Posted: 11 Feb 2020 06:31 PM PST
By Sara W. Koblitz —
As more biosimilars are approved (we’re up to 26 now!), FDA has been rolling out guidance documents under the Biosimilars Action Plan (“BAP”). The most recent guidance has been long awaited. While the Hatch-Waxman Act explicitly provides that an applicant can seek approval for only some of the uses for which the reference product is approved – ultimately resulting in a labeling “carve out” – the Biologics Price Competition and Innovation Act contains no such language. However, back in 2018, then-Commissioner Gottlieb slipped into the BAP roll-out a reference to a guidance intended to “provide additional clarity to biosimilar applicants who seek approval for fewer than all conditions of use for which the reference product is licensed because, for example, one of the licensed conditions of use of the reference product is protected by a patent,” signaling to industry that FDA intended to permit carve-outs in biosimilar labeling.
At last, that guidance has arrived. The new guidance, Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed, makes it explicitly clear that carve-outs are permissible for biosimilars. Like with NDAs, the guidance explains the situations in which a carve-out (or approval of fewer than all conditions of use for which the reference product is licensed) may occur when a condition of use is protected by exclusivity, such as Orphan drug Exclusivity, or by patent. In such a case, FDA can license the biosimilar for any indications or conditions of use that are not protected by the relevant exclusivities or patents.
As with NDAs, aBLA sponsors seeking to carve-out an indication must submit draft labeling including all information from the reference product labeling to support the relevant (uncarved-out) conditions of use. As part of the aBLA review, FDA will consider whether the information carved out is essential scientific information needed for safe use of the product; if it is, FDA will not permit the carve-out.
Given the stark differences between the patent dance for NDAs and BLAs, the process for carving out conditions of use in these submissions is different. Notably, the guidance explains that “FDA does not expect an applicant to submit a justification for the applicant’s decision not to seek licensure of a biosimilar for all of the reference product’s licensed conditions of use.” This differs from a carve-out in an NDA, in which a section viii statement or exclusivity statement is necessary to justify the carve-out. The lack of such a requirement for aBLAs is logical, as there is no requirement to certify to any reference product patents or discuss exclusivities in a given aBLA submission. However, FDA will accept “information that is intended to inform FDA’s review of the draft labeling,” such a justification of why certain clinical trial information can be carved-out without raising safety or efficacy issues.
When ready to add such a carved-out condition of use into the labeling, the aBLA holder must submit a supplement to the aBLA containing all data and information needed to support licensure of the biosimilar with that condition of use. FDA expects that it will review and act on aBLA supplements seeking licensure for additional conditions of use within 6 months. Though the Biosimilar User Fee Act Goals Letter gives the agency 10 months to do so, FDA thinks that it can surpass this goal, assuming the supplement does not raise novel review issues.
While carve-outs for exclusivity purposes will prevent FDA from approving a supplement adding in a carved-out condition of use until the expiration of exclusivity, the same bar does not extend to carve-outs based on patents (or other reasons). Indeed, FDA may license a product for conditions of use protected by patent as long as FDA determines that the requirements for licensure have met. For that reason, FDA warns applicants in this guidance that it may review and act on a supplement early, and that an applicant should request that FDA refrain from acting on a supplement before a specified date that falls within the applicable goal date. If the applicant requests a date beyond the applicable goal date, FDA will not honor the request.
FDA’s assertion about goal dates is important for purposes of infringement litigation. Because the PHS Act provides that the submission of a BLA is an artificial act of infringement, the submission of the supplement to add a patented condition of use constitutes an act of infringement. While the reference product sponsor would know about the supplement if the aBLA sponsor chooses to partake in the patent dance, the aBLA patent dance is optional; as such, a reference product sponsor may not know of the existence of an application or supplement to add a condition until FDA announces its approval. If FDA announces a supplement approval adding a condition of use and that condition of use is still protected by patent (because FDA approved the supplement early or the applicant submitted the supplement early), the reference product sponsor will become aware and can immediately sue for infringement – even if there’s only a few days left on that patent. Therefore, the exact date of approval of a supplement adding a carved-out condition of use could have a critical effect on infringement litigation.
The guidance also states, in a footnote, that FDA expects all applications for interchangeable products to include data to support that the product can produce the same clinical result as the reference product “in all of the reference product’s licensed conditions of use” (emphasis added). While the interchangeable can still carve-out a condition of use, the expectation is that all data demonstrating that the product is interchangeable for that condition of use is submitted with the initial interchangeable application rather than in a supplement. This too raises questions of infringement. Again, because the PHS Act provides that the submission of a BLA is an artificial act of infringement, if there’s a patent protecting a condition of use and an interchangeable application is submitted with the intent to carve-out that condition of use, the act of submission is enough to allege patent infringement. Therefore, FDA’s requirement that interchangeable applications include all data for all conditions of use, even those intended to be carved out, inherently requires interchangeable applicants to infringe patents for conditions of use that will be carved out. In a way, it actually encourages applicants not to seek approval as an interchangeable product until all patents have run out. In other words, because FDA’s requirement leaves interchangeable sponsors vulnerable to patent infringement allegations – even if the interchangeable is carving-out a condition of use – one might expect that aBLA sponsors would be hesitant to seek interchangeable status until all conditions of use can be included in the label.
As with all draft guidance documents, this document represents FDA’s current thinking on the matter. There is always a chance that FDA hadn’t considered the ramifications of its requirements for interchangeable products carving out a patent. Like always, FDA will accept comments on this guidance document. Comments are due by April 7, 2020.
