The soaring cost of drug development reaching an all-time high of nearly $1.5 billion is forcing drug developers to develop a business paradigm that can reduce cost of drug development. The main factor in the rising cost is the price of failure for drugs that don’t reach the market. Typically, fewer than 7% of the drugs in discovery ever reach the market for the small molecule, with a 27% success rate for large molecules. The real question is how one can lower the cost of failure, and thus lower the cost of healthcare. 

Biosimilars pose a variation of that question: how can we deliver lower-cost biosimilars that can enhance access to these critical drugs and lower the cost of healthcare in U.S.? The FDA’s recent draft guidance on biosimilars outlines a series of recommendations for developing and approving biosimilar therapies, in hopes of solving that conundrum. The three separate draft guidances map out the scientific considerations, quality analytical factors and other regulatory issues for bringing to market new therapeutic proteins that are similar, “but not the same” as a reference product. FDA officials have also discussed new user fees for biosimilars and generic drugs at a Congressional hearing.

The guidance describes a stepwise approval pathway, starting with extensive analytical, physico-chemical and biological characterization data that can demonstrate a high degree of similarity. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity. FDA will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product. To avoid redundant and unnecessary animal and clinical testing, FDA will permit sponsors to use a non-U.S.-licensed comparator in certain studies, with appropriate bridging data. Most applications, though, will require some additional clinical trials, and regulators would expect that all will need immunogenicity studies. This is a slightly different approach than that taken by the EU regulators.

Unlike the model for demonstrating bioequivalence in small molecule generics, in this case, once FDA determines that a product is biosimilar, the sponsor can certainly opt to demonstrate interchangeability. That will require additional switching studies to show that changing to the new product does not affect safety and efficacy. Interchangeability is a separate determination, and it’s sequential.

For years, large pharma and biopharma companies have been wrestling with a complex but fundamental challenge: how to cost-effectively bring promising biologics candidates through the development pipeline to successful commercialization. I had a chance to sit down with some of the members of Oncobiologics team members. The company contends that its rapid Proof of Concept (POC) approach can take a molecule from “DNA to IND” within one year, providing the speed that is necessary to ensure that winning molecules can succeed, and that losing molecules can fail before they drag the company down with them. One of the Oncobiologics team member explained, “The solution is to identify failures sooner, especially prior to Phase III trials, which is where clinical costs can skyrocket. ‘Failing faster’ also means failing cheaper. “

The cost and duration of clinical studies are determined by study design and clinical endpoints. Because these factors are largely beyond the control of the drug developer, the best available way to impact clinical trials is to reduce the time and cost associated with the preparation of the Chemistry, Manufacturing & Controls (CMC) package that dictates how the drug is to be produced. By eliminating the CMC package from the critical path (and doing so cost-effectively), the drug developer is able to move through clinical trials with less opportunity for disruption.

To achieve this speed, Oncobiologics’ team has primarily focused on assembling a team of long time industry experts from top-tier pharma and biopharma companies with an enabling culture. The culture has three key elements, as explained by chief executive officer Pankaj Mohan: agility, technical excellence and mutual respect. The culture has created a strong work ethic, enabling the company to pursue a three-pronged strategy to drive speed with scientific rigor. The company is ready for contract R&D, followed by cGMP contract manufacturing.

Technology 

Oncobiologics has established a state-of-the-art R&D facility designed with the latest technology and equipment. The facility was also designed to foster open collaboration, ensuring efficiency at every step of the POC process. Taken together, its technical capabilities enable high throughput CMC development with high scientific rigor. Key elements include:

IP-based Discovery Technology: Oncobiologics has developed next generation antibody platform designed to seek and penetrate tumors and other diseased tissue. The targeted scaffold design is ideal for oncology and immunology applications and is the basis for the company’s current therapeutic molecules. It is also capable of generating an extensive pipeline of additional molecules.

Process Development Technology: An essential component of biologics development is high-throughput screening. For the development and isolation of high producing recombinant cell lines, Oncobiologics employs Fluoresence Activated Cell Sorting (FACS). Bulk cell populations are either “enriched” for the top-producing clones, or sorted into microplates and monitored by the Celigo Cytometer for single cell per well. The use of these technologies together enables a logarithmic increase in the number of clones that are screened and reduces the time from DNA to a single, high producing clone by 50% compared to conventional methods.

The clones, media and physical process conditions best suited for larger scale manufacturing are next evaluated in micro-bioreactors. Recent advances in micro-bioreactor technology allow them to evaluate larger statistically designed experiments using a miniature version of a fully controlled production bioreactor. The miniaturized replica enables a rapid upstream development timeline with a rich data set.

