Biogenerics Conference Addresses Scientific and Regulatory Issues Surrounding Biosimilars

When considering how follow-on biologics will be compared to innovator products, Emily Shacter has a favorite question: If the drug substance of the innovator product is unavailable for testing, and therefore has to be tested in the formulation buffer or purified out of the formulated commercial product, how will we know the effect of those testing conditions or manipulations?

For Shacter, this question will soon move from theoretical to practical. Because sooner or later-and many think it is likely to happen before the end of 2009-the US Congress is expected to pass legislation creating an abbreviated pathway for the approval of follow-on biologics, also called biosimilars. And as the chief of the Laboratory of Biochemistry in the Division of Therapeutic Proteins in the US FDA’s Office of Biotechnology Products, Shacter knows her department will have to deal with these important and complex questions in submissions for follow-on biologics.

Shacter’s question was one of many important issues discussed at the “Biogenerics 2008” conference held on March 3 and 4 in Boston, MA, sponsored by the Barnett Institute of Northeastern University (Boston, MA).

Shacter never did get a definitive answer to her question, but the conference proved to be a useful forum for discussing important scientific and regulatory issues related to biosimilars.

Demonstrating Similarity: Analytical Methods and Clinical Testing

Any discussion of biosimilars naturally includes an assessment of the capability of analytical methods to demonstrate similarity between a follow-on product and the innovator drug to which it is compared. Speakers at the Biogenerics conference generally agreed that state-of-the-art analytical methods can provide very good characterization of protein molecules and their impurities, particularly if several orthogonal analytical technologies are used.

The real problem, however, is not the capability to detect variations between proteins, but to assess whether those differences are clinically significant. “We are still limited in our ability to make predictions about physiological function based on structure,” said Shacter. For that reason, she said, probably all biosimilars filings will require some clinical testing.

Limited Data for Comparisons

Several participants from innovator companies also expressed concerns about how little data biosimilars companies will have at their disposal, which will make comparisons more difficult. “Testing only 6–12 lots of the innovator drug is very limited,” said Andrew Fox, a director of regulatory affairs at Amgen. “During a recent comparability exercise at Amgen, we compared to 1,282 historical lots.”

Tony Lubiniecki, vice president of upstream drug substance development and technology transfer in pharmaceutical development at Centocor R&D, agreed. “Biosimilars companies should be required to conduct clinical trials of sufficient size and power to compensate for their lack of historical data.”

Immunogenicity Testing

The potential of all biologics to induce an immune response was discussed at length, including the tragic case of Eprex-induced pure red cell aplasia (PRCA). “We are not totally convinced as an industry that we know what caused the PRCA case,” said Steve Swanson, PhD, executive director of clinical immunology at Amgen. “That is very sobering.”

Swanson said that companies should take a risk-based approach to immunogenicity testing, taking into account the likelihood and clinical consequences of an immune response. And in all cases, immunogenicity trials must be well designed, and last at least six months. “Sometimes it takes as long as one to two years to see immunogenicity,” he said.

Unique Product Names and Restricting Interchangeability Facilitate Pharmacovigilance

The PRCA example also provides a good reason to restrict the interchangeability or substitutability between biosimilars and innovator products, said Jean-Hugues Trouvin, head of the Biologics Working Party of the European Medicines Evaluation Authority (EMEA), because keeping patients on a single product facilitates postmarketing surveillance. “When the Eprex problem arose, it was easy to track which patients had received Eprex, because there had been very little switching of patients between the approved products,” he said. “Although the decision about interchangeability in Europe is made at the national level, we at the EMEA do not recommend switching patients without a therapeutic justification.”

The question of postmarketing surveillance for biosimilars and other biologics also raised the issue of product naming. Several attendees said that biosimilars should have unique international nonproprietary names (INNs), to distinguish them from the innovator products to which they refer. The World Health Organization (WHO), which determines INNs, recently formed a working group to address this question.

If the WHO does not decide in favor of using unique INNs, said Alison Lawton, senior vice president of global regulatory and public policy at Genzyme, the US should come up with another system to ensure accurate postmarketing tracking, such as using barcodes at the pharmacy level or requiring prescribing by brand name.

Economics

Apart from scientific and safety issues, conferees also raised questions about the economics of biosimilars. “We need a system that balances the need for access to drugs with incentives for innovation,” said Randall Lutter, FDA’s deputy commissioner for policy. “That means including an appropriate number of years of data exclusivity, as well as some additional protection to provide innovators with an incentive to seek approval for additional indications.”

Charlie DiLiberti, global vice president, pharmacokinetics and bioequivalence at Barr Laboratories, raised a different economic issue, saying the lack of global harmonization could significantly reduce the profitability of follow-on biologics. If regulatory agencies do not allow filings based on clinical studies using reference products from another region, DiLiberti said, we could see a “biogenerics paradox,” in which the cost of expanding to additional markets would be higher for biosimilars than for innovator drugs. “The return on investment for a given drug might be insufficient to warrant a filing in some markets,” he said. “I also know of some cases where follow-on companies are considering filing under innovator provisions, because those requirements may be less onerous.”

Mathias Hukkelhoven, PhD, senior vice president and global head of drug regulatory affairs at Novartis, said his company recognizes the value of both innovation and biosimilars. “We recognize that the total amount of money available in the healthcare system is limited,” he said. “Biosimilars will free up money in the healthcare system to pay for innovation.”