Special To BioWorld Today

Editor's Note: This is part two of a two-part series on follow-on biologics and their regulatory pathway. Part one ran in Thursday's issue.

Biologics are prophylactic, in vivo diagnostic or therapeutic substances that can be produced only in living systems. Chemical pharmaceutical compounds usually stem from synthesized components, and that difference means biologics are more complex and exhibit more heterogeneity and potential variability.

That difference also means it is harder to establish bioequivalency for biologics, an issue that plays a large part in the debate over follow-on biologics. Whereas pharmaceutical compounds can be characterized via chemical tests for identity and purity, biologics often require more complicated bioassays. That, in addition to the complications of multiple active epitopes and post-translational modifications, can result in serious side effects if the manufacturing methods for generic biologics are different - in even the slightest way - from their pioneer counterparts. For example, small alterations in manufacturing can result in pollutants being deposited in the mix of therapeutic proteins, which could incite an unwanted immune response in recipients.

The manufacturing process itself can change the characteristics of the therapeutic protein. Each manufacturing step must be optimized for the particular biologic compound produced; there are no fundamental techniques that can be used for all products - something true for chemical compounds. Optimizing each technique is expensive and labor-intensive, and certainly a reason why manufacturers want to keep their techniques confidential.

Potential follow-on biologics manufacturers would have to replicate most of the manufacturing processes of the brand-name manufacturer in order to obtain a sufficiently bioequivalent product, but also they must avoid infringing on the pioneer drug-maker's manufacturing intellectual property. With respect to biologics, the research and development required to optimize them is not just more costly than chemical-based compounds, but also more complex.

In order for a generic biologic to meet the test of bioequivalence, the brand-name manufacturer would have to disclose proprietary details of its manufacturing processes and possibly even more intellectual property than already required for a BLA. Requiring brand-name manufacturers to disclose that type of information would result in the loss of hard-earned intellectual property rights and could deter innovation.

Legislation alone is not enough to ensure that follow-on biologics are as similar to the innovative product as found in the chemical pharmaceuticals field. And legislation likely would face stiff opposition from pioneer biologics manufacturers, as well as the Biotechnology Industry Organization (BIO): Pfizer Inc., Pharmacia Corp., Genentech Inc. and BIO have all filed citizen petitions with the FDA to prevent abbreviated approvals for biologics that rely in any way on a pioneer manufacturer's studies.

Also, abbreviated biologics applications might not be scientifically advisable. Until it can be shown that a generic manufacturer can develop a biologic product that is bioequivalent to the innovator product without using intellectual property in the form of trade secrets, know-how and technical information of the innovator after patent expiration, it is not realistic to expect generic biologics to enter the market. In addition, it likely might turn out that not all off-patent (or upcoming off-patent) biologics possess generic equivalents, since the ability to manufacture generic biologics might depend on its complexity and the current state and understanding of the biotechnology involved. While there might be scientific capabilities today to develop follow-on biologics via an abbreviated pathway for certain less complex biologics, as new technology emerges and/or our understanding of current technology progresses, more and more complex biologic products likely will become candidates, as well.

If generic biologics do become a reality, it seems likely that statutes and regulations will seek to strike a balance between innovators' rights and generic market entry. Lessons learned through the years of enforcement and administration of Hatch-Waxman in the context of chemical pharmaceuticals will be invaluable, but should not limit the range of thinking and the scope of possibilities that reflect the current socioeconomic and technological landscape. Even though considerable administrative hurdles first must be cleared, the possibility that Congress and the FDA will permit generic biologics is real. Forward-looking companies should begin to craft their patent strategies now, so that they will be properly positioned when and if the law changes.

As the debate continues, there will be many voices heard and a lot of ideas floated based upon the interests of the different parties. If a workable solution is to be found, the generic biologics debate requires new solutions and innovative ideas that are unencumbered by those of the past. n

Eugene Trogan is a technology specialist at Fish & Richardson P.C. in New York. The views expressed here are his own.