Two Months To Add Two Words – Biosimilar Supplement Review Times May Be Hindering Uptake
Executive Summary
Biosimilar supplement approvals by the US FDA take on average about five months as sponsors request easier and quicker ways to update labels.
Simple updates to biosimilar labels are taking several months to receive US Food and Drug Administration approval, potentially affecting the growth of the fledgling sector.
Slow supplement approvals may not constitute a major problem at the moment, but as more biosimilars enter the market, the need to quickly change a label to stay in line with the reference product or add indications no longer protected by exclusivity likely will be necessary to promote uptake.
The FDA has approved 10 supplements for nine of the 18 biosimilars it has cleared since the biosimilar pathway opened. The average time from receipt to approval was about 159 days, or about 5.2 months, according to a Pink Sheet analysis of the available supplement approval letters. (See chart below.)
Biosimilar sponsors are concerned about the assessment time, in part because the wait can eliminate advantages negotiated in patent settlement agreements, as well as slow talks with payers.
"From an industry standpoint, if biosimilar companies can't easily add indications back into their labels, that will make it very hard to get products to the market quickly," Cory Wohlbach, Teva Pharmaceutical Industries Ltd. VP of biosimilars regulatory affairs, told the Pink Sheet. "Realistically, companies need FDA approval to print their label, package their product, ship their product, and discuss their product with payers and prescribers. All of that already very long process gets pushed back because of unnecessary regulatory delay."
Wohlbach views the issue as lost in the complicated drug pricing debate.
"In the current conversations, the need for efficient labeling review is not being discussed as an area of concern for biosimilar market entry as much as patents and PBMs and all of the other hot-button issues," he said.
Typically, no new clinical data must be assessed for a biosimilar labeling supplement because the reference product already has received approval for the indication. Often the product is making the filing to ensure it conforms to the reference product label.
However, of the biosimilar supplements approved, in many cases the FDA needed about the same or slightly more time to approve them than for the same supplement submitted by the reference product sponsor.
Five biosimilar supplements were classified as Changes Being Effected (CBE) filings, which are used for labeling updates. They took on average about five months, about 155 days, for the agency to approve.
Four of the five applications with submission and approval dates were amended, which may have affected the assessment time.
The FDA said a prior approval supplement is the generally accepted method for biosimilar labeling changes. The biosimilar user fee program commitment letter states that supplements with clinical data will receive a 10-month review goal and manufacturing supplements will receive a four- or six-month goal.
The agency added that staff do not have to use the full assessment period to approve the supplement.
"There is no restriction for review divisions to act on supplements in advance of a user fee goal date or other commitment if practicable," FDA said.
As part of its Biosimilar Action Plan, the agency is writing guidance to clarify the process to more easily add indications to biosimilar labels. Sponsors have called for a faster labeling assessment pathway that could allow approvals before patent expiry. (Also see "Biosimilars: US FDA Asked To Clarify Thinking On Pediatric Studies, Indication Carve-Outs" - Pink Sheet, 21 Feb, 2019.)
However, the FDA may not be able to publish the guidance as soon as it may like, as the White House Office of Management and Budget recently required it review the economic impact of all federal agency guidances prior to release. (Also see "US FDA Guidance Production May Be Slowed By New OMB Review Requirement" - Pink Sheet, 14 Apr, 2019.)
Story continues after the chart…
Four Month-Assessment Was Among Fastest
Sandoz Inc.'s Zarxio (filgrastim-sndz), the first biosimilar the FDA approved, also was the first to have a supplement approved. About a year after the initial product clearance, the company gained approval for a CBE supplement to add glomerulonephritis to the Warnings and Precautions and Postmarketing Experience sections of the label and make other changes.
The supplement was approved 3 March 2016 after nearly six months.
Zarxio's reference product, Amgen Inc.'s Neupogen (filgrastim), added glomerulonephritis to its label on 30 July 2015. The approval took more than 5.7 months, based on the 5 February 2015 filing date.
Zarxio also is the only biosimilar with two approved supplements. The company submitted a second supplement on 29 September 2016 to revise the Patient Information and Instructions for Use section on proper use of the prefilled syringe and proper dosing, as well as make some packaging changes, according to the approval letter. The FDA took 4.6 months to approve the supplement, the third-fastest approval of those listed.
Sandoz's Erelzi (etanercept-szzs), a biosimilar of Amgen's Embrel (etanercept), also became the first biosimilar to have indications removed from its label. For patent reasons, Sandoz asked that the psoriatic arthritis and plaque psoriasis indications be removed. The six-month assessment was completed 26 January 2018, with the PsO and PsA language changed to "another indication." (Also see "Biosimilar Labeling Carve-Out Turned Erelzi's Psoriatic Arthritis, Plaque Psoriasis Uses Into 'Another Indication'" - Pink Sheet, 14 Mar, 2018.)
Among the quickest approvals was a CBE filing for Hospira Inc.'s Retacrit (epoetin alfa-epbx), a biosimilar of Amgen and Johnson & Johnson's Epogen/Procrit (epoetin alfa). The FDA needed four months to approve the revisions to the prescribing information intended to align with the Epogen/Procrit labeling.
