Source : 'Generics Bulletin'
After the US Food and Drug Administration issued Q&A guidance on developing abbreviated new drug applications during the COVID-19 pandemic, former FDA acting director for policy at the agency’s office of therapeutic biologics and biosimilars, Eva Temkin, has criticized the document for leaving much unsaid.
Temkin – who recently joined law firm King & Spalding as a partner with the FDA & Life Sciences team – observed that “the guidance talks about developing generic drugs and submitting ANDAs, but it is silent regarding the development of biosimilar and interchangeable biological products and the submission of 351(k) BLAs.”
“Hence, stakeholders are left to wonder whether the principles outlined in the guidance can inform treatment of follow-on biologics,” Temkin added.
In a co-authored blog post titled “Development of Biosimilar and Interchangeable Biological Products During the COVID-19 Pandemic: What the ANDA Guidance Left Unsaid,” Temkin suggested that “it would have been helpful for FDA to address the first interchangeable exclusivity considerations that may arise for interchangeable applicants who may have the approval of filed 351(k) BLAs affected by COVID-19 related inspection delays – even if only to say that the same “case-by case” approach described for 180-day exclusivity also would be appropriate for consideration of eligibility for first interchangeable exclusivity.” [GB150806]
Though the FDA has been outspoken in recent years about the critical role of biosimilar and interchangeable products in improving patient access and striking the Biologics Price Competition and Innovation Act balance between innovation and competition, according to Temkin, the agency’s decision to leave out the development of biosimilar and interchangeable biological products could be because “the biosimilars pathway differs from the ANDA pathway in a number of important ways, and the treatment of the two product categories by FDA has justifiably been separate in most cases.”
Among other reasons for the agency’s silence on development of biosimilar and interchangeable biological products, Temkin talks about approval of generic drugs being predicated on a demonstration of bioequivalence, while approval of biosimilar products is based on a demonstration that the biosimilar is highly similar to and has no clinically meaningful differences from the reference product.
Talking about labelling, Temkin noted that “unlike generics, which are required to have the same labelling as the reference product, labelling for biosimilar and interchangeable products is not required to be the same as the labelling of the reference product.”
When it comes to 180-day exclusivity for generics, Temkin said that guidance stops short of saying whether, or how, loss of exclusivity due to inspection-related delays might be evaluated.
“The guidance does not address the question of how exclusivity might play out in conjunction with inspection-related delays when there are multiple ‘first applicants,’ not all of whom have applications that are forestalled due to FDA’s inability to inspect,” said Temkin, pointing out that under normal circumstances, when multiple substantially complete ANDAs containing paragraph IV certifications are submitted on the same day, FDA considers all of the applicants to be ‘first applicants’ with an opportunity to share in 180-day exclusivity.
Talking about missing information from the guidance, Temkin said that the FDA’s case-by-case analysis framework could prove to be “filled with landmines if the agency ends up needing to navigate these complex equities.”
According to Temkin, the FDA would likely “go to great lengths to avoid a situation in which an ANDA applicant loses exclusivity to which it otherwise would be entitled because of the agency’s pandemic-related inability to conduct a pre-approval inspection.” Temkin added, “It also makes sense that FDA would not draw that bright line in guidance, falling back instead on the ‘case-by-case’ analysis to preserve its flexibility in the event of extraordinary circumstances.”
Temkin summarized that while the FDA’s guidance covers a wide range of issues relating to the development of generic drugs during the COVID-19 pandemic and about the submission and assessment of ANDAs for products that may be used to help address the pandemic or that may otherwise be affected by the pandemic, “the COVID Q&A guidance may be more notable for what it did not say than for what it said.”
“For example,” Temkin said, “the guidance explains that if an ANDA lists a manufacturing site that cannot be inspected due to COVID-19-related travel restrictions, the application will not automatically receive a complete response letter.”
She continued, “Instead, FDA expects to base its decision on the totality of available information, including information obtained through alternative inspection tools,” which includes requesting records in advance or in lieu of inspection, relying on recognized non-US agency inspections and leveraging the newly announced “remote interactive evaluations” of manufacturing facilities to inform approval decision-making.
Highlighting the structural similarities between 180-day exclusivity for generic drugs and first interchangeable exclusivity for interchangeable biosimilars, Temkin noted that “FDA did not publish concurrent guidance or make mention in the COVID Q&A guidance of the applicability of the principles articulated in that guidance to 351(k) BLAs or applicable biologics exclusivity.”
“We know that the COVID-19 pandemic has had a significant impact on biosimilar review by FDA, said Temkin.
“If there are multiple filed interchangeable applications that reference the same reference product, will a second or subsequent application be able to leapfrog the first because the first is bogged down in a COVID-19-related inspection delay?” she asked. “Or will FDA consider those circumstances in the same type of ‘case-by-case’ analysis laid out in the guidance?”
Noting the FDA’s emphasis on the availability of the interchangeable pathway for insulin products and the anticipation of additional interchangeable competition when blockbuster biological drugs come off patent in the next few years, Temkin insisted, “the impact of COVID-19-related inspection delays may need to be addressed sooner rather than later.”
By Akriti Seth