EXPERT SAYS MANUFACTURING CHANGES POSE CHALLENGES FOR BIOGENERICS

One potential problem with making follow-on biologics is that there isn't enough data to show how changes in manufacturing processes might affect a product's safety and efficacy, one expert said during a regulatory affairs conference in Baltimore. Therefore, postmarketing clinical trials may be the only way in some cases to determine whether the drug is safe.

"Analyses of final products may reveal similarities and differences," Philip Noguchi, who spoke at the Regulatory Affairs Professionals Society's (RAPS) 2005 Annual Conference, told FDAnews. "The difficulty in evaluating these data is that there is very little publicly available clinical data that authoritatively demonstrates what the consequences of differences or the consequences of similarities may be," said Noguchi, Amgen's director of regulatory affairs.

Subsequently, he added, "Changes in manufacturing may or may not result in adverse effects but, once again, there is very little public data that addresses this point."

In one case, described in a September 2004 article in The New England Journal of Medicine (NEJM), patients who took certain brands of epoetin (recombinant human erythropoietin), a drug to treat anemia, demonstrated an unusually high rate of pure red cell aplasia (PRCA). PRCA is a very rare adverse event seen with epoetins. In these rare cases, red cell production in affected patients shuts down.

In the case examined by the NEJM, there was an unexplained increase in PRCA among some patients taking one epoetin. Upon further investigation, the increase seemed to be associated with a change in manufacturing processes.

Because human epoetins generate an immunogenic reaction in animals, researchers will not be able to use animal studies to address the safety question of PRCA. Instead, a company would have to conduct a postmarketing study to determine if the drug poses safety problems, Noguchi told FDAnews.

Without a postmarketing safety analysis, a biogeneric could sicken or kill people and inspire people to avoid that type of drug, Noguchi said. He cited a case in 1901 when 13 children in St. Louis died after receiving diphtheria antitoxin. Although people knew the inoculations worked, after this event, many children susceptible to diphtheria were not allowed to receive the inoculations, he said.