The longest approval time for a biosimilar supplement so far was about 7.5 months. Celltrion Inc. submitted a CBE supplement for its Inflectra (infliximab-dyyb), a biosimilar of J&J's Remicade (infliximab) 12 December 2017, which was intended to update the Warnings and Precautions and Postmarketing Experiences sections of the label "to incorporate relevant information from the latest US-licensed Remicade USPI," according to the approval letter.
The FDA did not approve the supplement until 27 July 2018, although the filing was amended.
Some Reference Product Supplements Approved Faster
And yet, many of the supplements being approved for biosimilars took longer to approve than the original supplement submitted by the innovator product sponsor.
The FDA's quickest biosimilar supplement approval was a CBE for Coherus BioSciences Inc.'s Udenyca (pegfilgrastim-cbqv), a biosimilar of Amgen's Neulasta (pegfilgrastim). FDA needed only 60 days to approve the labeling update, which added alveolar hemorrhage to the Adverse Reactions under Postmarket Experience, according to the approval letter. The FDA received the application 15 February and approved the two-word addition 16 April. The company said the supplement was a change required class-wide to conform with reference product labeling.
Coherus' supplement assessment was 10 times longer than the same supplement Amgen submitted for the reference product Neulasta. The FDA approved that supplement in six days.
Both labeling changes were approved on the same day, which may explain the difference in assessment time. Coherus may have been forced to wait for the reference product change to be cleared first.
Sandoz's first CBE supplement for Zarxio also took seven more days to approve than the supplement submitted by Amgen in 2015 to make the same change.
Of the five biosimilar supplements with comparable reference product supplements, three took longer to approve than their reference product counterparts.
All biosimilar and biologic supplements are assessed by staff in the same office. There also is no internal policy prioritizing supplements for either approval pathway, the FDA said.
The agency also said supplement approval is based on several factors, all of which can impact the assessment time, including workload, pending goal dates, and supplement complexity.
"Complexity may not be limited to scientific issues, but may also involve new or complex regulatory issues," the agency said.
The largest difference in assessment time in favor of a biosimilar was a revision of the Humira (adalimumab) label. The FDA needed more than 9.7 months to clear AbbVie Inc.'s innovator product update of the Clinical Studies section on the product's effectiveness in psoriasis of the fingernail in adult patients with moderate to severe chronic plaque psoriasis. The same update for Amgen's biosimilar Amjevita (adalimumab-atto) took less than six months, 119 fewer days.
It is unclear how amendments affected the assessments both for the biosimilar and reference product supplements. The FDA also stopped collecting user fees for supplements at the start of the latest user fee cycle, which began in October 2017. (Also see "Biosimilars Will Get PDUFA-Style Reviews Under New User Fee Plan" - Pink Sheet, 28 Sep, 2016.)
Indirectly Limiting Uptake
Complaints about the labeling update process have emerged because of the assessment time required, especially given that many updates are intended to conform with reference product labeling and already have been assessed.
Long waits for agency approval could potentially affect biosimilar uptake. Payer negotiations can be difficult if the biosimilar label is not identical to the reference product.
Pfizer Inc. VP of Global Regulatory Affairs Lisa Skeens also wrote in formal comments to FDA's recent hearing on facilitating competition among biologics that "requiring a [prior approval supplement] in all cases could create unnecessary delays in patient access to biosimilars and hinders the biosimilar sponsor's ability to educate physicians and patients about the additional indication(s) through timely release of promotional materials."
Pfizer recommended the FDA allow extrapolation of all indications at the time of approval, including those that would not be licensed at approval, and permit CBE-0 supplements to add indications once exclusivity and patents expire.
Many biosimilar sponsors already are fighting uphill battles to gain formulary placement with innovator biologic companies offering exclusive contracts and large rebates maintain sales volume. Indeed, some biosimilars currently on the market have not gained much market share despite offering lower prices, in part because of brand company agreements with payers. (Also see "Humira's 'Unique' Number Of Patents Makes Biosimilar Entry Risky, Pfizer Says " - Pink Sheet, 10 Apr, 2018.)
Likely A BsUFA III Topic
The indication update issue was not addressed when the biosimilar user fee program was reauthorized in 2017, but it appears there will be a push for its inclusion in BsUFA III, which will begin in 2022.
Janssen Pharmaceutical Cos. has called for a streamlined process to add indications to labeling to be considered for BsUFA III, although only in certain situations. (Also see "BsUFA III: Industry Eyes Streamlined Review Of New Indications, Phased Review Process" - Pink Sheet, 22 Oct, 2018.)
Concerns about biosimilar launches and market dynamics affecting product uptake also are likely to come up during the talks, given the amount of money sponsors pay annually to support the program.
Planning for BsUFA III already has started, even though industry and the FDA are less than half-way through the current program cycle. (Also see "Generic Industry Market Forces May Impact GDUFA III Talks" - Pink Sheet, 21 Mar, 2019.)