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SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 10 March 11, 2019

F R O M T H E E D I TO R S O F S C R I P R E G U L ATO RY A F FA I R S , T H E R P M R E P O RT , G O L D S H E E T , P I N K S H E E T DA I LY A N D P I N K S H E E T

NEW PRODUCTS

Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial, p. 13

NEW PRODUCTS

EU CHMP Backs Three Conditional Approvals & Several Treatment Firsts, p. 9

BREXIT

Goodbye To All That: EMA Leaves London After 24 years, p. 6

ward-leaning way” not seen often.“He kind of drove the conversation

through very good communication exter-nally,” Myers said. “He was able to use a lot of the ideas percolating in the agency, pack-age them and get them moved forward.”

Gottlieb pushed FDA to the forefront of the drug pricing debate, a position the agency had not sought in the past. In his first speech to staff after confirmation, he said that even though the agency cannot set drug prices, it can promote competition. (Also see “Gottlieb Places Drug Pricing Out Front In First Speech To US FDA Staff” - Pink Sheet, 16 May, 2017.)

Gottlieb was vocal in chastising the brand industry for blocking generic com-petition, warning that Congress could make more drastic changes if it did not stop employing pay-for-delay and licens-ing tactics intended to prevent patent challenges. (Also see “Gottlieb: Real Risk Of Congressional Action If Anti-Competitive Actions Continue” - Pink Sheet, 3 May, 2018.)

He also publicly released a list of com-panies thought to be using the Risk Evalu-ation and Mitigation Strategy system to prevent generic companies from purchas-ing samples for testing, although it is not clear the move had much impact. (Also see “REMS Abuse Website: Celgene, Actelion Top List Of Suspected ‘Gamers’” - Pink Sheet, 18 May, 2018.)

In addition, Gottlieb blasted the rebate system that he alleged was holding back biosimilar competition for expensive biologic drugs. (Also see “Biosimilars Need

Gottlieb’s Short Tenure Will Be Felt Long After He Leaves US FDADERRICK GINGERY [email protected]

U S FDA Commissioner Scott Gott-lieb, one of the most popular and visible commissioners in decades,

will end his tenure as head of FDA in about a month, having moved the agency in new directions while also advancing high-pro-file policies.

Gottlieb amassed a legacy that includes new approaches to drug pricing and opi-oid policy, as well as record generic and novel drug approval output, despite run-ning the agency less than two years.

Gottlieb cited his family in his decision to leave. In a note to staff, he said “there’s perhaps nothing that could pull me away from this role other than the challenge of being apart from my family for these past

two years and missing my wife and three young children.”

THE PUBLIC COMMISSIONER Gottlieb may be most remembered for his approach to communications. He often appeared on television and his daily Twit-ter posts complemented the numerous press releases announcing policy changes and other moves within the agency. Previ-ous commissioners tended to avoid the limelight, as well as social media.

Nancy Myers, president of Catalyst Healthcare Consulting, said in an interview that Gottlieb was pro-patient, pro-industry and pro-safety at the same time, which is difficult. He also used the office in a “for-

“ There’s perhaps nothing that could pull me away from this role other than the challenge of being apart from my family for these past two years and missing my wife and three young children.”

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exclusive online contentCO V E R Gottlieb’s Short Tenure Will Be Felt Long After

He Leaves US FDA

B R E X I T

6 Goodbye To All That: EMA Leaves London After 24 years

7 UK Drug Pricing & IP Targeted As US Gears Up For Post-Brexit Trade Deal Talks

15 MHRA Reinforces Brexit Road-Map, Indian Firms Expect Tough Transition

N E W P R O D U C T S

9 EU CHMP Backs Three Conditional Approvals & Several Treatment Firsts

13 Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy Trial

R E G U L ATO RY U P D AT E

11 US FDA Expands Patient Input To New Area: Orphan Grant Applications

A D V I S O RY CO M M I T T E E S

17 Sanofi’s Dengvaxia: US FDA Panel Finds Pediatric Use More Acceptable Than Broader Target Population

19 Recent And Upcoming FDA Advisory Committee Meetings

inside: 17 6 7

Policy Reversal: FDA Will No Longer Require Suffixes For Older Biologicshttps://pink.pharmaintelligence.informa.com/PS124887

New US FDA draft guidance says that the agency will no longer change the proper names of originator biologics to include a four-letter suffix, although the agency will continue to attach suffixes to future approvals.

