One simple four-letter word can make a world of difference in how quickly biosimilars and interchangeables bring full competition to the U.S. marketplace of biologics, a handful of companies and industry groups told the FDA in comments on a draft guidance concerning the labeling of follow-ons that are licensed for fewer indications than the reference biologic.

“In many places throughout the draft guidance, FDA refers to the moment when a biosimilar may be licensed for a condition of use that has been previously omitted from labeling as being ‘after’ the exclusivity or patent expires,” the Association for Accessible Medicines (AAM) and the Biosimilars Council said in a joint comment.

If the intent is to enable follow-ons to add a carved-out or new indication as soon as possible once a patent or exclusivity ends, a patent has been invalidated or a licensure agreement has been reached, “the concept of ‘after’ should be converted to ‘upon,’” the groups said.

Unlike most small-molecule drugs, the lifecycle of a biologic often includes ongoing development for new indications, some of which may provide pediatric or orphan drug exclusivities. As the list of a biologic’s approved indications grows, so does the depth, and length, of its patent thicket. Consequently, sponsors wanting to launch a biosimilar sooner than later may seek a skinny label that carves out indications that are still protected by exclusivities or patents.

The draft guidance, issued in February, is intended to answer the question of how carved-out or new indications added by the reference biologic after a biosimilar was approved can be included in biosimilar labeling once the exclusivities or patents expire, especially since most of the other indications in a biosimilar label are extrapolated based on the follow-on’s demonstration of similarity to the reference drug.

In its comments, AAM also called out the FDA on other language used in the draft guidance that suggests an orphan drug designation could block the submission of a biosimilar application. That’s inaccurate, the generic drug trade group said, adding that applicants may seek licensure before the exclusivity expires and the FDA may license the indication upon that expiration.

Time of the essence

Before issuing the draft guidance, the FDA hadn’t created a clear process for seamlessly adding indications to the labeling of biosimilars once patent issues were addressed or regulatory exclusivities had expired, the Biosimilars Forum noted in its comment. Instead, the agency considered such applications as “supplements with clinical data” under BsUFA, subjecting them to a 10-month review. That approach increased the regulatory burden and limited the market uptake of biosimilars, according to the Biosimilars Forum.

Thus, industry welcomed the agency’s commitment in the guidance to reduce the review time for the supplements to six months, but several of the commenters pushed for even shorter reviews. The six-month proposal “is a positive step forward in addressing unnecessary impediments to bringing biosimilars to market,” the Biosimilars Forum said, but it still “perpetuates unnecessary lags in approval for a biosimilar product’s labeling.”

The group noted that such supplements generally don’t include clinical data. And often the sponsor has already scientifically justified the extrapolation of the indication that’s being added back into labeling, so there’s not much for the agency to review. The Biosimilars Forum compared the supplements with requests from generic drug manufacturers to update their labeling immediately when a changes being effected (CBE) supplement is filed for the reference drug.

“While the requirements relating to approval of indications and labeling for biosimilars differ from generics, a 10-month, or even 6-month, review time seems excessive when compared to a CBE-0 or a CBE30,” the Forum said.

Pfizer Inc. agreed, adding that such review timeframes not only delay patient access to biosimilars but they also “unnecessarily increase the burden on FDA reviewers, and may omit the contextualized knowledge and understanding of the initial BLA reviewers.” In its comments on the draft, Pfizer suggested the FDA should define “clinical data” for the purposes of establishing its review times so sponsors can understand how that determination will impact their timelines.

A six-month review time may be appropriate when a biosimilar sponsor submits clinical data to support an original supplement, Pfizer said. But shorter timeframes are more in line for supplements with a written scientific justification of extrapolation.

If the FDA must review the justification to make a determination that extrapolation of the requested indication is appropriate, it should be able to review and act on the supplement within three months of receipt, according to the company. However, if the agency has already determined that extrapolation is appropriate, it should be able to review and act on the supplement within one month.

If the FDA does not address the supplement review times when it finalizes the guidance, the issue could be raised in the agency’s negotiations with industry for the next round of BsUFA, as industry sees it as a hurdle to the market adoption of biosimilars.

A six-month review “creates unnecessary delays in patient access to biosimilars and hinders the biosimilar sponsor’s ability to educate health care providers and patients about the additional indication(s) through timely release of promotional materials,” the Biosimilars Forum said.

Timely education is a critical part of building a robust biosimilar market in the U.S. Results from a survey released last month by the Biologics Prescribers Collaborative show that, although the FDA approved its first biosimilar five years ago, patients still have a lot of questions, and misconceptions, about biosimilars.

When it comes to patient questions, topping the list, according to 82% of the survey respondents, is knowing what a particular biosimilar is approved for. Next, at 79%, is wanting to know how a biosimilar differs from the reference biologic.

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