The World's Biologics Drug Price Problem - Drug expenses have become a significant item in household and government budgets around the world as more innovative and pricey biotech products become available to treat diseases such as cancer or rheumatoid arthritis.

Among biologics drugs, antibodies are most successful; many are exceeding $5 billion in annual sales. Projections show that by 2014, 50% of the top drugs will be biologics. The high use of biologics is deemed to contribute to increasing health-care costs. For example, the price for Herceptin is from $40,000 to $70,000 per year depending on the treatment type, while treatment costs for a chronic disease such as rheumatoid arthritis or Crohn's disease with Humira is estimated around $14,000 per year. The cost to a Gaucher's patient for treatment with Cerezyme can be $200,000 per year for the rest of the patient's life.

Attractive earning potential, coupled with upcoming patent expirations, has drawn companies of all sizes to the biosimilar sector. As these companies compete for winning strategies to efficiently move their products through the regulatory pathway, many of them are realizing a daunting challenge: the estimated $50 million to $150 million cost for biosimilar development as compared with $2 million to $5 million required for a small-molecule generic product development.

The higher price tag for biosimilar development is, in part, explained by the high cost of production; biosimilars are complex heterogeneous molecules produced using recombinant DNA technology. On average the chemistry manufacturing control (CMC) component of the biosimilar development costs $30 million. Clinical studies with 500 to 800 patients are the second-largest contributor to the development cost. These large clinical studies are required by the regulatory agencies to ensure that the biosimilar product is as safe and efficacious as the originator product.

Affordable Biosimilars Development

Biosimilars undoubtedly have the potential to reduce revenue spent on biologics, both directly, as they are typically priced 20%-50% lower than the branded product, and indirectly, by driving down the price of the branded drugs through competition.

As is the case for generic drugs, the major driver for widespread development of biosimilars is the realization of cost savings. However, to achieve these savings, the safety and efficacy of all marketed biosimilars must be established, and a sufficient number of competitors must get to the market.

Looking back at 2009, significant skepticism surrounded biosimilar development as questions were raised regarding development feasibility and ability to match quality attributes between the originator and the copy. Brand name producers concerned with losing the revenues from sales of their blockbuster products lobbied heavily to increase barriers to entry, ultimately increasing the cost of development.

The high development cost will undoubtedly reduce the competition among developers in the biosimilar sector. After all, clinical trials enlisting almost a thousand patients will not be affordable for many companies.

Current advances in process development and analytical technologies are enabling detailed characterization, thus producing drug products highly similar to the originator. Perhaps there is a need to rethink the regulatory pathway for biosimilars to lower the costs associated with their development, so that patients and purchasers alike benefit from the promise of lower priced drugs without sacrificing quality and safety.

The regulatory principles for development of biosimilars should be consistent with those outlined in ICH Q5E where demonstration of comparability of product quality is sufficient for implementing even significant process changes with no or minimal clinical trials.

Mitigating The Safety Risks

Beyond product-specific safety concerns, which are well-understood for the originator, the primary safety concern with biosimilar drugs, as with biologic drugs in general, is the potential for immunogenicity and contamination with viral or bacterial adventitious agents.

Risks of contamination are addressed by implementing Quality Systems, raw materials qualification, design and operation of the manufacturing facilities (e.g., aseptic processing in the case of drug product), controls on the production process, and testing for bioburden and endotoxin, or sterility in the case of drug product. Risks to adventitious agents are addressed by characterization of the cell bank to be free of viruses, by avoiding use of materials of animal origin, and by including purification process steps with orders of magnitude ability to remove potential viral contaminants.

Immunogenic responses to biologic drugs can occur from process- and product-related impurities. Process-related impurities arise from host cell proteins and DNA, cell culture media additives, and residuals and leachates from the manufacturing process materials and solutions that are in contact with the product. Product-related impurities include fragments, aggregates, misfolded species, sequence variants, and potentially oxidized and deamidated species.

Several orthogonal analytical tools can verify the primary sequence and folded structure. Sensitive, specific and orthogonal assays should ensure that no species are missed. Risks related to product- and process-specific impurities can be mitigated by staying within the levels and types of species observed in the originator product lots.

For biosimilar expression, the same cell type as the originator - e.g., Chinese hamster ovary (CHO), NS0 or E. coli - is recommended. This strategy should minimize the differences in the types of host-cell-derived impurities. The design of the upstream manufacturing process should minimize generating impurities, and the downstream process should clear the unwanted impurities. Process conditions, hold times and product formulation maintaining the quality profile to match the originator product should lead to the development of a safe product. When possible, mass balance should be obtained for the impurities. Thorough understanding of the pharmaceutics could also avoid anti-drug antibody safety events such as the red cell aplasia in Eprex because of the interaction of leachates from the stopper used in the initial process.

Note that in the case of host cell proteins (HCPs), the panel of residual proteins in the final product might be different from the originator. Thus, the development of sensitive and process-specific assays is necessary to demonstrate high clearance of HCPs in the biosimilar product. Generally ppm levels of HCPs have not posed risks to patients, specifically for those products that are derived from well-known CHO, insect or human cell lines. One case of high incidence of anti-product antibodies was observed in Omnitrope lots made by the initial manufacturing process; this incidence was related to high levels of host cell proteins in the product; interestingly, there were no neutralizing effects or adverse events associated with such finding.

Mitigating The Efficacy Risks

The risks associated with lower or lack of efficacy of a biological product could arise from structural differences that influence pharmacokinetic (PK) and pharmacodynamics (PD) properties. These product attributes should be optimized during upstream process development stage.

Glycosylation is an example of properties that can affect biological activity. For example, the number of terminal galactose residues on glycans and the presence of fucose are known to affect antibody-dependent cell-mediated cytotoxicity (ADCC) of monoclonal antibody therapeutics. A number of analytical tools are available for glycosylation analysis, including glycan analysis by 2AB method, site-specific glycan analysis derived from peptide map-MS analysis, and intact protein mass analysis that assess glycosylation on each subunit of multimeric or multi-subunit proteins. Moreover, glycan linkage analysis with tandem mass spectrometric methods can provide a fingerprint level similarity of the detailed glycan structures for the biosimilar with the originator product. In vitro biological assays including Fc receptor and FcRn binding, ADCC or complement-dependent cytotoxicity (CDC) can then be used to confirm the analytical findings.

Once data is acquired from the side-by-side testing of multiple lots of the biosimilar and the originator products, it can be analyzed not only for the similarity of the predominant species, but also for the minor species and the detailed profiles. Statistical algorithms can be used to provide greater confidence in the similarity of the results for each assay. Composite data of all the analytics with risk-based weighing factors for each assay can be generated and used for statistical analysis of equivalence to highlight the degree of similarity and related confidence. In support of the in vitro work, confirmatory clinical PK bioequivalence studies with safety/tolerability assessment could be conducted to identify whether additional studies would be required. Since long-term clinical data is the best indicator of immunogenic potential, the best means of identifying potential problems is through careful post-marketing surveillance.

The higher precision analytical technologies than the in vivo studies with high variability, together with the diverse biological assays for detailed comparability assessment could provide a high level of assurance that the biosimilar product would have similar in vivo behavior as the originator product. By increasing the analytical rigor upfront to examine detailed structural and functional similarity, biosimilar products should display high similarities to the originator.

This approach will no doubt eliminate companies without thorough knowledge and experience in biologics development, and give incentive to those skilled in the fingerprinting approach, so that we all can benefit from the high quality medicines at a lower cost.