hormone somatotropin. In Canada, Sandoz has received market authorization for Omnitrope, where it is the first biosimilar of a previously approved recombinant drug to achieve approval from Health Canada under ‘Information and Submission Require-ments for Subsequent Entry Biologics’.
Following Sandoz’s move into the biosimilars market several years ago, the industry has seen regulators becoming more familiar with the process. Over the next few years a number of other generic companies are expected to attempt to enter western markets with biosimilars. Indian manufacturers including Ranbaxy, Dr Reddy’s Laboratories and Biocon among others, are aiming to gain approval for their biosimilars in Europe in the near future as well as eventually in the U.S. Despite these ambitious plans, there are still considerable barriers, including regulatory hurdles, patent litigation and marketing issues, that will continue to restrict companies’ attempts to enter the field.
The worldwide market for biosimilars is predicted to grow rapidly during the next few years, placing significant pressure on biopharma manufacturers as they jockey for position within the newly competitive marketplace. The manufacture of biosimilar drugs requires specialized capabilities, meticulous planning, highly skilled staff and significant financial investment. This investment in premises, equipment, technology, materials and personnel could however place strain upon a company, draining Resources and diluting its overall success. Companies that are looking for effective and efficient waysto produce biosimilars without the huge investment ofpurchasing expensive high-tech equipment are increasingly turning to CMOs and CROs that already offer these services and have well-trained professionals and state-of-the-art technology for developing and validating analytical methods,preclinical and clinical development strategies and biomanufacturing processes.
To ensure that the approval process for a new biosimilar is efficient with reduced time-to-market, manufacturers are starting to outsource to CROs that provide a full spectrum of services encompassing drug discovery, development, preclinical and clinical trial processes. This can incorporate preclinical evaluations, study design, trial management, data collection, statistical analysis and completion of product regulatory requirements. Aside from having access to a wealth of solutions, technology and equipment, CROs can offer a wide breadth of expertise, having in some cases been involved in the development of the original biological products; this can prove extremely helpful for manufacturers in the new biosimilar’s development and when technical issues arise.
A fundamental benefit of outsourcing is the reduction of pressure placed on the companies’ own resources and the ability to free up capacities for innovative or high margin products. Furthermore, outsourcing can prove to be beneficial in terms of capital efficiency, as it enables companies to fund their research in the most cost-effective manner possible, not having to invest in expensive pieces of equipment and software or employing the personnel to operate them before their biosimilar candidate has demonstrated viability in terms of regulatory and marketing potential.
Some outsourcing providers are also highly specialized in applying techniques such as mass spectrometry to characterize and profile biologics. For biosimilars, these companies can also conduct comparative analyses with a reference product and offer high quality immunoassay and bioanalytical services including Enzyme-Linked Immuno-Sorbent Assays (ELISAs), Radio-Immuno Assays (RIAs) and multiplexed Meso Scale assays.From a clinical trials perspective, outsourcing companies can offer a wide range of technologies including electronic data capture (EDC) and management systems, and can also implement risk management plans through follow-up systems such as web-based patient registries to identify possible safety signals and immunogenicity issues not apparent during the preclinical and clinical development phases.
There are clear market opportunities and challenges for biopharmaceutical companies engaging in the development of biosimilars, and outsourcing may enable a company to achieve the quickest and most cost-effective method of getting a new product to market. The wealth of knowledge, experience, understanding, technology, skills and financial control that CMOs and CROs can provide to manufacturers, make this a solution that many companies are using to their advantage.
The increasing demand from patients, insurers and government agencies to reduce the costs of blockbuster biopharmaceuticals has created numerous opportunities in the global biosimilars market. The growth of this market is also favored by the fact that numerous blockbuster biologicals are expected to go off-patent within the next five to 10 years. Recentregulatory developments in Europe and the U.S. have provided an approval pathway for biosimilar products. New legislation requires that biosimilars are tested to ensure that theyare safe and efficient for their intended use. In that way, the confidence of patients and physicians on biosimilars is expected to increase.
In order to take advantage of the new market opportunities, pharmaceutical companies are increasingly outsourcing the production of biosimilars to specialized CMOs and CROs. These organizations employ well-trained professionals and use state-of-the-art technology to develop and validate analytical methods, preclinical and clinical development and biomanufacturing processes, providing pharmaceutical companies with a feasible way of remaining competitive and financially viable.
2 http://www.emea.europa.eu/docs/en_GB/document_library/ Medicine_QA/2009/12/WC500020062.pdf
5 http://www.foleyhoag.com/People/Attorneys/~/.../ Biosimilar%20Pathway.ashx
Jeffrey J. Freitag, M.D. is senior vice president, PharmaNet Consulting and William Egan, Ph.D., is vice president, PharmaNet Consulting. For more information about this article, please contact email@example.com.