Biosimilar INDs could be placed on “financial hold” if sponsors fail to timely pay product development fees under FDA’s inaugural biosimilar user fee agreement with industry.

Although the mechanism is characterized as a financial hold, it would appear to have the same effect as a clinical hold in that it would halt an ongoing biosimilar product study under an IND.

The BsUFA agreement provides for the collection of initial and annual, pre-approval biosimilar product development fees that will help FDA ramp up its review activities under the new program.

Details about the BsUFA agreement covering the first years of the biosimilars program – FYs 2013-2017 – were released Dec. 6 in an FDA notice.

The agreement provides for the collection of initial and annual pre-approval, biosimilar product development (BPD) fees that will help FDA ramp up its review activities under the new program. The BPD fees would be subtracted from the fee required at the time of biosimilar application submission.

As in the case of its Prescription Drug User Fee Act counterpart, the BsUFA program agreement includes a draft commitment letter with FDA performance goals for application review and other regulatory activities. It also lays out a series of pre-submission meeting opportunities between the sponsor and FDA.

A Public Hearing At White Oak

The agreement reflects the results of negotiations that began in June between FDA and three industry groups – the Biotechnology Industry Organization, Pharmaceutical Research and Manufacturers of America and Generic Pharmaceutical Association – along with representatives from various innovator and generic companies Also see "Biosimilar User Fees: Industry, FDA Tussle On Ramp-Up Speed For Program" - Pink Sheet, 14 July, 2011..

Those negotiations concluded in late August with a tentative agreement. The deal included an appropriations trigger that requires at least $20 million a year in non-user fee funds be devoted to biosimilar product reviews in order for FDA to spend user fees collected under the program Also see "Biosimilar User Fee Agreement Reached, But Will Require Appropriations Boost" - Pink Sheet, 22 September, 2011..

FDA will hold a public hearing on the BsUFA agreement Dec. 16 at its White Oak headquarters and will accept comments on the proposals through early January. Based upon the public input received, the agency could revise the recommendations before transmitting them to Congress by Jan. 15.

The biosimilar user fee program is expected to be included in an omnibus bill that also will include reauthorization of PDUFA and the Medical Device User Fee and Modernization Act, along with authorization of a new generic drug user fee program and potentially other pieces of FDA-related legislation.

Product Development Fees Stray From PDUFA Model

The BsUFA program’s fee model and amounts generally follow the PDUFA model, with the exception of the new product development fees.

Marketing application fees, establishment and approved product fees for biosimilars will be set at the same level as those under PDUFA for a given year.

The initial BPD fee would be due upon submission of an IND for a study that FDA determines is intended to support a biosimilar application, or within five days after FDA grants a request for a BPD meeting – one of two main categories of pre-submission meetings envisioned under the BsUFA proposal.

Sponsors would pay one BPD fee per product regardless of the number of proposed indications for a biosimilar product. The fee is retroactive; sponsors that submit a biosimilar IND before the user fee program’s authorizing legislation is enacted would be subject to the initial BPD fee.

Beginning in the next fiscal year after a paying the initial fee, a biosimilar sponsor would be assessed an annual fee each year until it either submits a marketing application that is accepted for filing or discontinues participation in the BPD program for the product.

The initial BPD fee for each of fiscal years 2013-2017 would equal 10% of the application fee established under PDUFA for the given year. All BPD fees paid for a given product would be subtracted from the fee due at the time a marketing application is submitted.

Voluntary Discontinuation And Reactivation

The user fee agreement provides escape routes for sponsors seeking to leave the BPD program, which could save companies the burden of paying annual fees on INDs that are delayed due to clinical trial or manufacturing issues. The measure also includes strict sanctions for non-payment of fees.

Sponsors who have not submitted an IND may discontinue participation in the BPD program by filing a written declaration with FDA stating that they have no present intention to further develop the biosimilar product.

Sponsors with a pending IND must withdraw the application to discontinue participation in the program.

