The Last Days Of NDAs: Uncertainties Remain Ahead Of 23 March Move From Drugs To Biologics
Executive Summary
Exactly how many NDAs ultimately will make the switch, the impact of pending applications on 'Orange Book' listings, and the ramifications for ‘authorized generics’ are areas of focus as the regulatory transition date looms.
With just one week to go before some protein products in the US undergo a major regulatory transition 10 years in the making, uncertainties remain as to exactly what products will make the switch, when their patent and exclusivity information will be removed from the “Orange Book,” and the impact on currently marketed “authorized generics” of branded insulin products.
On 23 March, insulin, human growth hormone and certain other types of protein products that traditionally have been regulated as drugs will be “deemed” licensed biologics under the Public Health Service Act.
The transition, required under the Biologics Price Competition and Innovation Act, is expected to open the door to biosimilar and interchangeable versions of products that did not fall neatly into the regulatory framework for abbreviated new drug applications.
The FDA took its first major public action on the transition with a 2016 draft guidance explaining how it planned to implement the provisions. (Also see "BLAs More Appealing As 'Transition' NDAs, ANDAs Set To Lose Exclusivity" - Pink Sheet, 21 Mar, 2016.) It subsequently issued final guidance documents, proposed and final rules, policy statements, educational resources for patients and health care providers, and several iterations of a list of products affected by the transition.
Yet, as the clock ticks down to 12:00 a.m. EDT on Monday, 23 March – the magical hour when approved NDAs for the affected biological products are deemed BLAs and will cease to exist as NDAs – the Pink Sheet looks at some of the lingering questions surrounding the transition.
The List – Some Want Off, Some Want On
The most recent version of the FDA’s preliminary list of transition products contains 95 NDAs, a number that has grown since the initial list released in December 2018. (Also see "When Drugs Become Biologics: US FDA Guidances Explain 'Transition Provisions'" - Pink Sheet, 11 Dec, 2018.)
The current list was posted on 15 January and is up to date through 31 December. It reflects the addition of four products from the previous iteration. (Also see "Countdown To Transition: US FDA Says 91 Drugs Will Become Biologics In March 2020" - Pink Sheet, 27 Sep, 2019.)
Three of these products were added as a result of language in Further Consolidated Appropriations Act, signed into law in December, that removed the exception for “chemically synthesized polypeptide” from the statutory definition of protein for purposes of the transition. (Also see "Mylan/Biocon’s Insulin Glargine Would Get A Respite Under US Budget Legislation" - Pink Sheet, 17 Dec, 2019.)
The chemically synthesized polypeptides added to the list were Ferring Pharmaceuticals AS’ Acthrel (corticorelin ovine triflutate), Sanofi’s Adlyxin (lixisenatide) and Theratechnologies Inc.’s Egrifta (tesamorelin acetate), according to the FDA.
Notably, the diabetes drug lixisenatide is the only single-agent, GLP-1 receptor agonist included on the list. Sanofi’s Soliqua, a fixed-dose combination of insulin glargine and lixisenatide, also is set to make the transition, as will Novo Nordisk AS’ Xultophy, which combines insulin degludec and the GLP-1 receptor agonist liraglutide.
Shortly after the transition date, the FDA intends to post a final list of approved applications under the FD&C Act that have been deemed to be licenses under the PHS Act.
One sponsor currently on the list is lobbying to get off.
In 18 February comments to the agency, Theratechnologies said tesamorelin, a synthetic analogue of human growth hormone-releasing factor, is not a “protein” under the FDA’s definition or under the scientific meaning of the term and is more like a small molecule than a biologic.
“Having had three months and not 10 years, we have not had the opportunity to prepare for a biologics transition and were instead actively researching label-expansion initiatives for tesamorelin, which are no longer applicable under the BLA framework.” – Theratechnologies
The company also cites practical considerations for tesamorelin’s removal from the transition product list.
While other affected companies have had years to prepare for the transition, “Theratechnologies saw its product suddenly ripped from the NDA regime and forced into the BLA framework without the notice afforded these other companies,” the comments state. “Having had three months and not 10 years, we have not had the opportunity to prepare for a biologics transition and were instead actively researching label-expansion initiatives for tesamorelin, which are no longer applicable under the BLA framework.”
