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Approval Process for Biosimilars Examined by FDA

Bleeding disorders community concerned about potential approval shortcut
Author: Rebecca Clay

By now, most people with hemophilia and other bleeding disorders and their families know the Patient Protection and Affordable Care Act will increase access to insurance for millions of Americans, eliminate annual and lifetime caps, and create other consumer protections.

What’s less well-known is that the new healthcare law also charges the US Food and Drug Administration (FDA) with creating an abbreviated pathway for approving so-called “biosimilars.” Also known as “follow-on biologics,” biosimilars are potentially less expensive versions of biologic products, such as clotting factor concentrates.

Making a biosimilar is much more complicated than making a generic drug because the molecules involved are larger and more complex. Further, biosimilars can never be exactly the same as the original product because they are made from biological materials rather than chemicals. That’s what has the bleeding disorders community on alert.

Biosimilars have the potential to reduce costs, improving access to treatment, the way generic versions of brand-name drugs do. But that shouldn’t happen at the expense of safety, says the National Hemophilia Foundation (NHF). Arguing that clinical trials of biosimilars should be an essential part of the approval process, NHF is urging the FDA to exclude biosimilar clotting factors—whether plasma-derived or recombinant alternatives—from the abbreviated approval process it is developing.

“Our community’s biggest fear is the unknown,” says NHF CEO Val Bias. “You have to consider the unique history this community has had with blood and treatment products over the years—the transmission of hepatitis B, HIV and hepatitis C. You have a reluctant patient population with good reason to be concerned about change.”

Biosimilars Regulatory Shortcut

The mandate to create a new process for approving biosimilars is part of the Biologics Price Competition and Innovation Act of 2009, which was included in the healthcare reform law passed in March 2010. Designed to balance innovation and consumer protection, the act calls on the FDA to develop a shorter approval pathway for biological products that are demonstrably “highly similar” or “interchangeable” with a biological product that the FDA has already approved.

Like the law that allows an abbreviated pathway for approval of generic drugs, the new provision would let pharmaceutical manufacturers rely on what’s already known about the brand-name product when they apply for approval of a biosimilar version. The goal is to save time and money and avoid unnecessary duplication of animal or human testing.

To be deemed biosimilar, the new product must be “highly similar” to the original product and have only minor differences in its inactive ingredients. There can be no clinically meaningful differences in safety, purity and potency between the original and follow-on drugs.

Manufacturers can also go for “interchangeability,” which means a pharmacist can substitute the biosimilar product for the original without approval from the clinician who prescribed it. To meet this higher standard, the manufacturer must demonstrate that the new product can be expected to have the same effect on a given patient as the original.

Although there’s no deadline for finalizing the new approval pathway, an FDA working group, the Biosimilar Implementation Committee, has been working on the issue since the new statute was enacted last year. Part of the committee’s work is to gather input from scientists, pharmaceutical companies, patients and anyone else with a stake in the outcome. NHF has shared its views via letters to the FDA (see “Learn More”).

Balancing Benefits and Safety

One of the anticipated benefits of biosimilars is their reduced cost. “In an era of government budget deficits and escalating healthcare costs, lower prices for biologics could greatly benefit both patients and those who are responsible for paying for them,” says Mark Skinner, president of the World Federation of Hemophilia. “With 75% of the world’s population having limited or no access to treatment, pursuing strategies to improve access is an important objective.”

While achieving that goal would be great news, say Skinner and others, it’s simply not worth it if the cheaper drugs put patients’ health and safety at risk. “I would like to see the FDA proceed carefully, with safety being in the forefront of its decision-making,” Bias says.

The prospect of manufacturers skimping on clinical trials and other steps that help ensure that products are safe and effective causes grave concern, says Marion Koerper, MD, NHF medical advisor and director emerita of the hemophilia treatment center at the University of California, San Francisco.

“There’s an implication that if the new drug works the same way as the other one, it must be as safe as the other one,” says Koerper. That assumption is valid in the case of generic drugs because they’re identical to each other, she says. “But with biosimilars, there’s a different level of safety we worry about.”

One issue is the possibility of an infectious pathogen contaminating the cells or culture medium the biosimilars are produced in—something that’s not an issue with generics because they’re made with chemicals, rather than biological materials.

Another concern is biosimilars’ potential immunogenicity, the ability to trigger an immune response. Even a small tweak in the molecular structure could increase the chances that a biosimilar factor product will cause a patient to develop an inhibitor, or antibody, to infused clotting factor.

“We don’t know enough about what it is in the structure of factor that provokes the development of an inhibitor,” says Koerper. “With something that looks almost identical, there may be some slight change somewhere that causes more inhibitor production.”

Even a small change in factor structure could have huge consequences. “Once you have an inhibitor, what happens when the next infusion of factor is given is that the inhibitor neutralizes the factor,” Koerper says. Alternative methods of stopping bleeds in people with inhibitors aren’t as effective and are much more expensive, she adds.

Interchangeability is another cause for concern. Koerper predicts that if a biosimilar factor product came on the market, insurers would put that product on their preferred drug lists and prevent patients from choosing the more expensive products they currently use.

As a result of these risks, NHF wants the FDA to require clinical trial data from manufacturers seeking approval of a biosimilar factor product. “There’s no way around it,” Bias says. And because the rarity of bleeding disorders means smaller pools of patients available to participate in clinical trials, he wants to see both post-licensure and pre-licensure trials.

Requiring all that information is hardly a shortcut, NHF acknowledges. That’s why the foundation hopes the FDA will simply conclude that biosimilar factor therapies and other plasma protein products aren’t eligible for the new abbreviated pathway.

Biosimilars European Model

The European Union (EU) established its own regulatory framework for biosimilars in the early 2000s. Now it has general approval guidelines for biosimilars, specific guidelines for each class of drugs and a few biosimilars out on the market, says Sol Ruiz, PhD, head of the biotechnology and advanced therapies unit at the Spanish Medicines Agency, Spain’s equivalent of the FDA. Ruiz is also Spain’s representative to the biologics working party of the European Medicines Agency.

“The general guidelines say biosimilars should have the same pharmaceutical form, strength and route of administration as the innovator medicinal product,” says Ruiz. “Then there are annexes to the general guidelines that describe specific requirements for a product class to demonstrate similar efficacy and safety.”

What the EU doesn’t have is an abbreviated pathway for clotting factor and similar products. Manufacturers hoping to make biosimilar versions of these products would have to submit the same dossier of safety and efficacy data that they would if they were developing the product from scratch. The World Health Organization has taken a similar approach, Ruiz says.

NHF hopes the FDA will follow its lead. As Bias stated in a letter to the FDA in 2010: “Patients in the United States deserve the same high standards for approval.”