“A one-degree difference in the environment can make the cell react in different ways, and you may have a different drug at the end,” Gouty says. “It’s like if you cut yourself one day, you might bleed for one minute, but for some reason you might bleed for 10 minutes if you cut yourself another day. Living things have lots of variation that we don’t understand and we cannot control.”
When Genzyme attempted to scale up its manufacturing process for Myozyme in 2008, the FDA found that when the process moved from a 160-liter tank to a 2,000-liter tank, the carbohydrate attachments of the enzyme were somehow changed. The company had to repeat its safety and efficacy experiments, and ultimately it had to market the drugs from the larger facility under an entirely new brand name.
“Even within the same company with the same manufacturing process, the product can be different day to day,” Gouty says. A generic manufacturer is likely to have a very different process from the pioneer company, making it even more difficult to create a similar product.
3. Biological drugs pose unique safety concerns
In 2003 Johnson & Johnson learned the hard way that a seemingly small change to the manufacturing process can have devastating consequences. In manufacturing Procrit, a biological treatment for anemia, the company substituted one stabilizing agent for another, which was thought to be safe. Studies later found that 16 percent of Procrit users suffered sudden and sometimes fatal reactions to the drug. After the drug had gone to market, researchers learned that the new stabilizer had unexpectedly reacted with other ingredients, creating substances that caused immunogenic responses and intracranial hemorrhaging in some patients.
Because they are derived from living sources, most biological drugs will be recognized as foreign invaders by the patient’s immune system. It may send antibodies to bind and capture the drug, reducing its efficacy. Sometimes immune reactions to biological drugs can cause fatal side effects, such as organ failure, fever and cancer.
Currently there is no good way to predict how a body will react to a biological drug, says Jeff Mazzeo, a chemist at Waters, a company that designs molecular analysis tools. Bioassays, where a tissue sample in a petri dish is exposed to the drug, “could theoretically tell you how things would act in a biological system,” Mazzeo says. “The problem with bioassays is that they’re extremely variable. They need to be better.”
For these reasons and more, few experts foresee a day when a biological generic could be approved without running clinical trials first. To do so could be irresponsible, Gouty says.
The Federal Trade Commission estimates that generic biological drugs are “unlikely to introduce...discounts any larger than between 10 and 30 percent of the pioneer product’s price.” Nevertheless, those small savings may add up to $300 billion by 2029, according to some estimates, and future technologies that make it easier to assess the structure and function of a protein could add to those savings. “With enough tools and analysis, my sense is it could be possible to have biosimilars approved with relatively small clinical trials,” Kozlowski says.
At the very least, by encouraging the creation of new versions of biological drugs, the new FDA guidelines will give scientists additional opportunities to study protein structures and the ways they influence safety and effectiveness, Schellekens says. “We’re still in a learning process.”