In contrast, both Ipsen and Teva Pharmaceuticals USA Inc. are pushing to get their products into the club.
Ipsen asserts its synthetic polypeptide Somatuline Depot (lanreotide acetate) is a biological product under the amended definition and should be included on the list. Similarly, Teva asserts its multiple sclerosis blockbuster drug Copaxone (glatiramer acetate injection) qualifies for transition now that the carve-out for chemically synthesized polypeptides has been eliminated.
Leaving The 'Orange Book' Behind
The transition will necessitate a color shift in the drug regulatory world.
Biological products approved in NDAs that are deemed to be BLAs will be removed from the “Orange Book” on 23 March and will be added to the “Purple Book” listing of licensed biological products on or shortly after the transition date.
However, there may be a few products straddling the orange/purple line.
The December appropriations law included a grandfather clause for product applications subject to the transition that are pending as of 23 March. The FDA originally had proposed that such pending applications would receive complete response letters and would have to be resubmitted as BLAs. However, the legislative fix provided for continued review of the pending applications if they were filed on or before 23 March 2019.
The provision may have saved the fate of at least one application. Mylan NV and Biocon Ltd.’s insulin glargine has been in danger of not getting approved in time for the transition due to two CRLs resulting from manufacturing quality issues. (Also see " Mylan/Biocon Running Out Of Time To Get Insulin Approved Before US Transition " - Pink Sheet, 4 Sep, 2019.)
The troubled application is once again under FDA review, with a June target action date. (Also see "Biocon And Mylan's Fulphila And Insulin Plans On Track" - Generics Bulletin, 27 Jan, 2020.)
Applications for products that are subject to the transition submitted on or before 23 March 2019 and approved by 30 September 2022 will automatically be deemed BLAs at the time of approval. However, while such applications are pending, any transition product referenced in that application will continue to be listed in the “Orange Book,” according to a provision in the appropriations law.
Only after all pending applications that reference a specific deemed BLA are approved will the reference product be removed from the "Orange Book." Applications that are not approved as of 1 October 2022 will be deemed withdrawn.
During a recent podcast on the transition, Deborah Cho, an associate at Ropes and Gray in Washington, DC, suggested any grandfathered applications could be impacted by unexpired exclusivity for the reference products at issue.
Only unexpired orphan drug and pediatric exclusivity will survive the transition to BLAs. The agency has determined that any unexpired new chemical entity and Hatch-Waxman exclusivity will be extinguished – a policy stance that continues to remain unpopular among drug sponsors and industry attorneys.
Applications that are pending at the time of transition “are subject to the patent certification and statement requirements that apply to NDAs,” Cho said on the podcast. “And the date on which these applications can be approved is determined based on the last expiration date of any applicable period of Hatch-Waxman, pediatric, orphan or GAIN antibiotic exclusivity” for the reference product.
Cho said that although the FDA has not provided much clarity on this issue, “it seems like this means 505(b)(2) and generic applications submitted by March 23, 2019 referencing a transition product may be blocked by Hatch-Waxman exclusivity past the transition date.”
A Pink Sheet review of the most recent list of transition products identified eight NDAs with NCE or Hatch-Waxman marketing exclusivity that expires after 23 March 2020. (See sidebar.)
Seven of these are insulin products, two of which have Hatch-Waxman exclusivity periods that run beyond October 2022. The eighth product, lixisenatide, has NCE exclusivity that expires in July 2021.
'Authorized Generics' To Become 'Unbranded Biologics'
The agency’s recent Q&A final guidance document on the transition has raised questions about currently available “authorized generics” of reference products subject to the transition.
In the guidance, the FDA said the holder of a standalone biologics license application under Section 351(a) may not use the 351(k) pathway to bring to market a so-called “authorized” biosimilar or interchangeable version of its own reference product, although it may seek a biosimilarity or interchangeability determination relative to “another” reference product. (Also see "'Authorized Biosimilars' Can't Use 351(k) Pathway, US FDA Concludes" - Pink Sheet, 4 Mar, 2020.)
