Europe’s Biosimilars Ahead Of U.S., But Still Early

Beware confusion with generics, Biosimilars 2000 speakers warn.

Washington, D.C. - With nine products encompassing three drug classes approved under a regulatory pathway launched in 2004, the EU is far ahead of the U.S. in bringing follow-on biologics, often called biosimilars, to the marketplace.

But while Congress slowly works its way through establishing a follow-on biologics (FOB) process that FDA can implement, Europe's work is just beginning, explained speakers at the Biosimilars 2008 conference Sept. 22-23 at George Washington University.

To date, the European Medicines Agency has approved five requirement dossiers in four drug classes - erythropoietin, granulocyte-colony stimulating factors, human growth hormone and insulin - while it continues work on guidances for interferon-alpha and low molecular weight heparin, EMEA's Falk Ehmann told the conference.

This month's approvals of two G-CSF products - Ratiopharm's Ratiograstim and Teva's TevaGrastim - to compete in the neutropenia space with Amgen's Neupogen and Neulasta bring to nine the list of EU-approved FOBs (¹ (Also see "G-CSF Biosimilars Approved By EU Could Impact Amgen Sales" - Pink Sheet, 24 Sep, 2008.)). The list also includes Sandoz's Omnitrope and Biopartners' Valtropin - two human growth hormone products - and five EPO-stimulating agents, such as Sandoz's Binocrit .

Two other speakers warned the audience not to think of FOBs as the same thing as generic versions of small molecule drugs. FOBs are similar, but not identical to their reference products, explained Thomas Bols, Amgen's director of government affairs, Europe.

Because biologics and chemical drugs differ in molecular properties and manufacturing complexity, he said, it is not possible to make an identical copy of a biologic. Biologics include unique lines of living cells and cannot be characterized fully, as a small molecule can, because they contain a mixture of related molecules.

Therefore, the business of developing a biosimilar centers on painstakingly demonstrating similarity to the reference product, said Ingrid Schwarzenberger, head of biopharmaceutical regulatory affairs for Sandoz, the generics/biosimilars division of Novartis (² (Also see "Sandoz Hones Biosimilars Strategy" - Pink Sheet, 5 Sep, 2008.)).

"You have to demonstrate similarity and equivalence against the reference product in quality, safety and efficacy," she explained. This process begins with work characterizing many batches of the reference product, to note variability in batches and account for formulation differences.

The comparability exercise informs all stages of development of a biosimilar, Schwarzenberger said. At levels one and two, the development team must demonstrate physico-chemical comparability and then biological activity comparability. This establishes similarity to the reference product.

Those processes are followed by preclinical testing, then Phase I and Phase III trials to confirm similarity, she said. Phase I establishes pharmacokinetic and pharmacodynamic similarity, while Phase III confirms clinical safety and efficacy.

"Only when you have demonstrated all that and come up with a positive result, then you can say your product is biosimilar to the reference product" Schwarzenberger noted. "This rigorous comparability exercise really qualifies your biosimilar to be therapeutically interchangeable against the reference product from a scientific point of view."

Substitution among EU's key unresolved issues

Amgen's Bols differs somewhat on the issue of interchangeability, however. While Europe has developed a legislative pathway and regulatory guidance for biosimilars, he said, it still has substantial work to complete on issues of substitution, labeling, naming and pharmacovigilance of FOBs.

Again, because a biosimilar is not identical to the reference product, he said, it should not simply be substituted automatically by a pharmacist without a doctor's approval, as typically occurs with generic drugs in the U.S. Such a practice would be inappropriate with biosimilars for two primary reasons, Bols added.

"It all stems from the principle that, one, they're not identical and, two, a patient may react differently to different products. So, substitution may have clinical consequences," he said.

This is not to argue, however, that biosimilars are not safe, Bols added.

"I think the issue is not whether they're safe or not," he said. "When the EMEA or European Commission gives approval for a product, whether it is a biosimilar or any other kind of product, we have to indeed assume that the product is safe, that it has a positive risk/benefit balance."

"What is very important - and, again it is big difference [from] generics - is that the long-term safety profile of these products has not been established yet," Bols continued. "Just as with any other new product, it's nothing unique about biosimilars but we have to treat these as a new product, not a generic."

-Joseph Haas ([email protected])