Biosimilars and interchangeability: Many questions, few answers

The Biologics Price Competition and Innovation Act (BPCIA) of 2009, which created an abbreviated FDA process for approval of biosimilar agents, has left many issues unresolved, one of the most important of which may be interchangeability - how physicians, pharmacists, health systems, and other players can or cannot switch a biosimilar for the reference biologic agent.

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“BPCIA answered a lot of questions about biosimilars, especially with regard to the pathway to bring biosimilar to market, but it also left unanswered a lot of questions,” said Jeffrey Casberg, MS, RPh, director of clinical pharmacy for IPD Analytics, Bay Harbor Islands, Fla., speaking to a panel at the recent Biosimilars 20/20 conference in Philadelphia.

The key to interchangeability is that the biosimilar “must be able to be alternated with the reference product, without any loss of efficacy or change in risk of adverse events,” he said. The FDA approval process for biosimilars requires comparative data to assess the risk of immunogenicity with the reference biologic.

“Interchangeability means a lot of different things,” said panelist Steven Lucio, PharmD, BCPS, senior director of sourcing operations for the healthcare services company Novation, in Dallas, Texas. “When it comes to medications, interchangeability is in the eye of the stakeholder.”

Most people consider interchangeability akin to substitution - the relationship generic drugs have with reference branded drugs. For biosimilars, it’s not that straightforward. “The approach to interchangeability and substitution is very nuanced in actual practice,” Lucio said.

Federal and state regulations

FDA created two biosimilar pathways in the BPCIA: 351(k)(2)(A), which is a non-interchangeable biologic; and 351(k)(2)(B), which is interchangeable. The former is a brand-to-brand-style approval; the latter is more like an approval for a generic.

See also: FDA releases final guidance document on biosimilars

But the process of proving interchangeability is fraught with more questions than it answers, Casberg said.  “A biosimilar can have two of five indications of the reference biologic or all five indications,” he said. “Could we have a drug with some of the five approved indications interchangeable and some not?”

Other questions revolve around the process and risks for a biosimilar already on the market to apply for interchangeability. If a product has been on the market and successful, Casberg said, will the company hesitate to apply for interchangeability, fearing public perceptions if the application fails? Also, what additional studies will the FDA require to prove interchangeability? And what about the duration of the biosimilar approval process itself? “Is it one year, or two years?” he asked. “We don’t know.”

Meanwhile, the states themselves have tackled legislation on interchangeability. Twelve states have enacted legislation and 11 others are considering it, Casberg said. “Some legislation ignores federal law that states the pharmacist can substitute a biosimilar without intervention of the prescriber,” he said.

Healthcare stakeholders

Among healthcare stakeholders that may drive interchangeability, the health plans are key, Casberg said. “I think you’ll see increased activity in formulary management within managed care organizations,” he said. “Formularies are becoming more tightly managed; this will assist in provider adoption of biosimilars and translate into greater use of biosimilars.”

Health plans will have a key role in educating another important group of stakeholders: the doctors and outpatient centers that prescribe and administer the biosimilars. Doctors will need a better understanding of how biosimilars can be interchanged with the reference biological, including the policies of the health plan, Casberg said.

He cited findings from a National Cancer Care Network study in 2011 in which only about one in five physicians said they were moderately or highly familiar with biosimilars. Infusion centers will have more flexibility in interchanging biosimilars for reference biologics than specialty and retail pharmacies, he said.

Another key link in the success of biosimilars is the pharmacists who dispense the agents. “If the pharmacist wants to dispense a noninterchangeable biosimilar product, he or she has to call the doctor for permission. These may be challenging discussions for the doctor and pharmacist,” Casberg said.

Europe may serve as a model for how quickly providers adopt biosimilars, Casberg said. Finland, the Netherlands, and France are embracing biosimilars, and a good track record with safety and efficacy in those countries may help with adoption in the United States, Casberg said. He also cited a study reported at the Biosimilar Medicines 11th EGA International Symposium in 2013 that showed nearly twice as many patients got treatment with filgrastim after biosimilars were introduced in the United Kingdom. This translates into potential for improved standard of care delivered at a lower cost, he said.

Novation’s Lucio said that pharmacists and other healthcare professionals could turn to professional societies’ guidelines for some direction on interchangeability. The American College of Cardiology Foundation/American Heart Association statement on therapeutic interchange and substitution (J Am Coll Cardiol. 2011;58:1287–1307) hinges upon two areas: narrow therapeutic-index drugs and critical-dose drugs, both of which he characterized as “where you have efficacy levels that are close to toxicity levels.”

And the American Society of Health System Pharmacists guidelines  (Am J Health Syst Pharm. 2008;15;65:1368–1384) consider therapeutic interchange “an authorized exchange of therapeutic alternatives in accordance with previously established and approved written guidelines or protocols within a formulary system,” Lucio said. But in the hospital setting, “therapeutic interchange” can refer to drugs that are not generically identical, he said.

Payers could prove a major driver for resolving questions about interchangeability, Casberg said. The potential costs savings from using biosimilars are substantial. Casberg cited a range of estimates that averaged out to about $100 billion in savings to the healthcare system overall in the next 10 years.

Bumps ahead

One stakeholder that can erect obstacles on the road to interchangeability is the branded pharmaceutical industry, Casberg said. “The concern of branded pharmaceuticals is to defend their franchises,” he said. “We are seeing them coming out with new formulations.” One example he gave is that AbbVie, the maker of Humira (adalimumab), is working on a new formulation to reduce future substitution.  And biologics like Amgen’s Neulasta On-body Injector pose other issues for biosimilar interchangeable, since the delivery device itself is proprietary and may reduce the ease of substitution.

“For biosimilars, the first to market is going to be even more important than it was for the first-to-market generic manufacturers,” Casberg said. Once a patient gets started on a biosimilar there may be very little switching over time between other biosimilars, he said.

The naming of biosimilars poses another challenge for interchangeability, Casberg said. Pharma and biotech are advocating for different names, while stakeholders such as the American Medical Association, America’s Health Insurance Plans, and American Pharmacists Association are angling for letting biosimilars use the same names as the reference biologic.

For biosimilars, the highest level of similarity the FDA will award is “highly similar, with fingerprint-like similarity,” said Casberg. “This indicates a level of similarity that presents almost no differences and has been validated by methods of analysis permitting a very high level of confidence,” he said.

Role of health systems

Health systems face challenges in bringing biosimilars onto their formularies because physicians and pharmacists must navigate a learning curve.

 “We need to get comfortable with the idea of interchangeability,” Novation’s Lucio, speaking as a pharmacist, told the panel. “For pharmacists it’s hard; we like data.” Hospitals and health system committees will find the review process for biosimilar interchangeability more complex than that for generics. It will involve a more detailed evaluation of safety and efficacy, he said.

By the same token, health systems are well equipped to tackle these challenges, Lucio said. They already have the organizational infrastructure, such as formulary committees, to handle these decisions, and people within those organizations already have a high comfort level with “using chemically distinct products in therapeutically similar circumstances,” he said.

“But physicians and pharmacists are accustomed to having access to clinical trial data to support therapeutic interchange strategies,” he said. “Clinicians will need additional education.”

Richard Mark Kirkner is an independent healthcare journalist in the greater Philadelphia area.