Five years is long enough, several senators insisted Thursday as they pressed the FDA's Janet Woodcock for answers as to why the agency is taking so long to develop the biosimilar pathway laid out in the 2010 Biologics Price Competition and Innovation Act.

"It's time now for you to get this done. . . . I just want to underline the urgency of this," Sen. Elizabeth Warren (D-Mass.) told Woodcock at a hearing held by a subcommittee of the Senate Health, Education, Labor and Pensions Committee.

Driving that urgency is the rising cost of transformative biologics. Although biologics account for less than 1 percent of the drugs prescribed each year in the U.S., they claim 28 percent of the annual drug spend, Sen. Chris Murphy (D-Conn.) said.

Noting that just eight biologics make up 40 percent of Medicare Part B spending, Warren stressed the need for biosimilar competition to make biologics more affordable. But sponsors are still lacking FDA guidance critical to the development and marketing of the follow-ons. "Drugmakers need to know the rules of the road," Warren said.

"We have to get the science right," Woodcock responded. "We can't have problems with the first biosimilar out of the block." In developing the pathway, the FDA has faced many medical, technical and policy challenges, she added, as each biologic presents unique issues. As of July 31, the agency was working with sponsors on 57 biosimilars referencing 16 different biologics.

One of the biggest challenges facing the FDA is interchangeability, which would allow a follow-on to be automatically substituted for the prescribed reference biologic. Since interchangeability offers the best marketing opportunity, it is perhaps the most anticipated of the guidances the FDA hoped to deliver in 2015. (See BioWorld Today, Jan. 7, 2015.)

When Murphy asked if the agency was on track to get that draft guidance out this year, along with other promised ones, Woodcock declined to make a time commitment. "We're working very hard on these," she said instead.

For a follow-on to be deemed interchangeable, it must by law produce the same clinical results as the reference drug in any given patient. The risk, in terms of safety or diminished efficacy, of switching between an interchangeable and reference biologic must not be greater than from consistent use of the reference product. While the FDA has said that switching trials likely would be necessary to demonstrate interchangeability, it hasn't mapped out the path forward for interchangeables.

"We're going to get there," Woodcock said. Although interchangeability is scientifically possible, she noted concerns that continued switching between molecules could trigger an immune response – something that's been seen among various reference epoetin products. The FDA needs to make sure the interchangeability guidance is "bulletproof," she said.

That gave rise to whether an interchangeable and its reference product were like identical twins except maybe one has a freckle. "So the freckle makes a difference?" asked Sen. Bill Cassidy (R-La.), a physician.

"Possibly," Woodcock answered.

The ensuing discussion showcased the need for education about the follow-ons among doctors and patients. A misunderstanding about biosimilars could affect market uptake, Warren said, thus undermining the potential $44 billion in savings they could produce over the next decade.

"To a great extent, this falls on FDA shoulders," Woodcock said of education efforts. Even though the agency has been given no additional funding for biosimilar education, it has laid out campaigns and it plans to target physicians by subspecialty through continuing medical education courses. Education will be an ongoing process, just as it is with generics, which have been on the market for 30 years.


Another biosimilar guidance that was on the agency's 2015 to-do list deals with labeling. Having clear guidance available on biosimilar labeling before approving the first follow-on would have helped build physician confidence in the new drugs, Sen. Tim Scott (R-S.C.) said, noting that the label for Sandoz Inc.'s Zarxio (filgrastim-sndz), contrary to prior FDA statements, doesn't indicate the drug is a biosimilar. Given the other burdens being piled on doctors all at once with electronic health records, new codes, etc., Scott said the FDA can't expect a doctor to have to look up a drug to see if it's a biosimilar. The labeling should be clear.

Woodcock assured Scott that the FDA understands the criticality of issuing the labeling and other guidances as soon as possible. "It is really important for us to gain and maintain the trust of the medical community," she said.

In drafting the labeling guidance, Woodcock said the FDA intends to respond to a citizen petition submitted in June by Abbvie Inc. Spurred by the approved Zarxio label that mirrors the labeling of the reference product, Amgen Inc.'s Neupogen (filgrastim), the petition called for a distinction between generic and biosimilar labeling. (See BioWorld Today, June 4, 2015.)

Rather than duplicating the label of the reference product as is done with generics, a biosimilar label should indicate whether the FDA has determined the follow-on is interchangeable with the reference biologic and note which approved indications are based on extrapolation, according to the petition.

A third guidance the agency is developing addresses statistical approaches to analytical biosimilarity, which is foundational to the development of the drugs, Woodcock said. She expects the FDA will adopt a more flexible standard than the bioequivalency standard it uses with generics. The agency, which is working with the World Health Organization and other regulators on the standard, could issue that guidance within six months.

The senators are not alone in their concerns over the delay in guidance. Prior to the hearing, a coalition of more than 20 patient advocacy organizations urged the committee members to press for FDA final biosimilar guidance on safety and effectiveness, distinct naming and adverse event tracking, interchangeability, transparency and inclusion of the patient voice, and labeling to indicate a drug is a biosimilar. And several industry groups have repeatedly called on the agency to get the guidance out. (See BioWorld Today, Sept. 17, 2015.)


The lack of guidance has created enormous uncertainty – not just for industry, but also for doctors and patients, Emily Alexander, the biologic regulatory affairs lead for Abbvie, told BioWorld Today. While the one-on-one meetings the FDA is having with biosimilar sponsors are important, they shouldn't come at the sacrifice of the certainty guidance would provide.

So far, the thinking has been on one reference product vs. one biosimilar. But down the road, there could be several biosimilars referencing one biologic, and each could share different indications, Alexander said. That's why it's so important to get guidance on naming, labeling and interchangeability.

The guidance on analytical biosimilarity would be helpful for both innovators and biosimilar sponsors, Jerry Clewell, associate scientific director at Abbvie, told BioWorld Today. For instance, they need to know which key quality indicators are important to establishing fingerprint-like similarity and how they will be used to evaluate that similarity.

Clewell and Alexander acknowledged the challenges the FDA faces in drafting the guidances, given the complexities of both the biologics and the statistical methods used to establish similarity. Zarxio, the only biosimilar approved so far in the U.S., is a fairly simple protein, but other biologics could be much more complex. Coming up with one guidance to address the varying levels of complexity is quite a task, Clewell said.

"We have to get the science right," Clewell said, echoing Woodcock. "It is clear that key questions related to interchangeability and product labeling remain unanswered and need to be decided now and in a manner that prioritizes patient safety."