Novo Nordisk and Eli Lilly & Co. have introduced lower-cost, authorized generic versions of their NovoLog and Humalog-branded insulin products, respectively. (Also see "Lilly Adds Two More Humalog Authorized Generics As Insurance Deductibles Reset" - Pink Sheet, 14 Jan, 2020.) (Also see "Novo Nordisk Launches Low-Priced Insulin In US" - Generics Bulletin, 14 Jan, 2020.)
While these lower-cost versions still could be marketed under the reference product BLAs after the transition, they would not carry an interchangeability designation, which experts told the Pink Sheet is needed for automatic substitution at the pharmacy level without a prescriber’s intervention.
“As with authorized generics, an unbranded biologic will be considered by FDA to be equivalent to its brand-name biological product because it is the same product as the brand name under the same BLA.” – FDA
However, the agency and Lilly suggest there will not be an issue with substituting such products in place of their branded versions.
Because an authorized generic is marketed under the brand drug’s NDA and is the drug product approved under that application, it is not separately listed in the “Orange Book,” the FDA told the Pink Sheet. The agency noted the compendium preface states that an authorized generic “is considered to be therapeutically equivalent to its brand-name drug because it is the same drug.”
After the transition occurs, a deemed 351(a) BLA will include as “unbranded biologics” any products that were marketed under an NDA as authorized generics. The agency does not expect to separately identify unbranded biologics in the "Purple Book."
The agency confirmed that an authorized generic marketed under an NDA that is deemed to be a 351(a) BLA on 23 March will not become an “interchangeable biosimilar.”
“An interchangeable biosimilar is a biosimilar product that FDA has licensed as interchangeable with a reference product pursuant to section 351(k)(4) of the PHS Act,” the agency said. “However, as with authorized generics, an unbranded biologic will be considered by FDA to be equivalent to its brand-name biological product because it is the same product as the brand name under the same BLA.”
Lilly said it does not expect there will be any impact on pharmacists’ ability to substitute its unbranded insulin lispro for Humalog. The company said that both its branded and unbranded insulins will be available and marketed under the deemed BLAs.
“Pharmacies can automatically substitute Lilly’s Insulin Lispro for Humalog right now, and we believe they will continue to be substitutable in the same way after the transition,” the company said. “Unbranded versions of these transition products are currently being substituted at pharmacies. There is no reason for this to change as a result of the transition. FDA’s transition guidances have not raised any concerns about this practice.”
Novo Nordisk did not respond to questions about the impact of the transition on its authorized generics.
Sanofi said it does not currently offer authorized generics of its branded insulin products but it continues to work closely with the FDA on issues related to the transition. “We support solutions that provide patients with access to additional treatment options. We believe a robust and competitive marketplace, including the efforts by the US Food and Drug Administration, help to achieve this goal,” the company said.
Compounders Seek A Reprieve
Daniel Orr, a partner at Womble Bond Dickinson in Washington, DC, said he does not expect to see any major changes from the FDA in either its transition implementation plans or the affected products list ahead of 23 March.
In particular, he does not expect the agency to back off its position that four bulk drug substances affected by the transition – human chorionic gonadotropin, hyaluronidase, follicle stimulating hormone and menotropins – will lose their compounding exemption under the FD&C Act.
After the transition, such compounding will be subject to a 2018 guidance that describes the agency’s enforcement discretion policy for the mixing, diluting or repackaging biological products outside the scope of an approved BLA. (Also see "Compounders Complain They Can’t Make These Four Drugs Once They’re Deemed Biologics" - Pink Sheet, 9 Mar, 2020.)
Compounding pharmacies have warned the FDA the regulatory change could result in product shortages, and they, along with prescribers and patients, are lobbying the agency for a continued exemption.
However, Orr does not think these efforts will result in any change of heart by the regulator. “The agency already views compounding as elevated risk, and their statements have made it clear that they view compounding biologics an even higher risk,” he said.
He suggested that after 10 years of work, the agency is as prepared as it can be for the drugs-to-biologics conversion.
“They’ve spent a lot of time thinking through the issues,” Orr said. “I do think FDA has dotted its i’s and crossed many of the t’s.”