FDA needs to make formal determinations about whether a sponsor is granted a waiver or deferral of pediatric studies earlier in the drug development process, PhRMA, BIO and other industry stakeholders say, arguing that without swifter action, the agency is setting companies up for incomplete NDA and “refuse to file” determinations.

The comments come in response to a July 2013 draft guidance on the content and process for submitting initial pediatric study plans (PSPs) and amended plans. The guidance was written because under the 2012 FDA Safety and Innovation Act, drug manufacturers subject to the Pediatric Research Equity Act (PREA), must submit pediatric plans earlier – within 60 days of a sponsor’s end-of-Phase II meeting rather than well into Phase III – in order to identify the need for pediatric studies and begin planning for such studies earlier in drug development Also see "Pediatric Study Planning With FDA, EMA To Be More Closely Aligned" - Pink Sheet, 10 December, 2012..

The new requirement began in January but the draft says FDA will exercise enforcement discretion with regard to applications submitted before Jan. 5, 2014. However, it urges those applicants to submit an initial PSP for review as soon as possible.

FDASIA also requires FDA to promulgate proposed regulations to implement the PSP subsection of PREA one year after the passage of the law, a deadline FDA has missed already Also see "FDASIA Is Signed, Not That White House Wanted Anyone To Notice" - Pink Sheet, 16 July, 2012.. The guidance says FDA intends to publish a proposed regulation consistent with FDASIA.

Despite the law’s intent to speed up pediatric development, the draft guidance contains provisions that could slow down the approval of drugs for all populations, while also not speeding up pediatric development, industry argues.

According to the draft, requests for waivers or deferrals for pediatric development will not be formally granted or denied until the application or drug is approved, but this “seem[s] to be inconsistent with language of the FD&C Act, which requires either pediatric data, a waiver or deferral in order for an application to be eligible to be submitted for approval,” the Pharmaceutical Research and Manufacturers of America say in Sept. 12 comments on the draft.

“There is still a disconnect between the timing of FDA’s agreement on a PSP and, where applicable, final waiver/deferral decisions,” the Biotechnology Industry Organization said. “If this issue is not addressed, earlier PSP agreements may not ultimately translate into earlier or more efficient pediatric drug development,” BIO’s comments said. PhRMA’s comments include a nearly identical statement.

Comments from Merck & Co. Inc. and contract research organization also raise concerns about the timing of waiver and deferral determinations. “It is essential that FDA provide an initial assessment of waiver requests when they are submitted, in order to assure that any necessary pediatric studies can be designed and executed in a timely fashion,” Quintiles’ comments said.

Concerns about slow agency response are a running theme of industry commentary about FDA’s pediatric programs. Several companies recently attributed delays in conducting pediatric research to tardy agency decision-making, not foot dragging by the firms Also see "Pediatric Studies Delayed Mostly By FDA Red Tape, Companies Say" - Pink Sheet, 27 August, 2013..

According to FDASIA, which permanently reauthorized PREA, FDA is supposed to review the initial PSP within 90 days of submission. The sponsor then updates and revises its plan and submits it within 90 days, and FDA is supposed to confirm agreement with this resubmitted PSP within 30 days. This means the cycle could take up to 210 days total or about seven months. This is meant to happen prior to NDA submission as PSPs are to be submitted no later than 210 days prior to application submission.

PhRMA suggests that FDA include a statement in the guidance that, as long as the waiver/deferral is agreed upon in principle in the PSP, that then would be sufficient to meet the FD&C Act’s requirements regarding PREA and would not trigger potential “refuse to file”. The association also wants FDA to clarify what sections of the PSP sponsors must complete if they plan to request a waiver.

And PhRMA and BIO both say FDA should consider a waiver request in the PSP to be the “official waiver request.” PhRMA says FDA needs to clarify whether the PSP section on waivers negates the need to file a formal request as outlined in another draft guidance, “How to Comply with the Pediatric Research Equity Act,” issued in September 2005. BIO also asks that FDA consider a deferral request in the PSP to be the formal deferral request.

Both BIO and PhRMA do acknowledge that FDA may change its position on whether a waiver or deferral is permitted during the pre-approval process. FDA should utilize the policy currently outlined in the draft PREA guidance and insert language into the guidance indicating that waivers granted early in the pre-approval period reflect the agency’s best judgment at that time, and that FDA may reconsider its earlier decision, the groups say.