As more biosimilars are approved (we’re up to 26 now!), FDA has been rolling out guidance documents under the Biosimilars Action Plan (“BAP”). The most recent guidance has been long awaited. While the Hatch-Waxman Act explicitly provides that an applicant can seek approval for only some of the uses for which the reference product is approved – ultimately resulting in a labeling “carve out” – the Biologics Price Competition and Innovation Act contains no such language. However, back in 2018, then-Commissioner Gottlieb slipped into the BAP roll-out a reference to a guidance intended to “provide additional clarity to biosimilar applicants who seek approval for fewer than all conditions of use for which the reference product is licensed because, for example, one of the licensed conditions of use of the reference product is protected by a patent,” signaling to industry that FDA intended to permit carve-outs in biosimilar labeling.
At last, that guidance has arrived. The new guidance, Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed, makes it explicitly clear that carve-outs are permissible for biosimilars. Like with NDAs, the guidance explains the situations in which a carve-out (or approval of fewer than all conditions of use for which the reference product is licensed) may occur when a condition of use is protected by exclusivity, such as Orphan drug Exclusivity, or by patent. In such a case, FDA can license the biosimilar for any indications or conditions of use that are not protected by the relevant exclusivities or patents.
As with NDAs, aBLA sponsors seeking to carve-out an indication must submit draft labeling including all information from the reference product labeling to support the relevant (uncarved-out) conditions of use. As part of the aBLA review, FDA will consider whether the information carved out is essential scientific information needed for safe use of the product; if it is, FDA will not permit the carve-out.
Given the stark differences between the patent dance for NDAs and BLAs, the process for carving out conditions of use in these submissions is different. Notably, the guidance explains that “FDA does not expect an applicant to submit a justification for the applicant’s decision not to seek licensure of a biosimilar for all of the reference product’s licensed conditions of use.” This differs from a carve-out in an NDA, in which a section viii statement or exclusivity statement is necessary to justify the carve-out. The lack of such a requirement for aBLAs is logical, as there is no requirement to certify to any reference product patents or discuss exclusivities in a given aBLA submission. However, FDA will accept “information that is intended to inform FDA’s review of the draft labeling,” such a justification of why certain clinical trial information can be carved-out without raising safety or efficacy issues.
When ready to add such a carved-out condition of use into the labeling, the aBLA holder must submit a supplement to the aBLA containing all data and information needed to support licensure of the biosimilar with that condition of use. FDA expects that it will review and act on aBLA supplements seeking licensure for additional conditions of use within 6 months. Though the Biosimilar User Fee Act Goals Letter gives the agency 10 months to do so, FDA thinks that it can surpass this goal, assuming the supplement does not raise novel review issues.
While carve-outs for exclusivity purposes will prevent FDA from approving a supplement adding in a carved-out condition of use until the expiration of exclusivity, the same bar does not extend to carve-outs based on patents (or other reasons). Indeed, FDA may license a product for conditions of use protected by patent as long as FDA determines that the requirements for licensure have met. For that reason, FDA warns applicants in this guidance that it may review and act on a supplement early, and that an applicant should request that FDA refrain from acting on a supplement before a specified date that falls within the applicable goal date. If the applicant requests a date beyond the applicable goal date, FDA will not honor the request.
FDA’s assertion about goal dates is important for purposes of infringement litigation. Because the PHS Act provides that the submission of a BLA is an artificial act of infringement, the submission of the supplement to add a patented condition of use constitutes an act of infringement. While the reference product sponsor would know about the supplement if the aBLA sponsor chooses to partake in the patent dance, the aBLA patent dance is optional; as such, a reference product sponsor may not know of the existence of an application or supplement to add a condition until FDA announces its approval. If FDA announces a supplement approval adding a condition of use and that condition of use is still protected by patent (because FDA approved the supplement early or the applicant submitted the supplement early), the reference product sponsor will become aware and can immediately sue for infringement – even if there’s only a few days left on that patent. Therefore, the exact date of approval of a supplement adding a carved-out condition of use could have a critical effect on infringement litigation.
The guidance also states, in a footnote, that FDA expects all applications for interchangeable products to include data to support that the product can produce the same clinical result as the reference product “in all of the reference product’s licensed conditions of use” (emphasis added). While the interchangeable can still carve-out a condition of use, the expectation is that all data demonstrating that the product is interchangeable for that condition of use is submitted with the initial interchangeable application rather than in a supplement. This too raises questions of infringement. Again, because the PHS Act provides that the submission of a BLA is an artificial act of infringement, if there’s a patent protecting a condition of use and an interchangeable application is submitted with the intent to carve-out that condition of use, the act of submission is enough to allege patent infringement. Therefore, FDA’s requirement that interchangeable applications include all data for all conditions of use, even those intended to be carved out, inherently requires interchangeable applicants to infringe patents for conditions of use that will be carved out. In a way, it actually encourages applicants not to seek approval as an interchangeable product until all patents have run out. In other words, because FDA’s requirement leaves interchangeable sponsors vulnerable to patent infringement allegations – even if the interchangeable is carving-out a condition of use – one might expect that aBLA sponsors would be hesitant to seek interchangeable status until all conditions of use can be included in the label.
As with all draft guidance documents, this document represents FDA’s current thinking on the matter. There is always a chance that FDA hadn’t considered the ramifications of its requirements for interchangeable products carving out a patent. Like always, FDA will accept comments on this guidance document. Comments are due by April 7, 2020.
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