PMDA Chief Defends Japan Spinal Cord Therapy Approval https://pink.pharmaintelligence.informa.com/PS124882

The head of Japan’s drug and device regulator has defended and supported the country’s recent world-first decision to grant approval to a novel cell-based therapy for spinal cord injuries, saying that patient considerations came first.

Missed Opportunities: 10 Questions We Wish Senators Had Asked At The Drug Pricing Hearinghttps://pink.pharmaintelligence.informa.com/PS124889

Getting seven top pharma leaders in the same room, required to answer tough questions on drug pricing, is rare. Members of the Senate Finance Committee got that opportunity recently, but there are some questions our Pink Sheet reporters think they missed.

‘Extreme Outlier’ Vertex Slammed For Orkambi Pricing Approach In Englandhttps://pink.pharmaintelligence.informa.com/PS124884

Vertex has come under fire for its alleged extreme rigidity on pricing for its cystic fibrosis drug in England.

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4 | Pink Sheet | March 11, 2019 © Informa UK Ltd 2019

U S F D A

Better Reimbursement, Not ‘Kabuki’ Cover-age, Gottlieb Tells Insurers” - Pink Sheet, 7 Mar, 2018.)

His emphasis on creating generic com-petition was partially successful. The agency set a record for generic drug ap-provals in fiscal years 2017 and 2018, al-though critics argued that not nearly as many of those products were reaching the market. (Also see “US FDA Sets Generic Ap-proval Record, But Generic Sponsors Aren’t Celebrating” - Pink Sheet, 12 Oct, 2018.)

At the same time, the agency also ap-proved a record number of novel drugs in 2018, which for the first time comprised mostly orphan products. (Also see “Or-phan Drugs Compose Majority Of Novel US Approvals For First Time Ever In 2018” - Pink Sheet, 3 Jan, 2019.)

The Association for Accessible Medi-cines said in a statement that the generics and biosimilars industries “will miss this true champion of patient access.”

“Dr. Gottlieb set a high bar for those who are working to bring relief to Ameri-can patients from the burden of high drug costs,” the trade organization said. “Gottlieb understood that approvals were not enough to spur competition, and his leadership extended to improving mar-ket conditions to ensure these generic and biosimilar medicines would not be blocked by ‘shenanigans.’”

The Pharmaceutical Research and Manu-facturers of America also praised Gottlieb’s pricing mission, as well as his commitment to help new drugs reach the market.

“During his tenure, he focused on inno-vation in drug development and review, increased competition, and advanced the regulatory framework for approving novel technologies, including gene therapies,” the brand drug trade group said. “His ef-forts have made a meaningful impact for patients in need of innovative medicines.”

Gottlieb also oversaw several policy changes intent on fighting the opioid epi-demic, most recently calling for new trials assessing long-term opioid efficacy and new prescribing guidelines. (Also see “Long-Term Opioid Efficacy Studies Will Take Years, Gottlieb Says” - Pink Sheet, 28 Feb, 2019.)

AN INDEPENDENT COMMISSIONER During his tenure, Gottlieb was unafraid of bold pronouncements, whether about areas not under the purview of FDA (such as drug rebating) or public health areas where the agency has more of a role to play (two of his higher-profile statements in recent weeks have been support for raising the minimum age to purchase tobacco to 21 and suggest-ing the federal government could do more to mandate vaccinations).

Gottlieb’s independence earned admira-tion, said former FDA Principal Deputy Com-missioner Joshua Sharfstein.

Gottlieb “surprised many people by chart-ing his own course at FDA, focusing on sev-eral important topics for public health,” said Sharfstein, who now is vice dean for public health practice and community engage-ment at the Johns Hopkins Bloomberg School of Public Health. “These included the harms of nicotine and tobacco, the impor-tance of lowering drug prices through ge-neric competition, and the opioid epidemic.”

“FDA staff respected him for his commit-ment to the agency’s longstanding public health mission,” Sharfstein added.

Peter Pitts, president of the Center for Medicine in the Public Interest and former FDA associate commissioner for external re-lations, said Gottlieb “did the right thing,”

“He called it as he saw it,” Pitts said. “And that’s a rare commodity in Washington these days.”

A WHITE HOUSE FAVORITE Gottlieb also enjoyed unwavering public support from his boss, President Trump, an-other reason his departure was so surprising.

Trump tweeted that Gottlieb had done “an absolutely terrific job” as commission-er, adding that “his talents will be greatly missed.”