Purification yields and product purity rely on the careful selection of modes of chromatography and optimal mobile phases. The use of micro-array plate-packed columns and liquid handling units enables a rapid evaluation of many modes of separation across multiple molecules. They utilize this rich data set to develop robust process while minimizing the number of unique buffers and changes from product to product.

Conventional glass bioreactors and chromatography systems are used to finalize the process conditions before scaling to 200 L pilot scale. 

Analytical and Formulation Technology: Oncobiologics has built state-of-the-art labs to enable rapid protein characterization and elucidation of structure-activity relationships (SAR). Thorough protein characterization drives discovery, process and product development. 

Whether the product is a monoclonal antibody or a bi-specific construct, protein engineering begins with the end in mind. The company’s analytical and formulations lab infrastructure was designed to ensure successful, well-characterized protein therapeutics. From project initiation, target product profiles are considered, which informs specifications and control strategy. Throughout the platform, multiple orthogonal techniques are used to obtain a complete assessment of product quality and stability. Characterization methods are used to achieve specific objectives, using protocols and approaches that will answer the question at hand, as opposed to running experiments to “check the boxes.” Stage-appropriate methods are employed that are fit for purpose and flexible for products in development. 

One highlight of the analytical toolkit allows sequencing of monoclonal antibodies, accurately pinpointing the location and composition of post-translational modifications. UPLC systems provide high-speed and high-resolution chromatography, and are used for a variety of protein release and characterization methods. Formulations development is fully integrated with analytics, based on the recognition that protein stability is best fostered by thorough protein characterization through multiple orthogonal techniques. High throughput configurations are used throughout for assessment of thermal and colloidal stability, enabling rapid pre-formulation screens with highly powered Design of Experiments. The analytical and formulations team works in close partnership with process development colleagues on in-process stability, helping to refine process choices. The team employs a pairing of in vitro and in silico work to augment characterization and guide the protein engineering of bi-specific constructs. 

BioAssay: Ultimately, product quality comes down to biological activity. The company seems to have recognized this focus, and has built capabilities to assess and confirm product mechanism of action through a myriad of methodologies. The team recognizes that protein products are inherently heterogeneous, and that product development and commercialization requires classification of product variants as impurities (with changes in functionality) or substances (where differences have no impact). The team delves into the structure/function relations in our protein products, and carefully develops physiologically relevant and interpretive bioassays, to characterize the impact of protein modifications in concert with other orthogonal methods. Advanced statistical ap-proaches are used across all analytical methods and in the pooling of data to derive meaningful conclusions that secure the quality of products.

cGMP Manufacturing Technology: Oncobiologics is currently building a cGMP production facility composed exclusively of single-use-technology to manufacture its Phase I and II clinical supplies. The facility will feature a single-use 220 L scale bioreactor and will also include a 2000 L bioreactor for scale-up demonstration prior to commercial scale transfer. The facility is scheduled to be in production in by the fourth quarter of 2012.

Integration

The integration of technologies and scientific discipline is critical to achieving speed in a well-designed execution engine. Discovery, process development and clinical manufacturing are integrated to eliminate tech transfer and to ensure a smooth transition of the process into cGMP manufacturing. The company has a well-integrated process development, analytical and formulation group in a project-management driven environment.

Strategic Alliances

While Oncobiologics has established extensive in-house capabilities, it also recognizes that certain expertise is best accessed through strategic partnerships. As a result, the company has entered several alliances to complement its core capabilities and to fill-in with expertise as needed. Current partners include Fox Chase Cancer Center, Biologics Consulting Group, Schiff Harden. Advent Engineering and Princeton Design Group.

It appears to me that the market dynamics, the rising healthcare costs and a patient outcry for low-cost drugs is leading to the creation of a new business paradigm where the riskiest parts of development will be partnered with small biotech companies that can deliver a proof of concept with agility, speed and lower costs. Such a development engine should then be partnered with the highly evolved commercialization engine of large biopharma company leading to commercialization, sales and marketing, regulatory filing and the infusion of capital. I believe that this synergy between small biotech and large pharma is the paradigm shift that will speed drug development and that a company like Oncobiologics represents a new model of such a small biotech company. 
 

Makarand (Mak) Jawadekar most recently served as Director, Portfolio Management and Performance at Pfizer Global R&D, until February 2010, when he opted for an early retirement after 28 years at Pfizer Inc. He currently serves on several companies’ advisory boards and also consults with bio/pharmaceutical companies for global outreach in emerging market regions. He can be reached at [email protected].