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Four of first 10 publicly disclosed applications were approved on first review cycle, and FDA has issued at least seven complete response letters. Increasing first-cycle approvals is a primary goal of the BsUFA II agreement.


Biosimilars drug approval  




Five years into the legislation that created FDA's biosimilar user fee system, a 40% first-cycle approval rate for publicly disclosed applications leaves ample room for progress under the program's next iteration.


While FDA has consistently met its Biosimilar User Fee Act (BsUFA) performance goals for reviewing and acting on a set percentage of original 351(k) application submissions within 10 months, those actions, for the most part, have not been approvals.


Four of the first 10 publicly disclosed biosimilar applications were approved on the first review cycle, while six received complete response letters. There has been one second-cycle approval, Celltrion Inc.'s Inflectra (infliximab-dyyb), and one publicly disclosed second-cycle complete response letter, for Hospira Inc.'s (Pfizer Inc.) erythropoietin Retacrit.


While FDA has consistently met its BsUFA performance goals for reviewing and acting on original 351(k) submissions within 10 months, those actions, for the most part, have not been approvals.


The first-cycle approval rate, as well as FDA's struggles to hold timely meetings with sponsors, under the inaugural program reflect the targeted objectives for the BsUFA II agreement negotiated by FDA and industry. While the agency wants to see an improvement in the quality and completeness of 351(k) applications submitted for review, industry wants more timely and complete advice from the agency on development programs and agency expectations.


However, a key Republican lawmaker has already said that the number of biosimilar approvals, and the rate of first-cycle approvals, will be key to gauging FDA's performance over the next five years under BsUFA II. (Also see "Biosimilars: Next User Fee Cycle Will Be Judged On US FDA's Approvals, Rep. Burgess Says" - Pink Sheet, 15 Mar, 2017.)


15 Disclosed Submissions = 5 Approvals …


The FDA Safety and Innovation Act (FDASIA), signed into law July 9, 2012, established the biosimilar user fee program that took effect on Oct. 1, 2012.


Through July 5, 2017, sponsors have publicly disclosed the filing of 15 biosimilar applications. Of these, five have been approved, although only two – Sandoz Inc.'s Zarxio (filgrastim-sndz) and Amgen Inc.'s Amjevita (adalimumab-atto) – were licensed within the standard 10-month review period on the first review cycle. (See report card graphic.)


Two of the five licensed biosimilars – Sandoz's Erelzi (etanercept-szzs) and Samsung Bioepis Co. Ltd.'s Renflexis(infliximab-abda) – required three-month user fee extensions during the first review cycle, while the other licensed biosimilar, Celltrion's Inflectra, was approved in the second cycle.




… 5 CRL'ed Applications …


Another five applications have been held up by complete response letters, with three of these coming on applications referencing Amgen's Neulasta (pegfilgrastim), a pegylated leukocyte growth factor which is proving to be a tough biologic to copy, at least to FDA's satisfaction. (Also see "Taking Biosimilars Down A PEG: Why Copying Neulasta Isn’t So Easy" - Pink Sheet, 13 Jun, 2017.)


Following its receipt of a complete response letter in June, Coherus BioSciences Inc.suggested its proposed Neulasta biosimilar would be delayed at least a year. Sandoz, meanwhile, is conducting a new study on its pegfilgrastim product to satisfy FDA's July 2016 complete response letter; the application is targeted for resubmission in 2018.


Apotex Inc., a privately held company, has not confirmed receipt of complete response letters for its proposed biosimilars to Neulasta or Amgen's Neupogen (filgrastim). However, both applications had user fee goal dates in 2015, and FDA's BsUFA performance reports for the applicable fiscal years indicate the agency took timely action on the applications – actions presumed to be complete responses.


Hospira's Retacrit, a proposed biosimilar of Amgen's Epogen (epoetin alfa), has the ignominious distinction of drawing two complete response letters, the second of which came in June and resulted from lingering compliance issues at a Kansas manufacturing facility. (Also see "Pfizer’s EPO Biosimilar Stalls In US On Hospira Compliance Woes" - Pink Sheet, 22 Jun, 2017.)


… And 5 Pending


FDA is currently reviewing the remaining five publicly disclosed applications, with goal dates that range from September 2017 to February 2018.


Two of the pending applications – Mylan NV's and Biocon Ltd. MYL-1014O, a proposed biosimilar to Genentech Inc.'s Herceptin (trastuzumab), and Amgen Inc. and Allergan PLC's ABP 215, which references Genentech's Avastin (bevacizumab) – head to an FDA advisory panel review on July 13. Although the Oncologic Drugs Advisory Committee previously reviewed the applications for Zarxio and Retacrit, the upcoming panel meeting will mark the first for biosimilars of anticancer drugs, as opposed to supportive care agents used in the oncology setting.


