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Biosimilar Drugs Face Challenges to Reach the U.S. Market
by Kathleen Louden
CHICAGO - The U.S. Food and Drug Administration (FDA), which can now abbreviate the licensure pathway of biosimilar drugs under a provision of the 2010 Patient Protection and Affordable Care Act, is seeking public comment about approving similar but less expensive versions of biologic therapies whose patents have expired.
In its own discussion of the merits and obstacles to biosimilar drugs, the ACR sponsored a panel session titled, “Biosimilar Products in the U.S. Market: Fact or Fiction?” at the 2011 ACR/ARHP Annual Scientific Meeting here in November. [Editor’s note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
To date, the FDA has not approved a biosimilar product. Yet session moderator Eric M. Ruderman, MD, professor of medicine at Northwestern University in Chicago, said, “this is an area that has garnered a great deal of interest in the last few years because of the financial aspects; branded biologic products are expensive.”
Also driving interest in biosimilar agents is that patents for several top-selling biologic agents in rheumatology are expected to expire in the next few years, said panelist Vibeke Strand, MD, a consultant to pharmaceutical and biotechnology sponsors for new product development in rheumatic diseases. She also is adjunct clinical professor in the Division of Immunology and Rheumatology at Stanford University in Palo Alto, Calif.
What Is a Biosimilar?
The FDA defines a biosimilar product as a drug that is “highly similar” to or “interchangeable” with an approved biologic medicine. The European Medicines Agency (EMA) considers a medication biosimilar if it is comparable or similar to the reference drug, the original biological, said another speaker, Andrea Laslop, MD, head of the scientific office of the Austrian Agency for Health and Food Safety in Vienna, Austria. In the European Union, 14 biosimilar drugs have been approved since the first one (somatropin) in 2006.
“Biosimilars are not generics,” said Dr. Laslop, a liaison to the EMA. “The whole undertaking is a lot more complicated.”
Unlike generics, most biologicals are complex, large-molecule drugs, said Thomas Felix, MD, scientific affairs director for global development with Amgen in Thousand Oaks, Calif. For instance, a large biological, a monoclonal antibody, measures about 150,000 daltons, has more than 1,000 amino acids and 20,000 atoms, and degrades over time, thus usually requiring special storage to maintain stability, he explains. On the other hand, a small-molecule drug, aspirin, is 180 daltons with 21 atoms, is stable, and has a lower potential for immunogenicity than do monoclonal antibodies.
“The challenge to create biosimilar drugs is essentially a reverse-engineering process,” Dr. Felix said.
The manufacturer of a biologic agent starts with a unique cell line and takes many proprietary steps to ensure that the final product has the target protein and minimal to no impurities. A company trying to copy a biological has only the active drug substance in its final form, which has already begun to degrade.
“The manufacture of a biosimilar is not impossible,” Dr. Felix said, but adds that it will not be identical to the original biological. What must be an exact copy in order for the FDA to approve a biosimilar drug, he believes, is the protein’s amino acid sequence.
In addition to a biological’s molecular structure, its manufacturing process is also important for reproduction. Manufacturing steps are not identical between drug makers of biologicals, Dr. Felix said.
Whereas many differences in the manufacturing process of biologicals will not matter, some differences are important, Dr. Felix stressed. Even a single process change by the original manufacturer after a biological goes to market can require further clinical trials if it is major, such as changing cell culture media or using a new cell line.
Because creating a biosimilar agent will use different manufacturing steps, Dr. Felix expects that FDA approval of biosimilar products in the United States will most often require phase I and phase III clinical trials in a single disease state as well as postmarketing surveillance. He said that chemistry and manufacturing controls will be needed to compare a biosimilar to the reference product.
Challenges of Biosimilar Drugs
A biosimilar product is “expected to produce the same clinical result in any given patient,” according to the FDA.
Dr. Strand called that expectation “a tall order” for monoclonal antibodies and soluble receptors, and warns that process changes for a biosimilar agent may result in unpredicted effects.
“The challenge,” Dr. Strand said, “is to demonstrate that differences in a biosimilar product do not have a significant impact on clinical efficacy, safety, and stability.”
She believes that the FDA, which has not yet issued a guidance document on biosimilar products, will ask drug makers to prove biosimilarity using predefined margins.
“The FDA must set scientific criteria that address the key question of ‘How similar is similar enough?’ Given the complex nature of monoclonal antibodies and soluble receptors, it’s unlikely there will be a one-size-fits-all definition,” Dr. Strand commented.
These difficulties, she said, may make it hard to create a low-cost version of these types of biologic agents.
European Versus U.S. Process
Europe, however, recognizes that biosimilar agents are possible, said Dr. Laslop, who added, “We anticipate future approval [even] of biosimilar monoclonal antibodies.”
A draft EMA guideline on biosimilar monoclonal antibodies, according to Dr. Laslop, would require drug makers to establish that a biosimilar is equivalent to the reference product, although the agency is discussing a noninferiority approach.
Under its 2005 general guidelines on biosimilars, the EMA requires a biosimilar development program to establish biosimilarity to a reference drug, not to establish treatment benefit for the individual patient. Therefore, it may waive efficacy studies. For clinical comparability studies of biosimilar monoclonal antibodies, the EMA prefers to see an endpoint based on treatment response, said Dr. Laslop.
She acknowledged that it is becoming more challenging to rate the clinical relevance of small differences in quality. The EMA is revising its current guidelines to address changes in manufacturing during a product’s life cycle.
“For clinical comparability, it is about choosing the most sensitive and homogeneous population, which may be healthy volunteers or patients,” Dr. Laslop said.
However, Dr. Strand said, “In rheumatology, we don’t typically have homogeneous populations, or necessarily ones we can identify as most responsive to a given therapeutic agent.” Dr. Strand also stated that the FDA most likely will not use noninferiority to compare a biosimilar to a reference product.
“We’re not going to be able to say a biosimilar is noninferior, because that would allow a broader definition of equivalence,” Dr. Strand said. “Unfortunately, ‘biobetter’ won’t happen because the FDA defines a biosimilar as clinically equivalent and substitutable.”
How Close Are We?
The challenges of creating biosimilar products rise with the increasing complexity of the biologic product. For peptides and short proteins, it may even be possible to create bioidentical products, according to Dr. Laslop.
“For more complex and variable molecules such as large blood-derived products and so-called advanced therapy medicinal products, the question is whether they can ever be biosimilar,” Dr. Laslop said. “Currently we are still far away from that.”
The take-home message of this symposium, Dr. Ruderman told The Rheumatologist, is: “Biosimilar drugs are coming to the United States, but there are a large number of challenges before we can get to that point.”
Dr. Felix is an employee and stockholder of Amgen. Dr. Strand discloses that she is a consultant to Abbott, Alder, Amgen, Anthera, AstraZeneca, Biogen Idec, Biotest, BMS, Centocor, Genentech, GSK, Human Genome Sciences, Incyte, Lilly, Medimmune, Millenium, Merck-Serono, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche, Sanofi Aventis, Savient, and UCB. Dr. Laslop and Dr. Ruderman report no financial conflicts of interest.
Kathleen Louden is a freelance medical journalist based in the Chicago area.