PhRMA says FDA should consider updating the PREA guidance, which is referenced in the PSP guidance, since it is nearly eight years old and does not reflect the current version of PREA. FDA should ensure it is consistent with the PSP guidance, it adds.

Biosimilars Also Disrupted By Pediatric Timelines

Biosimilar applications also may be tripped up by the misalignment of PSP deadlines with FDA’s other drug review deadlines.

Per the guidance, a sponsor that is subject to PREA – anyone that is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration – is required to submit a PSP. Per statute, a biosimilar that has not been determined to be interchangeable with the reference product is considered to have a “new active ingredient” for purposes of PREA.

However, as generic-drug maker Apotex Inc.points out, sponsors are not going to know whether FDA considers a biosimilar to be interchangeable during the IND stage. While guidance on interchangeability has not been issued, such determinations likely will be made at the time of approval Also see "Sandoz Pushing FDA To Make Biosimilar Interchangeability Decisions" - Pink Sheet, 17 December, 2012.. Apotex also points out that the end-of-Phase II meeting structure is not applicable to biosimilar development under section 351(k) of the Public Health Service Act.

Novartis Pharma AG, whose Sandoz International GMBH arm already has biosimilars approved in Europe, also comments that regardless of an interchangeability designation, when a reference product for the biosimilar is labeled for both pediatric and adult use, the biosimilar sponsor should be able to fulfill its PREA requirements by extrapolating from the reference product to the biosimilar product. “Extrapolation is a well-accepted regulatory approach in the realm of biosimilars,” Novartis notes.

Or if the reference product label already includes useful prescribing information for pediatrics, Novartis says the biosimilar should be able to rely on the reference product for pediatric information and should not have to submit additional pediatric data. Extrapolation in these instances is a “science-based approach,” the company says.

Faster, Fewer Amendments

PhRMA also told FDA that it should make clear that the timeline for review and action on a PSP amendment is the same as an initial PSP. However, it recommends FDA expedite the review of certain PSP amendments and outline the criteria and mechanism for expediting these reviews. For example, a review might be sped up if the amendment results from additional Phase III study data from adults, PhRMA says.

Both PhRMA and BIO want clarity on how amendments to an agreed-upon PSP that are submitted less than 210 days prior to a marketing application will be handled. It asks whether these amendments could be submitted with the marketing application or after the submission of the marketing application.

BIO also said it is unclear what constitutes an amendment that would require the submission of a PSP versus an amendment that would only require submission of a protocol amendment to the IND for an abbreviated version of the 210-day process.

And Quintiles also warns that the current draft guidance “will precipitate the submission of one or more amendments for nearly every PSP, necessitating additional resource expenditures by both the sponsor and FDA.” This will occur because the guidance directs sponsors to provide timelines for completion of any pediatric studies, but Quintiles says that it often won’t be possible to predict timing prior to execution of adult Phase III studies.

Don’t Mandate BPCA Requests … But Give Us Advice If We Provide Them

Beyond timelines, PhRMA and BIO both ask FDA to make clear it is optional – not required – that sponsors discuss additional, potentially beneficial, yet non-obligatory pediatric uses of a product in a PSP.

The guidance says sponsors “should” include, as appropriate, information related to its plans to submit a proposed pediatric study request asking the FDA to issue a Written Request in the future per the Best Pharmaceuticals for Children Act (BPCA). Unlike PREA, BPCA is voluntary, but companies that complete a study requested by FDA get an additional six months of marketing exclusivity.

The guidance also says sponsors should include a summary of any clinical investigation conducted under an IND for an indication other than the indication that is the subject of the initial PSP.

But while the trade groups want to make sure companies aren’t mandated to include this information, they also want FDA to add that if companies choose to voluntarily disclose this information that FDA will reward this disclosure by agreeing to review and provide comments on these studies.

BIO says it “strongly believes this optional, earlier dialogue on a comprehensive pediatric drug development plan, including both required research under PREA and potential pediatric uses under BPCA, will result in a more efficient pediatric drug development process.”

Novartis, on the other hand, told FDA it recommends deletion of any reference to uses in children beyond the disease or indication being sought in adults because it is outside of the scope of PREA. The company says it should be the discussion of a different guidance regarding BPCA.

Pediatric Study Waiver, Deferral Determinations Could Harm Approvals, Firms Tell FDA

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