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Commentary By Paul Howard

FDA Must Test Some Biologics' Generic Forms

Health Pharmaceuticals

Congress is debating legislation that would create an approval process for "generic" (unpatented) biological drugs, like insulin, similar to the existing generic process for chemical drugs, like fluoxetine (Prozac).

A sticking point in the debate is whether companies developing copycat biologics should be required to conduct clinical trials testing the safety and efficacy of their medicines. A good case can be made that, at least in some cases, they should. The manufacturing process for many biologics (proteins, vaccines and gene therapies) is so complex that making a "generic" version can be akin to producing an entirely new medicine.

Traditionally, companies that make generic drugs don't have to conduct clinical trials for FDA approval: They only have to prove that their knock-off has the same active ingredient as the original drug, is absorbed the same way and has a reliable and effective manufacturing process.

Spared from research or clinical testing costs, generic companies can offer the same medicines as their branded competitors at a fraction of the price — as much as 80% less. Indeed, many generic drugs are cheaper in the U.S. than anywhere else in the world.

Experts doubt this process can work for biologics. While drugs are produced through a chemical process that is relatively easy to reverse engineer, biological drugs are grown in living systems (cells, viruses or bacteria) that are sensitive to changes in manufacturing. The results can be unpredictable.

Sometimes the changes are harmless or even beneficial. David Koplow writes in his history of smallpox that, at some point in the last 200 years, the cowpox virus that had been used since the late 18th century to inoculate humans against smallpox mutated into an entirely new viral strain.

"The virus that has been used over a period of several decades to vaccinate against smallpox — all the various strains employed throughout the United States and the world—is no longer true cowpox," he says. "The modern prophylactic, known as vaccinia virus, is a novel, separate creature." That transformation "was somehow inadvertent, invisible to its practitioners, and global."

But sometimes the changes are life-threatening. In 1998, Johnson & Johnson added a new stabilizer to the European manufacturing process for its drug Eprex, an erythropoietin molecule grown in cloned Chinese hamster ovary cells and used by cancer and kidney-failure patients to help stimulate production of red blood cells.

Later, J&J noticed that some Eprex patients developed a dangerous blood disorder: antibody-mediated pure red cell aplasia, where bone marrow stops producing new red blood cells. It took J&J four years of painstaking research to learn the PRCA cases were caused by an interaction between its new stabilizer and uncoated rubber stoppers used in some syringes.

The moral is that even Eprex's original manufacturer — with financial and technical resources that few generic producers could hope to match — was caught off guard by an adverse event after a seemingly harmless manufacturing switch. Generic firms with fewer resources or less experience are apt to be at an even greater disadvantage.

Not all copies of biological drugs present such complex problems. And not all manufacturing changes will raise red flags. But the FDA should have a free hand to ask for clinical-trial data (and possibly postmarketing surveillance) from follow-on biologics when the science is in question.

The European Union already has established an approval process for follow-on biologics that U.S. legislators should study carefully. Companies that want to copy a biologic drug have to follow a licensing process separate from that for traditional generics, though the generic route is still open.


The EU has entrusted its version of the FDA — the European Medicines Agency — with approving what it calls "biosimilars." The EMEA decides, on a case-by-case basis, what data will need to be submitted along with each biosimilar application. Some medicines may get away with just providing analytical laboratory data. Others may undergo extensive clinical testing, perhaps as rigorous as the process for new biologics.

The EU sees that there are bound to be differences between innovator biologics and biosimilars, and that these differences may have important implications for safety and efficacy. Consequently, there is no "one size fits all" approval route for all biosimilars.

The simple message to Congress: Don't micromanage the FDA's science-based regulations. Limited clinical-trial data may be needed in many cases, although as science evolves, standards for clinical trials (for both innovative biologics and biosimilars) should become streamlined.

It is only fair that companies making biologic medicines should face market competition once their patents expire. The public certainly will benefit from lower-cost biosimilars. But companies that produce follow-on biologics also have a responsibility to prove that their medicines are as safe.

This piece originally appeared in Investor's Business Daily

This piece originally appeared in Investor's Business Daily