Thus far, FDA has stuck to its publicly stated plans to take the first biosimilar application for a given reference product to a panel review, at least in the BsUFA program's early years.


The July 13 AdComm on proposed biosimilars to Herceptin and Avastin will mark the first for anticancer drugs, as opposed to supportive care agents used in the oncology setting.


However, the agency also has said it will only take to panel review those first-in-class applications for which the analytical data support a finding of high similarity to the reference product. This explains why advisory committee meetings, thus far, have not been convened for applications that end up with first-cycle complete response letters. The Retacrit meeting occurred during the second review cycle, seemingly after substantive issues raised during the application's first-cycle review had been addressed by Pfizer.


The agency also has shown that it is willing to skip a panel review for subsequent biosimilars to the same product. Samsung's Renflexis, the second biosimilar to Janssen Biotech Inc.'s Remicade(infliximab), was the first 351(k) application to win approval without an advisory committee stopover.


Similarly, no meeting has been announced for Boehringer Ingelheim GMBH's BI 695501, which is in line to become the second biosimilar to AbbVie Inc.'s Humira (adalimumab), following in the footsteps of Amgen's Amjevita,


Hidden Applications?

FDA may have more on its biosimilar application review plate than meets the eye.


The agency's FY 2016 BsUFA Performance Report states that it received five original biosimilar product applications from Oct. 1, 2015 to Sept. 30, 2016. (See table) However, only three of those applications appear to have been publicly disclosed: Amgen's Amjevita, Samsung's Renflexis and Coherus' CHS-1701.


Original Biosimilar Product Applications: Review Goals And Performance

Original Biosimilar Applications

FY 2015

FY 2016 (Preliminary)

Total Submissions












Performance % On-Time



BsUFA Goal: On-Time Target %



Goal Met Status


Currently meeting, pending

Source: FY 2016 BsUFA Performance Report (data as of Sept. 30, 2016)


FDA said the BsUFA report provides the preliminary numbers for FY 2016 and reflects data as of Sept. 30, 2016.


"The number indicated of five on the original biosimilar product applications submitted in FY 2016 includes those applications that have been filed, and those applications that are currently within the 60-day filing period and have not yet reached their filing date," FDA said in response to questions from the Pink Sheet. "It does not include applications that were refused-to-file, withdrawn before filing, or unacceptable for filing due to nonpayment of user fees."


For years, FDA officials have made clear that their public remarks about the number of biosimilar applications refer only to those submissions publicly disclosed by sponsors.


"Companies can elect to voluntarily disclose their application status to the public and this could vary from the numbers that FDA reports depending on the status of their application at any given time," the agency said of the number of submissions reported in the FY 2016 performance report.


It's possible that the two undisclosed applications submitted in FY 2016 were the subject of an FDA refuse-to-file action or voluntary withdrawal by the sponsor after Sept. 30. However, if the applications were filed by the agency their user fee dates would be coming due. For example, an application submitted at the end of September 2016 would have a 10-month review goal date in late July.


FDA reported receiving five original biosimilar product applications between Oct. 1, 2015 to Sept. 30, 2016, although only three of those submissions appear to have been publicly disclosed by sponsors.


It's possible that an application submitted near the end of FY 2016 could have received a refuse to file letter and been resubmitted in FY 2017. To date, five applications have been publicly disclosed as having been submitted during the current fiscal year.


Amgen said its November submission for ABP 215 was its first for that product. Similarly, Mylan's 351(k) applications for MYL-1401H and MYL-1401O, referencing Neulasta and Herceptin, respectively, are the original applications, the company said.


Celltrion said the BLA for CT-P10, a proposed biosimilar to Genentech's Rituxan (rituximab) that was accepted for filing in June, was company's first submission for the product.


Boehringer Ingelheim declined to comment as to whether the November submission for its proposed Humira biosimilar was the original application for the product.


Coherus said its August 2016 submission for CHS-1701 was the first application for that product.


Apotex, which has publicly disclosed only the 2014 submissions for proposed biosimilars to Neulasta and Neupogen, said it has not submitted any 351(k) applications that FDA has either declined to review or the company has voluntarily withdrawn.


Sandoz, which holds two of the first five approved biosimilar applications, declined to say whether it has submitted any 351(k) applications that FDA either refused to file or the company voluntarily withdrew.


Neither Pfizer nor Hospira has voluntarily withdrawn a 351(k) application or had FDA refuse to accept an application, Pfizer said.


Samsung declined to comment on whether it has submitted any biosimilar applications that were turned away or voluntarily withdrawn.


FDA said it could not provide data on the numbers of complete response letters, refuse-to-file actions, applications voluntarily withdrawn before filing, or applications deemed unacceptable for filing due to nonpayment fees under BsUFA.


