Teva Identifies ‘Problem Pattern’ Of Complex CRLs Ahead Of GDUFA III

Major complete response letters for complex abbreviated new drug application products are something of a “problem pattern,” Teva has told Generics Bulletin, with manufacturers keenly aware that there is “a lot of work to be done with the US Food and Drug Administration in speeding up that time to approval and keeping communication going back and forth” during the review process.

In the second part of Generics Bulletin’s exclusive interview with the Israeli generics giant, executive vice-president for North America commercial Brendan O’Grady discussed complex generics, both from Teva’s commercial standpoint and considering the planned reauthorization next year of the Generic Drug User Fee Amendments, or GDUFA, which is currently being negotiated by the FDA and industry.

Meanwhile, O’Grady also pressed the advantages of Teva’s North America operation since it was created under the company’s sweeping changes and global restructuring in late 2017; and the broader effects for the US market of Teva’s actions to rationalize the company’s generic product portfolio.

Building on comments made during Teva’s fourth-quarter earnings call in February, O’Grady said the company had between 10 and 12 complex ANDA products it could introduce potentially in 2021, with an acknowledgement that Teva could not achieve them all.

“It’s hard to say which ones will or will not launch, but you know there’s some potential ones that I mentioned before: octreotide, teriparatide; we’ve already launched generic NuvaRing (etonogestrel/ethinylestradiol), and brinzolamide is another one that we’ve just launched,” (Also see "Teva Debuts US Azopt Rival" - Generics Bulletin, 9 Mar, 2021.)

“So, there’s some in the stable. We’ll see how things evolve as we go through the year. I think the FDA is still working through COVID, that they are still very much in a remote mindset but conversations with the FDA are progressing, and we hope to see several of those approved and bring them to market.”

Were there any Hatch-Waxman court dates opening the door to complex generics that stood out to Teva in 2021? “I hate to speak about litigation because you never really know what’s going to happen there, it’s very complicated,” O’Grady reasoned.

Pushed on Teva’s pending generic version of Allergan’s Restasis (cyclosporine) ophthalmic emulsion, following the dissolution of any intellectual property hurdles in 2017, O’Grady delivered an upbeat message, while analogizing it with the greater struggle to get complex ANDA approvals over the line.

“That’s one of those ones that I would very much hope to see in 2021,” he underlined. “We’ll see how things go. That one’s been a little two steps forward, one step back, but again conversations with the FDA are ongoing.”

It was “hard to predict where FDA goes with that,” O’Grady said. “We brought generic EpiPen (epinephrine) to the market and it took us, I think, between seven and nine years to get it approved. Hopefully Restasis doesn’t turn intothat but again complex generics are very difficult.”

Inefficiencies Delaying Complex Generics Access

Remarking that the FDA typically had a median time of around 37 months for a normal generic approval, and 44 months for a complex ANDA product, O’Grady pressed the point of greater urgency and transparency “so that when you get your GDUFA date, you don’t get hit with a major CRL and get set back another year. And that’s been a problematic pattern with the FDA and something we need to work with the FDA to overcome; not just Teva, with all manufacturers.”

Brendan O'Grady Teva

Earlier this year, at a webinar hosted by The Hill, Teva’s senior vice-president and chief operating officer for US generics Christine Baeder reiterated the call for increased transparency, assessment process predictability and better guidance practices under GDUFA III. She added that the reauthorization would be a great vehicle to align the policy and structure. (Also see "Complex Generics: US FDA, Sponsors View Roadblocks Very Differently" - Generics Bulletin, 11 Feb, 2021.)

“Now that we have more complex drugs, there are new needs and new systems and infrastructure that needs to be built to support those approvals,” Baeder said at the time. Specific initiatives previously suggested by the company include the FDA and the generic drug industry at-large taking lessons from the way the agency works with new drug sponsors to ensure that generic applications for complex formulations are in shape to be approved when submitted. (Also see "Treat Complex Generics More Like NDAs In GDUFA III, Teva Says" - Generics Bulletin, 23 Jul, 2020.)

O’Grady continued the message, telling Generics Bulletin that “more can be done to improve patient outcomes and access by addressing the inefficiencies with the current FDA approval process for complex generics. Current inefficiencies,” he said, “delay patient access or even keep complex generics off the market entirely.”

Recent steps taken by the FDA include handing two US universities a five-year, $5m grant to establish a Center for Research on Complex Generics, with the aim of enhancing research collaborations with the generics industry to “further the FDA’s mission of increasing access to safe and effective generic products.” (Also see "FDA Grant Establishes Complex Generics Center To Increase Access" - Generics Bulletin, 30 Sep, 2020.)

The FDA has also recently championed the success of its pre-ANDA program, which was established under the second iteration of GDUFA, and has a special focus on complex generic drug products, including inhaled or injectable products. (Also see "FDA’s OGD Takes Fight To COVID-19 With Half-Century Of Approvals" - Generics Bulletin, 18 Feb, 2021.)

