Posted 22 December 2020 | By
In guidance released Monday, the US Food and Drug Administration (FDA) provides the timelines it will stick to when reviewing responses to complete response letters (CRLs) for drugs and biologics when a facility assessment or inspection is required in order for the agency to make a decision on the application.
FDA’s ability to conduct on-site inspections has been dramatically curtailed amid the COVID-19 pandemic due to public health concerns and travel restrictions. In the early days of the pandemic, FDA halted most foreign and domestic inspections and has since issued guidance explaining its approach to inspections and inspection-alternatives. (RELATED: Coronavirus prompts FDA to cancel travel, postpone inspections and meetings, Regulatory Focus 10 March 2020; FDA looks to resume domestic inspections this month, Regulatory Focus 10 July 2020; FDA issues pandemic inspections FAQ guidance, Regulatory Focus 19 August 2020).
In the intervening months, FDA has rejected or deferred its decision on several applications due in part to its inability to conduct on-site inspections.
In one recent example, Novartis said last week that it received a complete response letter (CRL) for its new drug application (NDA) for its heart drug inclisiran “due to unresolved facility inspection-related conditions” pertaining to a European manufacturing site.
“No onsite inspection was conducted of the single third-party facility in question. If a facility inspection is needed, FDA will define an approach once safe travel may resume based on public health need and other factors,” Novartis said.
In November, Alkermes said it received a CRL for its investigational schizophrenia and bipolar disorder treatment ALKS 3831 (olanzapine/samidorphan) after a remote records review done in lieu of a preapproval inspection turned up issues related to the tablet coating process at the company’s Wilmington, OH facility.
And back in June, Nabriva Therapeutics said the CRL it received for its antibiotic injection Contepo (fosfomycin) cited inspection “observations at our manufacturing partners that could not be resolved due to FDA’s inability to conduct onsite inspections because of travel restrictions.”
FDA’s inability to conduct inspections has also resulted in deferred actions on other applications, including Bristol Myers Squibb’s biologics license application (BLA) for its CAR T-cell therapy liso-cel and Specrum Pharmaceuticals’ BLA for Rolontis (eflapegrastim) to treat neutropenia in patients receiving myelosuppressive anti-cancer regimens.
Guidance
In the guidance, FDA says it is “facing difficulties in conducting facility assessments that are necessary before regulatory decisions can be made on marketing applications,” and that it is relying on alternative tools such as records requests and review of inspection reports from trusted foreign regulators when onsite inspections are not feasible.
FDA also says that its inspection-alternatives “can be as resource intensive as inspections, if not more,” adding to the strain on the agency during the pandemic.
FDA explains that the guidance applies to original and supplemental applications that were rejected and require an inspection that “cannot be conducted in a timely manner because of COVID-19” or require “time- and resource-intensive alterative tools to assess a facility or [bioresearch monitoring] BIMO site.”
For amendments to original abbreviated new drug applications (ANDAs) and amendments to prior approval supplements to approved ANDAs, FDA says it will treat applicant responses as major amendments that will be reviewed in accordance with its July 2018 guidance on Generic Drug User Fee Amendments (GDUFA) review goals for ANDA submissions. According to that guidance, the agency plans to review and act on 90% of standard major ANDA amendments within 8 months of the amendment submission date when a preapproval inspection is not required and in 10 months when an inspection is required.
When it comes to resubmissions of original applications and efficacy supplements for 505(b)(1) and 505(b)(2) NDAs and 351(a) BLAs, FDA says it will stick to a Class 2 review timeline of 6 months. “This timeline is consistent with existing policies and practices when a facility inspection is required,” the agency writes.
FDA also says, “There will be no changes in the timelines used” for resubmissions of original applications, supplements with clinical data and manufacturing supplements for BLAs for biosimilars or for resubmissions of manufacturing supplements for 505(b)(1) and 505(b)(2) NDAs and 351(a) BLAs, all of which “will continue to be subject to existing user fee timelines.”
FDA
FDA’s ability to conduct on-site inspections has been dramatically curtailed amid the COVID-19 pandemic due to public health concerns and travel restrictions. In the early days of the pandemic, FDA halted most foreign and domestic inspections and has since issued guidance explaining its approach to inspections and inspection-alternatives. (RELATED: Coronavirus prompts FDA to cancel travel, postpone inspections and meetings, Regulatory Focus 10 March 2020; FDA looks to resume domestic inspections this month, Regulatory Focus 10 July 2020; FDA issues pandemic inspections FAQ guidance, Regulatory Focus 19 August 2020).
In the intervening months, FDA has rejected or deferred its decision on several applications due in part to its inability to conduct on-site inspections.
In one recent example, Novartis said last week that it received a complete response letter (CRL) for its new drug application (NDA) for its heart drug inclisiran “due to unresolved facility inspection-related conditions” pertaining to a European manufacturing site.
“No onsite inspection was conducted of the single third-party facility in question. If a facility inspection is needed, FDA will define an approach once safe travel may resume based on public health need and other factors,” Novartis said.
In November, Alkermes said it received a CRL for its investigational schizophrenia and bipolar disorder treatment ALKS 3831 (olanzapine/samidorphan) after a remote records review done in lieu of a preapproval inspection turned up issues related to the tablet coating process at the company’s Wilmington, OH facility.
And back in June, Nabriva Therapeutics said the CRL it received for its antibiotic injection Contepo (fosfomycin) cited inspection “observations at our manufacturing partners that could not be resolved due to FDA’s inability to conduct onsite inspections because of travel restrictions.”
FDA’s inability to conduct inspections has also resulted in deferred actions on other applications, including Bristol Myers Squibb’s biologics license application (BLA) for its CAR T-cell therapy liso-cel and Specrum Pharmaceuticals’ BLA for Rolontis (eflapegrastim) to treat neutropenia in patients receiving myelosuppressive anti-cancer regimens.
Guidance
In the guidance, FDA says it is “facing difficulties in conducting facility assessments that are necessary before regulatory decisions can be made on marketing applications,” and that it is relying on alternative tools such as records requests and review of inspection reports from trusted foreign regulators when onsite inspections are not feasible.
FDA also says that its inspection-alternatives “can be as resource intensive as inspections, if not more,” adding to the strain on the agency during the pandemic.
FDA explains that the guidance applies to original and supplemental applications that were rejected and require an inspection that “cannot be conducted in a timely manner because of COVID-19” or require “time- and resource-intensive alterative tools to assess a facility or [bioresearch monitoring] BIMO site.”
For amendments to original abbreviated new drug applications (ANDAs) and amendments to prior approval supplements to approved ANDAs, FDA says it will treat applicant responses as major amendments that will be reviewed in accordance with its July 2018 guidance on Generic Drug User Fee Amendments (GDUFA) review goals for ANDA submissions. According to that guidance, the agency plans to review and act on 90% of standard major ANDA amendments within 8 months of the amendment submission date when a preapproval inspection is not required and in 10 months when an inspection is required.
When it comes to resubmissions of original applications and efficacy supplements for 505(b)(1) and 505(b)(2) NDAs and 351(a) BLAs, FDA says it will stick to a Class 2 review timeline of 6 months. “This timeline is consistent with existing policies and practices when a facility inspection is required,” the agency writes.
FDA also says, “There will be no changes in the timelines used” for resubmissions of original applications, supplements with clinical data and manufacturing supplements for BLAs for biosimilars or for resubmissions of manufacturing supplements for 505(b)(1) and 505(b)(2) NDAs and 351(a) BLAs, all of which “will continue to be subject to existing user fee timelines.”
FDA
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