Sponsors who discontinue participation in the biosimilar product development user fee program would have to pay a reactivation fee to get back in.

Sponsors who discontinue participation would have to pay a reactivation fee to get back into the BPD program for that biosimilar product. The reactivation fee would be equal to twice the initial BDP fee for that fiscal year.

FDA will not hold a BPD meeting if the sponsor owes outstanding BPD or reactivation fees for that product. If a sponsor that owes BPD fees submits an IND for a biosimilar, FDA would not consider the IND to have been received “except in extraordinary circumstances.”

“In addition, if a sponsor that owes BPD fees has an existing IND that FDA determines is intended to support a biosimilar biological product application, FDA would prohibit the sponsor from continuing the investigation (this action would be referred to as ‘financial hold’),” FDA’s notice states.

PhRMA has previously opposed allowing the agency to invoke its clinical hold authority to stop a biosimilar’s development for non-payment of fees. The organization suggested clinical holds should be used only to ensure patient safety in clinical trials Also see "Reactivation Fee Is Proposed For Biosimilar INDs Placed On Hold" - Pink Sheet, 9 August, 2011..

FDA’s user fee program notice does not characterize the sanction for non-payment of fees as a clinical hold, instead using the term financial hold. Nevertheless, it appears the effect would be the same in that the study conducted under the IND would be halted.

It is unclear from FDA’s notice whether sponsors who are placed under a financial hold would have to pay the higher reactivation fee to get back in good standing, or whether they merely would have to pay any outstanding BPD fees.

If a sponsor has failed to pay required BPD fees, “then any biosimilar biological product application or supplement submitted by that sponsor would be considered incomplete and would not be accepted for filing until all fees owed by the sponsor have been paid,” the notice states.

More Aggressive Performance Goals

The user fee agreement includes performance goals on a variety of metrics, including action on original and resubmitted applications and supplements, proprietary name review, major dispute resolution, clinical holds, special protocol assessments and meeting management.

The draft commitment letter calls for FDA to act on 70% of original biosimilar product applications within 10 months of receipt in FY 2013 (see chart).

Performance Goals For Original And Resubmitted Applications And Supplements
Application Type	FY 2013	FY 2014	FY 2015	FY 2016	FY 2017
Original Biosimilar Biological Product Application Submissions to be acted on within 10 months of the receipt date	70%	70%	80%	85%	90%
Resubmitted Original Biosimilar Biological Product Applications to be acted on within 6 months of the receipt date	70%	70%	80%	85%	90%

This is a more abitious target than was included in the agency’s initial user fee proposal, which called for action on 50% of all original applications within 10 months of the conclusion of a 60-day filing period in FY 2013. Industry, however, wanted more aggressive goals Also see "Biosimilar User Fees: Industry, FDA Tussle On Ramp-Up Speed For Program" - Pink Sheet, 14 July, 2011..

The final agreement reflects not only a higher initial performance target, it also seems to have eliminated the 60-day filing period provision which has been incorporated into the PDUFA V agreement, where it will extend the review time for standard drug applications to at least 12 months Also see "PDUFA V Commitment Letter Front-Loads Guidance, Meeting Milestones" - Pink Sheet, 5 September, 2011..

Pick Your Meeting Type

The BsUFA agreement also delineates a slew of meeting opportunities available to sponsors who are developing biosimilars.

FDA’s notice describes four types of BPD meetings:

Type 1: to address issues necessary for a stalled development program to proceed, special protocol assessment or an important safety issue.
Type 2: to discuss a specific issue or question where FDA will provide targeted advice about an ongoing development program.
Type 3: in-depth data review and advice.
Type 4: discussion of format and content of a biosimilar product application.

Biosimilar Initial Advisory Meetings would be limited to general discussion regarding whether licensure under the biosimilar provisions may be feasible for a product and general advice on the expected content of a development program. Such meetings would not involve a fee.

Biosimilar User Fee Agreement Includes “Financial Hold” On Development Programs For Failure To Pay

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