to lower the price of recombinant protein drugs. Biologics made up the top six drugs for Medicare Part B expenditures in both 2006 and 2007 by the US Government, as reported by the Washington Post. One can easily visualize the strong attraction to Big Pharma of selling biologics, where generic competition is not currently a threat.
Generic versions of small molecules are generally introduced into the marketplace without doing clinical trials. However, it is not at all clear that the same thing will happen with biogenerics. If makers of biological generics are required to run clinical trials before approval, then this only raises the bar higher to keeping out competitors. Even if biogenerics do make it onto the market, they won’t be priced as cut-rate bargains like traditional small-molecule generics, because the biologics will cost more to manufacture, and develop, according to a detailed analysis by the FTC. Partly because of their higher prices, biogenerics are predicted to capture much less market share than small molecule generics. As a result, makers of biologics will be much less concerned than makers of small molecules about a potential loss of revenue once the patents expire on their molecules. In addition, the barrier to entry in making biogenerics is significantly higher than with small molecules, due to much higher production costs as well as the yet undefined regulatory pathway.
Why is there no straightforward regulatory path for biogenerics? Biological molecules are significantly more complicated than small chemical compounds. Any seemingly minor modifications of the protein during manufacturing (like the pH or temperature being just a little bit inconsistent) can potentially result in a protein that is perceived by the immune system as foreign. The net result is that the body can make neutralizing antibodies against the protein drug—essentially rendering it useless over time. In the case of monoclonal antibodies, the consequences would be that they could only be used in one course of treatment. They would be ineffective if administered after that. In the case of administering proteins that naturally exist is the body but are either missing or present in reduced levels in various disease states (e.g. insulin for diabetes, erythropoietin for chronic kidney disease), the consequences can be much more severe because it would stop the effect of a drug that people’s lives depend on.
An example of this problem was seen in a small number of patients in Europe given recombinant erythropoietin in the late 1990’s. These patients developed a very serious complication known as pure red cell aplasia (PRCA). This happened because they developed neutralizing antibodies against not just the recombinant protein that they were being injected with, but also against the erythropoietin protein their bodies produced naturally. As a result, they needed frequent blood transfusions with red blood cells since they stopped making any of their own. What caused them to develop this disorder? After a lengthy investigation, it is believed that the development of pure red cell aplasia was likely caused by different stabilizers used in the formulation, the composition of materials in the syringe that contains the protein to be injected, and possibly even the route of administration as well. As a result of these issues, regulatory agencies are likely to be extremely conservative in approving generic versions of recombinant proteins.
Biogenerics Will Operate Differently From Small Molecule Generics
There are often many different brands of small molecule drugs that all attack the same target. For example, there are 12 different beta blockers for heart conditions and five brands of statins that your doctor can choose from to lower your cholesterol. Because there are often multiple drugs that exploit the same biologic target for a given medical condition like high blood pressure, the introduction of a generic version of any one member of the class can seriously erode sales of another drug within the same group. Let’s look at the No. 1 selling drug in the world, Pfizer’s cholesterol-lowering drug atorvastatin (Lipitor), which generated worldwide sales of more than $13 billion in 2008. The introduction of a generic version of Merck’s competing drug simvastatin (Zocor) took a big bite out of not just Zocor’s sales, but Pfizer’s Lipitor
