High-Tech Medicines, Built to Mirror Originals, Can Have Dangerous Differences

If you walked into a restaurant and ordered an espresso, but the waiter gave you a coffee instead, you'd be unhappy—especially if the waiter insisted that there was no difference between the two. Yes, both are made from coffee beans and hot water—and both are loaded with caffeine—but they also taste very different and may have different effects in different people.

Right now, some in Congress are attempting to create a law that would allow a similar, but far more dangerous, substitution that could impact patient safety.

This new rule would apply to biologics, which are the high-tech prescription drugs made through biotechnology, and "follow-on" biologics, which are close—but not identical—copies of these drugs.

Advocates want follow-on biologics to be regulated just like ordinary, small-size, generic drugs such as the pills we get from our pharmacies, treating them basically as no different than the original forms they are trying to copy. To that end, Democratic Rep. Henry Waxman of California has introduced a bill that would allow follow-on biologics to pass through the FDA approval process without the same rigorous testing applied to original biologics.

But follow-on biologics aren't like the generic drugs in your medicine cabinet, and should not be treated as if they are identical to the original drug.

Chemically, biologics are significantly larger and more complex than ordinary pharmaceuticals. Tylenol, for instance, is made up of just 20 atoms. By contrast, the widely used anticancer biologic Herceptin is composed of more than 20,000 atoms. Moreover, biologics are unique in that they are created by living organisms, which serve as customized biological drug factories. By nature, this production process is highly unpredictable and difficult to reproduce, even in the same company using the same organisms.

Both of these differences mean biologics can't be replicated in the way conventional, small-sized medicines can. In fact, a recently published survey of medical studies determined that follow-ons "differed widely in composition, did not always meet self-declared specifications, and exhibited batch-to-batch variation."

Why is this variation important? Because complications in making biologics have caused significant side effects in the past. In 2001, for example, a U.S. biologic that had been tested and approved in Europe was licensed to be created there. However, the foreign versions of the drug unexpectedly caused many patients to suffer from "pure red cell aplasia"—the inability to make new red blood cells. Some patients died; others were permanently injured. Ultimately some patients became allergic to their body's own form of the drug.

Despite almost a decade of investigation, researchers still don't know why patients had these reactions. Hence, even for biologics that undergo clinical trials and are cooperatively licensed, there are still dangerous patient-safety uncertainties involved in the manufacturing process.

Therefore, Representative Waxman's plan to allow clinical use of follow-on biologics without first subjecting them to rigorous safety testing presents a significant risk. The fact that the original biologic has proven safe is no guarantee that any follow-on version will also be safe. Thorough testing, as required in Europe, will help protect patients from adverse health effects.

It is also imperative that Congress require that original biologics and follow-ons have some designator that allows rapid identification of the specific version of the drug being used.

Currently, the FDA classifies small generic medicines using the same scientific name as the original drug. That's as it should be, since generic forms of conventional drugs are identical to brand-name forms. There's no difference, for example, between brand-name Advil and store-brand ibuprofen.

But in the case of biologics, without a distinction between originals and follow-ons, such as an "alpha" or "beta" distinguisher on the follow-on form, physicians may end up prescribing a follow-on form with very different or unknown health effects than the biologic they intended to prescribe. In the event of an adverse reaction, it would be much harder for regulators to track which drug form was taken.