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The times, they are a changin’ in the biopharma market
The biopharmaceutical development community has successfully developed a broad range of highly effective therapies for a wide variety of serious and debilitating diseases. However, developing biopharmaceuticals is inherently an extremely challenging and commercially risky undertaking, often working to tight timelines and typically resource-constrained. For many, this means adopting a pragmatic approach to development, where the goal is to get the product to a point where its clinical performance and analytical characterization are "good enough" to satisfy the regulatory authorities and get to market.
Very often, we do not have the time, resources, or indeed, the motivation, to work toward an optimum "best-it-can-possibly-be" position. Typically, the "good-enough" approach may be adopted during selection of candidates, development of formulations and manufacturing processes and in the degree of analytical characterization performed. Although this approach has successfully delivered safe and efficacious drugs to the market, we are now moving into a new era for biopharmaceuticals, characterized by increased competition in the marketplace. Good enough to satisfy the regulators may no longer be good enough to compete effectively in the marketplace.
There are a number of drivers simultaneously working to move the biopharmaceutical industry into this increasingly competitive era, including: the availability of multiple innovator products to treat the same indications; the emergence of biosimilar products and development of a framework by which they can get approval; arguably, an increasingly demanding regulatory environment; evolving scientific understanding that also highlights areas of ignorance; and emerging markets such as those in Asia.
As a result, healthcare refunders, practitioners and patients will have an ever-increasing choice about which drug to buy and can increasingly be expected to base their purchasing decisions on factors such as relative price, convenience and cost of administration, effectiveness and degrees of adverse reactions. Both innovator and biosimilar developers will need to adapt in order to compete effectively in this new environment. A number of aspects of the development process, although already very important, will become increasingly critical to the commercial success of the resulting products.
It would seem that both originators and biosimilar developers will need to do more—and do it better, faster and more cheaply—if they are to succeed in the new marketplace. However, for many, the economic reality in the current climate may be that there will be little, if any, additional resources available to achieve these ambitious goals. New strategies and ways of working will be required; developers will need to be more open to new ideas and approaches, and to embrace new and emerging technologies that conservative attitudes may previously have prevented. Working harder is probably not enough, or in many cases, possible. Developers will need to work smarter.
Every stage of the development and manufacturing process has potential for optimization, and a wide range of innovative technologies and strategies are already available. Embracing new technology, however, brings with it some risk and fear of the unknown. If current practices are considered good enough, why risk something new? As a result, many innovations have struggled to gain acceptance; this may be the time to reconsider some of these, in the drive to move beyond "good enough" and toward "the best things can be." As these innovations, both relatively developed and just emerging, are too numerous to detail here, a few areas where the development process might be advanced to improve product competitiveness have been selected for discussion.
Speeding development: Start right, move faster
A key potential cause of slow and expensive development can be early selection of a candidate molecule that, while efficacious and specific, is fundamentally unstable and consequently difficult to develop, manufacture and achieve adequate storage stability in a convenient dosage form. Picking the right candidate is, however, easier said than done. Early in development, both time and protein material are typically in short supply, limiting the number of candidates that can be investigated and the extent of analytical characterization that is possible for each.
To overcome these issues, analytical screening technologies are needed which are rapid and automated (high-throughput), consume very little material and also make analytical measurements that are in some way predictive of how the protein will behave during manufacture and subsequent storage. Such technologies allow candidate protein molecules to be screened for "developability"—or, in the context of this article, "competitiveness"—in addition to basic therapeutic function. If the measurements made have some predictive power, the risk of progressing too far with a molecule which is ultimately incompatible with modern, cost- effective platform manufacturing processes, or which can't be made suitably stable for long-term storage in a convenient dosage form, is reduced. The same small-volume, high-throughput approach also offers the potential to rapidly and cost-effectively test the efficacy of protein engineering efforts to improve stability earlier in development, and to identify optimum solution conditions for processing and storage.