‘We’re A Leader If Not The Leader’

Returning to Teva’s commercial ambitions amid the broader industry trend of increased access for complex products, O’Grady identified only Sandoz and recently-formed Viatris as having “the breadth to focus on complex generics from a wide perspective.”

Challenged on Viatris’ recent declaration that it was number one last year in the US in terms of volume, value and total prescriptions filled for complex products, O’Grady acknowledged the might of Teva’s competitor while maintaining that the very nature of the industry itself meant that title was prone to change hands.

“I think that over the last three years, [from 2018 to today], we’ve led the generics space every year with the most approvals with as many as 88 launches, somewhere in that neighborhood. And many of them have been complex generics,” O’Grady pointed out.

“I think we will continue to be successful and it’ll ebb and flow from year-to-year as to what manufacturer gets what approved and who can somewhat claim leadership there. But, certainly, if we’re not the leader, we’re a leader, and will continue to be.”

Given the success of Teva’s external projects in biosimilars, were collaborations the answer to push through a greater number of complex products? “I think that we’re certainly open to that,” O’Grady noted.

For example, Teva’s recently launched first generic version of Novartis’ Azopt (brinzolamide) 1% solution was developed and manufactured by India’s Indoco Remedies at its facility in Goa.

Nevertheless, he acknowledged also that Teva had “the capabilities to do a lot of the complex generics on our own,” singling out the company’s factory in Waterford, Ireland that could manufacture both generic and branded inhalers.

“We have most of the major technologies that we need internally, but sometimes it’s more efficient and better to partner, whether it be on active pharmaceutical ingredient, the device, the total product itself. And we’ve done that in numerous cases, so we would certainly look to partner if we thought it was in our best interest and represented a good strategic opportunity for us.”

Manufacturers Followed Teva’s Lead On US Portfolio

O’Grady’s more than two decades with Teva has taken him outside of his native US, overseeing both generic and branded products in a multitude of different roles. He stepped into his current one, encompassing the entire North America region for both specialty and generic products, in December 2017, as Teva embarked on a corporate overhaul under its new CEO Kåre Schultz.

Schultz did away with Teva’s traditional separation into generics and specialty units, in favor of single commercial organizations. At the same time, he took drastic steps to reduce Teva’s mammoth cost base in order to ease Teva’s debt worries, slashing jobs and closing factories across the globe, while rationalizing Teva’s generics portfolio, mainly in the US.

“It’s a very different Teva today than it was in 2017,” O’Grady noted, describing how under his own remit in North America, “there’s of course Canada which has both generics and brands, as well an OTC business. In the US, we have brand or specialty depending upon the terminology you want to use, as well as generics, and even our Anda distribution business.”

“So, from a commercial structure we look a lot different, and I think that has a couple of benefits,” O’Grady commented, pointing to simplified and improved communication. “We were able to take all of those competencies and bring them together, and really look at the market in totality, which helps with investment. I think it helps on execution and I think that bringing the specialty and the generic mindsets together has really given us an advantage on how we execute on biosimilars. So, I think that has all been very good.”

Meanwhile, with Teva’s manufacturing footprint dropping from 80 to 60 facilities, there was “still work to be done, simplifying the network and maybe modernizing it to some extent is a focus.”

“The dialog has been good with our customers and I think that they realize that there has been some value in stability of the supply chain; and we’ve certainly seen that during the COVID pandemic.” 

“And of course, the rationalization,” O’Grady noted. “So our share has come down in the last three years as we’ve rationalized unprofitable products and I think we’ve balanced that out as we rationalized those products we saw margin gains over those three years also,” he commented.

“That’s something we continue to look at, our portfolio, and other opportunities to lean in more and take additional share. I think there probably are and you’ll probably see us do that. But at the same time, we will continue to look at our portfolio and certainly look to sustain products for as long as we can.”

Ultimately, it was “important to have a certain presence in the market,” he said, matching the commitment offered by Schultz three years ago. (Also see "Teva chief commits to a broad offering" - Generics Bulletin, 10 Aug, 2018.)

“To be dedicated to certain markets, sometimes it makes sense to be in products or therapeutic areas where the margins are very thin. But we try to look at the overall portfolio with a focus on share volume and margin.”

When it came to Teva’s rationalization initiatives, Schultz at the beginning of last year had suggested that more stable operating conditions in the US retail generics market were due in large part to actions taken by the Israeli firm. (Also see "Teva Chief Claims Credit For US Stability" - Generics Bulletin, 15 Jan, 2020.)

Did O’Grady agree with this assessment? “I think that’s a fair comment and I think we were somewhat leaders in that,” he underlined. “I remember, right after taking over North America, meeting with many of our customers, kind of in the first half of 2018 and having those conversations. Once we led the way, other manufacturers did very similar things and there seems to be a pivot away from price now to a greater focus on stability of the supply chain and quality.”

There was a recognition that these factors were important in generics and “it’s not just all about price,” O’Grady added. “I think that the actions that we took in 2018 help lead the market and others followed, and you still see others following today, and taking that kind of approach. I think the dialog has been good with our customers and I think that they realize that there has been some value in stability of the supply chain; and we’ve certainly seen that during the COVID pandemic.”