FDA to Approve New Generics, But Health Care Savings Will Be Minimal

New biological drugs are too complex to be regulated the old way

Flickr/Andres Rueda

In 1984 the Hatch-Waxman Act made it cheaper and easier to put generic versions of a drug on the market. As a result of the expedited approval process, generics now make up more than 60 percent of prescription drugs sold in the U.S. and have saved the health care system $734 billion between 1999 and 2008 alone.

By the end of 2011 the FDA plans to release a similar set of guidelines to approve generic versions of biological drugs—a newer breed of pharmaceuticals that includes enzymes, antibodies and other molecules derived from living cells. Unfortunately, experts say, generic versions of biological drugs probably will not be able to reproduce the dramatic savings of the Hatch-Waxman bill.

Biological drugs are used to treat hundreds of types of diseases, including cancer (Herceptin), anemia (Epogen), arthritis (Enbrel), diabetes (Humulin) and human growth disorders (Genotropin). Demand is increasing rapidly for these drugs, even though they tend to be more expensive than traditional synthetic drugs. For example, Cerezyme treatments for a person with a life-threatening enzyme deficiency can cost up to $500,000 per year, and the cancer drug Avastin costs patients $100,000 a year. In the U.S., generic versions of these drugs are currently unavailable, at the expense of the patient and the health care system.

Biological generics will be less expensive than brand-name biologicals, says Dominique Gouty, laboratory director for Intertek Pharmaceutical Services, a company that helps pharmaceutical and biotech companies to test drugs, “but they will still be expensive.”

Under the Hatch-Waxman Act, as long as a manufacturer proved its generic drug was chemically identical to the pioneer drug, the generic could piggyback on the pioneer’s clinical research. By avoiding those expensive animal and human trials to assess the drug’s safety and efficacy, generic drugs were able to cut costs by up to 80 percent. Lowering prices will not be so easy for biological generics, however, largely because they will have a harder time avoiding those costly clinical trials. Here’s why:

1. Biological drugs are bigger and more complicated than traditional drugs

A traditional drug such as aspirin is synthesized entirely from precise chemical reactions carried out in a laboratory. Aspirin weighs a relatively light 180 daltons. Getting FDA approval for a generic drug such as this can be almost as simple as supplying the molecular formula.

In contrast, interferon beta—an antibody treatment for multiple sclerosis—is harvested from cultures of living cells. It weighs 19,000 daltons and contains complicated folds, twists and carbohydrate attachments. The drug can also come in combination with other cellular proteins.

Tools that would describe and compare these complex features are not fully developed yet. So, whereas analytical tools can tell the FDA whether two proteins have the same amino acid sequence, the higher-order features—folds, twists, carbohydrates and overall shape—largely remain in a black box. And nobody knows how differences in those higher-order features may affect patients taking the drug, Schellekens says.

Stephen Kozlowski, director of the FDA’s biotechnology products office, says that more and better analytical tools will make the approval process for biological generics easier. “We think that if you have a better molecular analysis, it reduces uncertainty about similarity,” he notes. “And if you have more confidence that molecules are structurally and functionally similar, then the number of clinical and animal studies should decrease.”

2. Biological drugs depend on touchy manufacturing processes

Because biological drugs are manufactured in living cells, there can be tremendous variation in the drug molecules produced. Getting exactly the right molecule depends on a precise culturing and extraction process, with very specific environmental conditions.

“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.”

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