BioWorld International Correspondent

LONDON - The guidelines for registering biogeneric drugs in Europe are vague and leave a lot unanswered. That includes how equivalence can be shown without relying on the innovator's data, whether the safety requirements are sufficiently robust, and if the risk/benefit test has been passed, said Thomas Bols, director of government affairs in Europe for Amgen Inc.

In addition, two further issues - naming biogenerics (called biosimilars in Europe), and when and whether they can be substituted for the original product - are not even addressed in the guidelines.

The European Medicines Agency (EMEA) wants to bring its shorter pathway for approving biosimilars into force in the first quarter. It has set out general guidelines, along with specific requirements for four products - erythropoietin (EPO), granulocyte-colony stimulating factor, insulin and human growth hormone - and is inviting comments by the end of the month.

Bols said Amgen acknowledges biosimilars could be approved by what he termed a "third route," which would require less data than a full application, but would not be abbreviated to the same extent as the approval pathway for generic chemical drugs. "We agree they can be approved without a full package, providing safety and efficacy is demonstrated," he said.

Amgen will submit comments to EMEA asking for clarity in the wording of the guidelines.

"There is too much use of the words may' or could,' leaving things open to interpretation," Bols said. The company also will question some of the specific requirements. For example, the requirement for EPO suggests a 12-month immunogenicity study in 300 patients.

"For some of our own [manufacturing] changes we have done 1,000 [patient studies]. We think they should say what the statistical rationale is for the number they have chosen - in other words, what is the risk level EMEA takes?" he asked

Amgen also argued that products should not be approved automatically in all indications for which the innovator product is registered, but indication by indication.

"This is because the mode of action can be completely different depending on the disease," Bols said. "For example, the use of EPO in chronic kidney disease, compared to its use in cancer."

Bols told delegates at Cordia in London last week that two significant issues are not raised in the guidelines.

"We feel somehow there should be guidance about what [biosimilars] are called," he said. Because the products are by definition similar but not identical to the original product, they should not have the same International Nonproprietary Name (INN).

"If you accept they are not identical, they should have different INNs otherwise it will not be possible to [conduct] pharmacovigilance. If there is a problem with a biosimilar, you may get a class effect - that is, all EPO products could be negatively affected," Bols said.

The second issue is substitution. Some countries in Europe have laws allowing pharmacists to substitute generic products even if the prescribing physician names the original drug. "With chemical drugs there is no problem, but we think this should not be done with biosimilars because they are not identical and there is a risk of immunogenicity," Bols said.

Although Amgen's EPO still is under patent protection in some territories - most notably the U.S., where the patent has five years to run - it is no longer covered in Europe. Around 20 generic versions are in development, and some are on the market already in countries, including India and China.

EMEA is organizing a meeting for interested parties in Paris on Dec. 8 and 9 to discuss the comments, with the aim of finalizing the guidelines in the first quarter of 2006.