Legislation & Regulation

FDA’s Gottlieb Aims To End Biosimilars Groundhog Day

The FDA commissioner has an 11-step ‘action plan’ to get biosimilars out of a repeat mode of unrealized potential. But issues like interchangeability still need clarifying if biosimilars are to have a major effect on drug expenditures.

Richard Mark Kirkner
Contributing Editor

You have to wonder if key players in the biosimilars industry in the United States don’t feel like Phil Connors, the character played by Bill Murray in the 1993 classic movie Groundhog Day. (Is it safe to call it a classic?) Connors is condemned to relive the same events of February 2 until he transforms from being a jaded, binge-drinking souse to a charitable, conscientious person.

Those observing—and working in—the biosimilars industry might sometimes feel like the unrepentant Connors, waking to Sonny and Cher’s “I Got You Babe” every morning. For more than two decades, biosimilars in this country have been stuck in a repeat mode of potential and promise. Now hopes for breaking out of that loop are clinging to FDA Commissioner Scott Gottlieb and the “Biosimilars Action Plan”—or BAP—he announced last July. The idea is to dismantle the regulatory hurdles that have prevented the American health system from adopting biosimilars and cashing in on the price difference between the copycats and the brand-name medications. The problem is that even if Gottlieb’s BAP were to be fully implemented, there are still all sorts of legal and other obstacles in the way of biosimilars catching on.

FDA footdragging

Gillian Woollett

Industry frustration with the FDA’s oversight of biosimilars goes back decades. Gillian Woollett, a senior vice president at Avalere Health, coauthored a Forbes op-ed critical of the FDA’s biosimilars approval process with Gottlieb when he was a resident fellow at the conservative American Enterprise Institute. In a recent interview with Managed Care, Woollett noted that the 1996 FDA guidance resolved the regulatory science on how reference biologics may differ from themselves after multiple manufacturing changes. Then, in 2010, Congress enacted the Biologics Price Competition and Innovation Act (BPCIA). In essence, it established an abbreviated regulatory approval process for biological products that are “highly similar” to and have no clinically meaningful differences from a previously approved product.

That should have opened the floodgates for approvals of biosimilars but didn’t, thanks to FDA footdragging on writing guidances and confusion about what has been written. Christine Simmon, executive director of the Biosimilars Council, an industry trade group that’s a division of the Association for Accessible Medicines, calls the 16 biosimilars that the FDA has approved so far “fantastic,” but then adds, “Of those 16, only six are available on the market.” One of the hang-ups: the post-approval patent disputes between the biosimilar and the makers of the “originator” biologic manufacturers. Brand manufacturers construct “patent thickets” by accumulating dozens of patents on additional changes at the end of a product’s life cycle. The cost of challenging all those patents can cause biosimilar developers to give up.

Fixing that process and getting more biosimilars onto the market to compete with brand-name biologics has become a priority for Gottlieb as part of the Trump administration’s overall desire to curb drug prices through more choice and competition. A Rand study estimates biologics have accounted for 70% of the growth in drug spending from 2010 to 2015.

Gottlieb’s 11 steps

It is against this backdrop that Gottlieb unveiled his plan for biosimilars. “So, enabling a path to competition for biologics from biosimilars is a key to reducing costs and to facilitating more innovation,” Gottlieb said when he introduced the BAP last summer in an address at the Brookings Institution.

The BAP outlines 11 action steps to streamline the biosimilars approval process. They include making the application and review steps more transparent and easier to navigate, establishing a new Office of Therapeutic Biologics and Biosimilars to oversee the process, and publishing new or revised regulations to clarify interchangeability between a biosimilar and its biologic reference.

For Woollett, correcting the misunderstandings around the last point is key to making the whole action plan work. While physicians can prescribe any biologic for their patients, an FDA interchangeability designation allows a pharmacist (subject to state law) to switch to a biosimilar when the reference drug is prescribed, not unlike generic substitution for small-molecule drugs. In Europe, regulators have said biosimilars are interchangeable even though there is no such formal designation. Health authorities there have switched thousands of patients from the reference drug to the biosimilar with no change in clinical outcomes, according to a 2018 study in the journal Drugs. The FDA has not been so forthright in its definition of interchangeability, Woollett says.

Leah Christl, the FDA’s associate director for therapeutic biologics, said at a biosimilars conference last year in London that the FDA agrees with the European regulators—a statement the FDA press office has confirmed. Christl also clarified that to the FDA, “interchangeability” means the pharmacist may substitute a biosimilar for a reference product without the prescriber’s intervention.

However, Christl also noted the FDA’s definition of “interchangeability” differs from how European regulators typically apply the term, and that “interchangeability” is a distinct statutory term in the United States. She said the FDA’s position is that biosimilars can be prescribed for patients already on reference products as well as for previously untreated patients, which is also in line with the description provided in the publication by the European regulators.

Woollett, who was at that conference, calls Christl’s words “a heck of an important statement.” Woollett adds, “I requested that it be put on the FDA website, but was told it was a clarification for European audiences. My point remains that American audiences need that clarification, too.” In August 2018, Pfizer added its voice to the call for clarity on interchangeability when it filed a citizen petition with the FDA.

Fixing the Purple Book

Updating the “Purple Book” and making it easier to navigate and find information about approved biologics is another key point of the BAP—and another long overdue move, says David Gaugh, senior vice president of the Association for Accessible Medicines, which changed its name from the Generic Pharmaceutical Association two years ago. The Purple Book lists biological products, including biosimilars and interchangeable biological products, that the FDA has approved. Gaugh says it’s an important tool for biosimilar developers.

“We’re asking the [FDA] to update and provide the patent information and clarify which products are determined not to have exclusivity,” says David Gaugh of the Association for Accessible Medicines.

He notes the Purple Book contains very little information about patents and exclusivity periods—the period the FDA grants to a reference biologic that’s free from biosimilar competition. “We’re asking the agency to update and provide the patent information and clarify which products are determined not to have exclusivity,” Gaugh says. “That would help foster some more developments.” He adds that the Purple Book doesn’t indicate which reference product a specific biosimilar is based on.

Perhaps more burdensome are FDA requirements for further testing of biosimilars in humans, even if they’ve already been approved in Europe. Because of that requirement, in the United States a biosimilar costs about 100 times more to develop than a generic small-molecule drug, Woollett says. “A generic is $2 million to $5 million; a biosimilar takes $200 million to $500 million—on a good day.”

But in his action plan, Gottlieb has proposed the FDA share data with foreign regulators in reviewing biosimilar applications. U.S. clinical trials that mirror foreign studies are known as “bridging” trials. “We’re saying that bridging is not required, and Commissioner Gottlieb is questioning if it should be, too,” Gaugh says.

Consider that somatropin, a biosimilar to Pfizer’s growth hormone Genotropin, was the first biosimilar approved in Europe. That happened in 2006, nine years before the FDA approved Zarxio.

Cue “I Got You Babe.”

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