A tough, stable molecule, selected from the outset to be inherently compatible with modern platform manufacturing processes and for which the successful results of long-term storage stability studies can be (almost) assured, has a better chance of progressing through development more rapidly, costing less to develop and reaching the market sooner. Once at market, the selected and/or engineered-in attributes should result in lower manufacturing costs, longer shelf life and potentially other benefits to the customer, increasing the molecule's chances of commercial success. Instrumentation suitable for this type of stability screening is readily available from a wide range of vendors at comparatively modest cost, and a number of the largest biopharmaceutical developers are already embracing this approach.
Analysis as a route to market … and as a roadblock
Analytical characterization plays a pivotal role in biopharmaceutical development and manufacture, and takes on a new importance with the emergence of biosimilar products. Therapeutic proteins are highly complex entities, and fully characterizing them is challenging, or indeed arguably not possible, with current technology. This presents a key challenge to biosimilar developers, who need to demonstrate to the regulatory authorities that their product is "highly similar" to the marketed reference product.
U.S. and European regulators have indicated that the scope and extent of expensive and time-consuming clinical testing they will require will depend on the apparent similarity, based on initial physiochemical characterization. The authorities recognize the current limitations of the analysis of proteins and recommend the use of a wide range of analytical measurements, each of which may have limitations, but which, when combined, build as complete a picture—or "fingerprint"—of the molecule as possible.
This is sometimes described as a "totality-of-the-evidence" approach. It is therefore potentially highly advantageous for biosimilar developers to present as comprehensive a physiochemical analytical comparison of their new proposed product and the reference material, rather than taking a more limited, "play-it-safe, bare-minimum" approach.
A range of both new and established, but traditionally underused, analytical techniques are available which can add considerably to a convincing picture of similarity. Embracing new analytical technologies is not without risk, but the potential rewards of a faster, cheaper route to market could be significant for biosimilar developers. The corollary, of course, is that innovative developers may wish to build a more comprehensive analytical fingerprint of their "reference" product to demonstrate dissimilarity of a potential biosimilar with their material.
New technologies to meet new challenges
Two related areas where innovation may potentially improve the competitiveness of a product are the way it is administered to the patient (delivery) and the use of stabilizing additives to improve stability and shelf life (formulation). However, for many time- and cash-pressed developers, the concept of thoroughly optimizing the protein formulation or adopting new formulation technologies for improved long-term storage stability or delivery properties may be seen as a luxury. Additionally, biosimilar developers may consider any deviation from the originator formulation as a risk that will need explaining to the regulatory authorities.
However, in a newly competitive market, improved formulation may be a route to achieving a market advantage. This thinking can already be seen with a move away from lyophilized products—which need reconstituting and administering by healthcare professionals—toward liquid formulations, prefilled syringes and patient self-administration. The technical challenge of this shift is sometimes considerable and not free of risk for the developer, but in this example, the benefits to the customer are significant, going beyond simple convenience and extending to overall cost savings for the healthcare provider.
For innovator and biosimilar developers alike, delivery and formulation provide not only improved product performance, but also the potential to engineer useful additional intellectual property protection into products where the patent on the basic therapeutic protein has expired. There are multiple companies around the world with innovative formulation and delivery technologies that offer the potential reward of increased product competitiveness and improved IP position. Maybe now is their time to shine.
Good enough isn't good enough anymore
A host of innovative approaches and technologies exist that have the potential to improve almost every stage of the process of developing and manufacturing biopharmaceuticals. Embracing them, however, is not without risk to developers, and in an environment where the status quo is considered good enough, they struggle to gain acceptance. A change in the market dynamics for biopharmaceuticals may, however, mean this attitude will have to change and opportunities for innovation will increase. In the meantime, for all the small companies with the innovative analytical, formulation, delivery and manufacturing technologies—hang in there!
Simon Webster is chief scientific officer and co-founder of Avacta Analytical, a specialist contract research organization providing biophysical characterization services and innovative instrumentation to the biopharmaceutical market.