Guest post by Rebecca Weires, a 2L in the J.D./M.S. Bioengineering program at Stanford
In their 2016 paper, Manufacturing Barriers to Biologics Competition and Innovation, Price and Rai argue the use of trade secrets to protect biologics manufacturing processes is a social detriment. They go on to argue policymakers should demand more enabling disclosure of biologics manufacturing processes, either in patents or biologics license applications (BLAs). The authors premise their arguments on an assessment that (1) variations in the synthesis process can unpredictably affect the structure of a biological product; (2) variations in the structure of a biological product can unpredictably affect the physiological effects of the product, including immunogenicity; and (3) analytical techniques are inadequate to characterize the structure of a biological product. I am more optimistic than Price and Rai that researchers will soon overcome all three challenges. Where private-sector funding may fall short, grant-funded research has already led to tremendous advances in biologics development technology. Rather than requiring more specific disclosure of synthesis processes, as Price and Rai recommend, FDA could and should require more specific disclosure of structure, harmonizing biologics regulation with small molecule regulation. FDA should also incentivize development of industrial scale cell-free protein synthesis processes.
In the past few years, researchers have made rapid progress developing techniques for synthesizing, assessing the physiological effects of, and characterizing the structure of biologics. Researchers have been developing cell-free protein synthesis systems to make biologics synthesis more predictable and less path-dependent. Historically, cell-free synthesis systems have been application-specific and difficult to scale. Cell-based systems have dominated because cells maintain their own internal environments, including necessary components for protein synthesis. But cell-based systems are not perfect. For example, as Price and Rai explain at p. 1035, the pattern of carbohydrates attached to a protein is particularly challenging to replicate across different cell lines and is important for efficacy and immune response. Recently, researchers have created more flexible, generalizable platforms for cell-free synthesis. Some are developing industrial-scale cell-free synthesis processes. Others have demonstrated cell-free production of increasingly complex, proteins with attached carbohydrates. These cell-free synthesis techniques are more predictable than current cell-based synthesis, eliminating variations that arise from differences between cell lines.
Researchers have developed improved models of the immune system to improve preclinical assessment of biologics. Traditional preclinical toxicity assays and animal models have been insufficient for biologics, which are often not directly cytotoxic but instead trigger species- and patient-specific immune reactions. As the biologics industry has grown, researchers have developed sensitive in silico methods, 2D in vitro assays, and 3D in vitro models of immune response. For example, computer models can now provide good estimations of the ability of immune cells to bind with a biologics, which a sponsor can use to predict whether a product with a slightly different structure than its reference product has the same immunogenicity. If the two products are likely to be biosimilar, the sponsor can validate immunogenicity in vitro before investing in a clinical trial. The sponsor may use 2D assays to measure the response of immune cell cultures directly exposed the biologic, or the sponsor may introduce the biologic into 3D artificial lymph nodes, which model flow and other mechanical forces that affect immune cell response. With these tools, the variations arising from different synthesis processes become less of an obstacle to biosimilar development.
Technology for characterizing the structure of biologics has come especially far in the past decade, enabling high-resolution characterization of protein folding and glycosylation for increasingly large biologics. Structural characterization has been limited in the past because protein sequencing does not provide folding or glycosylation information, X-ray crystallography requires prohibitively complex sample preparation, and nuclear magnetic resonance (NMR) spectroscopy is ambiguous and computationally expensive for large molecules. In the past few years, though, researchers have developed 2D NMR methods for characterizing products as large as monoclonal antibodies. Cryogenic electron microscopy (CryoEM) is a newer technique suitable for characterizing larger biologics. CryoEM can be used to image large glycosylated structures such as viral coat proteins, and even whole cells, at near-atomic resolution. Though 2D NMR and CryoEM may be too time-consuming or expensive for rapid prototyping, computational methods for predicting protein structure and function are now adequate for prototyping new biologics.
Price and Rai theorize that the private sector underinvests in these three areas of research, but total funding may be sufficient. The above-cited advances were largely grant-funded. Defense department funding for synthetic biology has skyrocketed in the past decade, accounting for 67% of U.S. public-sector research investments in synthetic biology in 2014. Public sector investment has made technologically feasible what was once nearly impossible: reverse engineering biologics.
Price and Rai argue the costs of trade secrecy in biologics manufacturing likely outweigh the benefits, but research advances may soon reverse that assessment. As reverse engineering biologics becomes easier, the private value of keeping manufacturing methods trade secrets will decline, and we can expect biologics makers to reduce their reliance on trade secrets. Furthermore, tools for assessing immunogenicity function in silico and in vitro will eliminate some expense of failed clinical trials. Thus, the social value of disclosing synthesis processes will also decline.
Overall, these scientific advancements reduce the urgency and importance of Price and Rai’s policy prescriptions but do not render them irrelevant. Policymakers should consider the regulatory levers the paper describes at pages 1050-56 to incentivize full and specific disclosure; however, full disclosure of structure, rather than synthesis process, should be the focus. Biologics sponsors should be required to define their exact formulations. Heightened patent disclosure requirements are an option, but as Price and Rai suggest, the FDA may be in a better position to enforce heightened disclosure requirements. In fact, detailed structural characterization, to the extent it is technologically feasible, is already required to prove biosimilarity. With improved characterization and deterministic, cell-free manufacturing, it will become possible to make true generic biologics. Heightened disclosure requirements could take the form of harmonized generics and biosimilars regulation.
Policymakers should supplement disclosure requirements with incentives for the private sector to further develop cell-free synthesis processes. Reverse engineering requires both structural information and deterministic synthesis processes. Biologics sponsors may not have sufficient incentives to invest in cell-free synthesis because it facilitates biosimilars development. Fortunately, current research provides a basis for FDA to set a reasonable timeline for biologics makers to develop and adopt cell-free synthesis. Now is an appropriate time for the FDA to announce cell-free synthesis requirements, along with immunogenicity assay requirements, for biologics license applications. As escalating fuel efficiency standards have done for the auto industry, escalating application requirements would stimulate private-sector research and development to meet requirements.
Price and Rai highlight legitimate concerns with the current use of trade secrets to inhibit the development of biosimilars. However, biologics manufacturing technology has advanced enough that an end to these practices is in sight. New scientific developments will enable FDA to treat biosimilars more like generic small-molecule drugs, which would simplify the approval pathway for biosimilars and enable more effective product inspections. Though this course of action would not immediately accommodate new and complex biologics such as whole cell therapies, it does suggest a model for regulating them. For new types of biologics, FDA can start with a flexible regulatory scheme allowing approval based on manufacturing process information. Then, as deterministic synthesis processes, preclinical assays, and structural characterization techniques advance, it can transition to more rigid disclosure requirements.