Such metrics "represent data associated with unapproved applications," FDA said, adding that it cannot discuss products in development.


First-Cycle Approval Rate Comparable To PDUFA I


Despite stakeholder dissatisfaction with the number of first-cycle approvals for publicly disclosed biosimilars, the rate is comparable to that seen in the early years of the Prescription Drug User Fee Act (PDUFA) program and well ahead of its brethren generic drug program.


PDUFA I ran from FY 1993-1997. Of the novel applications submitted in FY 1996, 44% were approved in the first cycle, and that number reached more than 50% for the FY 1997 cohort, according to agency performance reports.


PDUFA is now in its fifth iteration; FDA's FY 2016 PDUFA Performance Report shows that 65% of standard applications and 85% of priority applications submitted in FY 2015 received a first-cycle approval.


Like BsUFA, the Generic Drug User Fee Act (GDUFA) program also was established in FDASIA. The first-cycle approval or tentative approval rate for original abbreviated new drug applications (ANDAs) submitted in the third year (beginning October 2014) of GDUFA I was 8%, with 43% receiving a second-cycle approval or tentative approval, according to preliminary data as of Sept. 30, 2016. (Also see "Generic Drug First-Cycle Approval Rates Lagging Under GDUFA I" - Pink Sheet, 25 Oct, 2016.)


Despite the relatively favorable comparisons for BSUFA I relative to PDUFA I and GDUFA I, the high price of biologics and the potential for significant cost-savings with biosimilars, particularly when multiple versions of the same reference product enter the market, mean there will continue to be high external expectations for FDA to approve more 351(k) applications more quickly.


Pre-Submission Meetings Could Help Turn The Tide …


The agency is hopeful that changes negotiated with industry in the BsUFA II agreement will improve the quality of biosimilar applications that come through the door and boost the first-cycle approval rate.


A key feature of BsUFA II, which is making its way through the House and Senate as part of comprehensive user fee legislation, is the addition of two months to the review period in exchange for increased communications and interactions between FDA and sponsors before and during the review process. (Also see "Biosimilars Will Get PDUFA-Style Reviews Under New User Fee Plan" - Pink Sheet, 28 Sep, 2016.) This review model, known as The Program, was implemented in PDUFA V for new molecular entities and novel biologics.


"The goal of The Program is to improve the efficiency and effectiveness of the first-cycle review process by increasing communication during application review," FDA said in a recent Federal Register notice on the biosimilar program. "This will provide sponsors with the opportunity to clarify previous submissions and provide additional data and analyses that are readily available, potentially avoiding the need for an additional review cycle when concerns can be promptly resolved without compromising FDA's standards for approval."


At the Drug Information Association's annual meeting in June, Leah Christl, associate director for therapeutic biologics in FDA's Center for Drug Evaluation and Research, highlighted the importance of the BsUFA II review program's pre-submission meeting between the agency and sponsor to discuss the planned content of an application and reach agreement on which application components can be submitted late. (Also see "Best Of Biosimilar Agreement: FDA, Industry Tout Written Response, Pre-Submission Meeting" - Pink Sheet, 29 Jun, 2017.)


"We are hoping sponsors have pre-application meetings and not just submit an application to FDA and hope for the best," Christl said. "That will be a change for both industry and FDA on how we approach application review."


… As Could More Timely FDA Advice

The BsUFA II agreement also includes measures aimed at addressing FDA's continuing struggle to meet some of its meeting management performance goals under BsUFA. (Also see "FDA Met Biosimilar Review Timelines But Missed Meeting Goals In 2015" - Pink Sheet, 25 Apr, 2016.)


The preliminary FY 2016 data show the agency continues to fall short of its performance goals for scheduling four out of five types of meetings under BsUFA and in providing meeting minutes to sponsors.


From a scheduling perspective, the most problematic are Biosimilar Biological Product Development (BPD) Type 2 meetings. These meetings – which are held to address a specific issue, such as study design or endpoints, or other questions where FDA will provide targeted advice – represent the largest single category of meetings in the BPD program.


In FY 2015, only 49% (20 of 41) of Type 2 meetings were scheduled within 75 days, falling well short of the 80% performance goal, according to the final data for the year. The situation in the preliminary FY 2016 data appears far improved but is still shy of the 85% performance goal for the fiscal year – as of Sept. 30, 2016, 73% of Type 2 meetings were scheduled on time, with a highest possible performance of 74%.


The BsUFA II agreement allows sponsors to request a written response to questions rather than a face-to-face meeting or teleconference in the BPD Type 2 category, which could provide more efficiencies for sponsors and FDA alike. In addition, the scheduling timeframe for such meetings is increased from 75 to 90 days, giving agency staff more breathing room.

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