June 1, 2007 (Vol. 27, No. 11)

Generic Biopharmaceuticals Require a More Thorough Evaluation than Other Generic Drugs

Healthcare costs are rising at about double the general inflation rate, and increases in drug prices have been even steeper. Congress is trying to control those prices with legislation that would allow for the manufacture of lower-cost generic, or follow-on copies, of biopharmaceuticals.

Since 1984, the marketing of generic drugs has been governed by the Drug Price Competition and Patent Term Restoration Act, commonly known as the Hatch-Waxman Act. By allowing approval of generic products through an abbreviated and less costly route than for innovator drugs, this legislation has given rise to a robust and valuable generic drug industry.

When Hatch-Waxman was conceived, biopharmaceuticals were new; now they are both common and expensive, accounting for some 13% of U.S. drug expenditures. To extend the benefits of Hatch-Waxman, Rep. Henry Waxman (D-CA) has introduced legislation designed to speed up the process by which follow-on versions of biopharmaceuticals can be marketed. Supporters of these efforts want generic drug producers to do for biopharmaceuticals what they currently do with traditional drugs. They believe that generic versions of biotech drugs should be approved for the market immediately after patents expire, with a minimum amount of testing.

Before Congress and FDA move too hastily to mandate follow-on copies of biopharmaceuticals, however, they need to consider that not all drugs are equal and not all efforts to drive down prices will be safe for patients.

Biopharmaceuticals are not like the traditional, small molecule pharmaceuticals that control pain, blood pressure, or high cholesterol. They are made in living cells. Biopharmaceuticals are larger and have more complex molecular structures than traditional, small molecule drugs. Recognizing this difference is critical to understanding that generic, or more accurately follow-on versions, cannot be regulated in the same way as small molecule generics.

Scientifically and medically, biopharmaceuticals and traditional drugs are not comparable. Because most conventional pharmaceuticals can be manufactured with easily replicable chemical processes, the clinical trial data that supported approval of the original version can be relied upon for the generic versions. The latter need only demonstrate bioequivalence to the original version by means of simple tests.

The production of biopharmaceuticals is far more complex. Protein folding, various kinds of enzymatic modifications, and impurities inevitably introduce variation, sometimes with unexpected results. Even minuscule differences in the substances that accompany or contaminate the active drug substance can be clinically significant, and because the same biopharmaceutical may be purified from widely differing substrates—bacteria, yeast, or cultured mammalian cells, for example—the contaminants may vary widely.

Biopharmaceutical Failures

When I was a medical reviewer at FDA in the early 1980s, a completely unexpected side effect occurred in the clinical testing of a new formulation of human growth hormone synthesized in bacteria that had been modified with recombinant DNA techniques. At the outset of the initial clinical studies on healthy human volunteers, who happened to be executives of the drug company, the drug caused extreme pain at the injection site, fever, and blood chemistry abnormalities that indicated an inflammatory process.

The problem resulted not from any anomaly in the growth hormone molecule itself but from a low-level contaminant that stimulated human white blood cells to release a substance that caused the signs and symptoms. The contaminant had not been detected in the standard, sophisticated screening tests that are supposed to assure a drug’s purity and quality. Neither was it found in preclinical studies because of the indirect mechanism of its toxicity and its specificity for human cells. Thus, prior to injection into humans, the problem was exceedingly difficult to detect.

Another example occurred between 2001 and 2003, when anemia therapy Eprex, a supposedly identical version of the gene-spliced drug Epogen, caused a 30-fold increase in a severe condition called antibody-associated pure red cell aplasia.

Late last month, FDA Deputy Commissioner Janet Woodcock acknowledged in testimony before Congress the safety challenge posed by follow-on biopharmaceuticals. She said that the agency “will be influenced by the extent to which the follow-on product can be demonstrated to be sufficiently similar (structurally, functionally, and clinically) to an approved protein product to permit some degree of reliance on the findings of safety and effectiveness for the approved product.”

Rule #1: Don’t Let Policy Get Ahead of Science

This kind of adjustment of public policy requires a difficult balancing act. Treatment with biopharmaceuticals can be expensive, reflecting the hundreds of millions of dollars in capital and opportunity costs required to bring these drugs to market. Those development costs also imply the need for a return on investment. Preserving incentives for innovative R&D is vital to ensure that biotech firms will produce the next generation of miracle therapies, but as Competitive Enterprise scholar Gregory Conko has observed, innovation is “driven by competition, which is why patent terms expire. Once the patent and data exclusivity protection for a biopharmaceutical ends, consumers would benefit from an abbreviated regulatory pathway that lets follow-on products get to market.”

So what should policymakers do to address the concerns of patients looking for cheaper alternatives? Rule one is not to let policy get ahead of the science. Rep. Waxman and his colleagues must keep in mind that some things cannot be dictated by legislators: Science is a law unto itself.

Henry I. Miller, M.D., is a fellow at the Hoover Institution, Stanford University. E-mail: [email protected].

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