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A Primer on Follow-On Biologics

By: Bryan A. Liang, MD, PhD, JD E.
Donald Shapiro Distinguished Professor
Executive Director, Institute of Health Law Studies, California Western School of Law
Co-Director, San Diego Center for Patient Safety, UCSD School of Medicine

Biologic drugs are today's most advanced medicines. These complex medicines are biotechnology drugs tested through clinical trials that provide therapy to victims of cancer and other diseases.

Biologics represent the fasting-growing sector in the medicines market, with more than $30 billion spent on these drugs each year. Indeed, the top five drugs in terms of Medicare expenditures administered in physicians' offices are biologics. By 2010, worldwide spending on biologics is estimated to grow to $100 billion, and biologics will make up nearly half of all newly approved medicines.

"Follow-on" biologics are attempted copies of the original biologic drugs by manufacturers other than the original developer of the biologic drug. However, although they are similar to the original, follow-on biologics are not identical.

Chemical Drugs versus Biologics
Drugs we're familiar with, like the pills we get from the pharmacy, are "small-molecule" drugs - simple chemical compounds compared to the vastly larger and more complex biologic drugs. The anti-convulsant chemical drug valproic acid, for example, has a total of just 26 atoms. Compare that with the brand name drug Herceptin, a biologic that's widely used to treat cancer; it's made up of roughly 25,000 atoms. Large biologics can have millions of atoms.

In addition, biologics aren't made by combining chemicals in a flask. They're made by life forms such as mammalian cells, yeast and bacteria. Like humans, these life forms exhibit diversity in metabolism and composition, making the final product a unique, heterogeneous mix that cannot be copied exactly.

So follow-on biologic forms of the drug can only be similar to the original, not identical because they do not use the original drug developer's life forms to make the drug. In comparison, chemical drugs, because of their small size, can be made identical to the original drug using standard large industrial processes that are highly predictable and uniform.

Safety Regulation
Because of the complexity of biologics, there's much more regulation. In comparison to common chemical drugs that can have generic versions - such as penicillin, which only require 50 to 60 manufacturing tests for safety and quality - biologics require at least four times that number.

In addition, the current state of science makes ensuring safety of follow-on biologic drug forms difficult. Currently, the technology to map out the exact medical nature of one large biologic versus another is not available, and hence, unanticipated adverse reactions have occurred. 

For example, several years ago, a fully tested biologic created in the United States was cooperatively licensed overseas to be made in Europe. But the European version caused patients to suffer "pure red cell aplasia," whereby their bodies could not make red blood cells. This may have contributed to the deaths of patients, with many others permanently injured.  Yet today, after eight years of research, the cause of these reactions is still unknown.

Recognizing these challenges, the European Union developed an assessment system for follow-on biologics, or "biosimilars" as it is known there. Clinical testing of follow-on products in Europe as well as extensive risk management plans are required before approval. The U.S. has not yet devised an assessment system for follow-on biologics.

Biologic drugs are the cutting edge of medicine. They are large, complex, use living entities for production, and treat some of the most severe diseases afflicting humans. Follow-on biologics are similar but not identical copies of original biologic drugs. Because of limitations of science, follow-on forms require extensive assessment including clinical trials and risk management plans before approval in Europe. The U.S. has yet to develop a policy on follow-on biologic approval.





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