Myers said that Gottlieb cultivated a good relationship not just with Trump and the White House, but also with lawmakers on Capitol Hill, “which gave him the cred-ibility in those circles that he was going to do the right thing.”

Trump became especially enamored with Gottlieb during the 2018 World Economic Forum in Davos, Switzerland, calling him a “star.” (Also see “US FDA Commissioner A ‘Star’ At Davos: Hopefully Not A Bad Omen” - Pink Sheet, 29 Jan, 2018.)

Unfortunately for Gottlieb, Trump also placed him in charge of the administration’s efforts to pass right-to-try legislation, plac-ing him in the awkward position of shep-herding a bill that many agency officials and other stakeholders did not support. (Also see “Trump On Right-to-Try: Gottlieb’s ‘Heading It Up’?” - Pink Sheet, 2 Feb, 2018.)

Even as he worked to rein in what he saw as abusive brand tactics, Gottlieb also re-ceived criticism for his perceived deference to industry. (Also see “Gottlieb’s Confirmation: Will Industry Ties Remain A Big Deal After The Hearing?” - Pink Sheet, 3 Apr, 2017.)

Sid Wolfe, founder and senior advisor of Public Citizen’s Health Research Group, said Gottlieb brought a financial bias favoring the pharmaceutical industry to his role as commissioner.

Wolfe specifically criticized Gottlieb’s han-dling of the opioid crisis, particularly the agency’s decision to approve AcelRx Phar-maceuticals Inc.’s sublingual opioid Dsuvia (sufentanil). (Also see “Dsuvia Approval May Be Followed By New Opioid Review Paradigm At FDA” - Pink Sheet, 2 Nov, 2018.)

Wolfe and Raeford Brown, chairman of the Anesthetic and Analgesic Drug Prod-ucts Advisory Committee (AADPAC), also slammed the agency for not convening the full Drug Safety and Risk Management Advi-sory Committee as part of AADPAC’s review of the controversial product. (Also see “Pub-lic Citizen: US FDA Deliberately Excluded Risk

CONTINUED FROM COVER

Gottlieb was unafraid of bold pronouncements,

whether about areas not under the

purview of FDA (such as drug rebating) or public health topics (such as tobacco and

vaccinations).


U S F D A

Committee From Dsuvia Panel To Get Positive Vote” - Pink Sheet, 18 Oct, 2018.)

IS ABERNETHY NEXT? Until President Trump nominates a re-placement, Principal Deputy Commission-er Amy Abernethy may be in line to head the agency on an acting basis.

Abernethy, who joined FDA about a month ago from Roche subsidiary Flat-iron Health Inc., has little experience inside the agency but has worked with FDA in other roles. She is an oncologist and has worked at Duke University, which employs former commissioners Mark Mc-Clellan and Robert Califf. (Also see “Com-missioner Succession Plan? Abernethy As Gottlieb’s Number Two Offers One Option” - Pink Sheet, 17 Dec, 2018.)

Former Commissioner Margaret Ham-burg employed a similar strategy in hiring Califf as deputy commissioner for medi-cal products and tobacco. Hamburg an-nounced her departure a few weeks later and Califf soon was nominated for the per-manent position. (Also see “FDA Lands Cal-iff As Top Deputy, Potential Next Commis-sioner” - Pink Sheet, 2 Feb, 2015.)

Califf told the Pink Sheet that Gottlieb’s departure “will be a big loss for the country. Scott had the skills and did a great job of

meeting the mission of the FDA under difficult circumstances.”

A QUICK EXIT While Gottlieb’s succession pattern may follow Hamburg’s, his departure timing certainly doesn’t. Hamburg, President Barack Obama’s first FDA com-missioner, stayed for most of his presidency.

Indeed, most recent com-missioners have either left after a long tenure or due to a change in administration. Gottlieb would be the second-quickest voluntary departure in at least several decades.

Gottlieb hinted last year that his time at the agency may end sooner than expect-ed. He told a congressional committee in 2018 that he may to have less time as commissioner than initially thought. (Also see “US FDA Commissioner Gottlieb Sees His Job As A Race Against The Clock” - Pink Sheet, 23 May, 2018.)

And following the mid-term election, stakeholders began suggesting that Gott-lieb may consider leaving the agency since it is a natural departure time. (Also see “US FDA May Largely Avoid House Democrats’

Investigation Agenda” - Pink Sheet, 7 Nov, 2018.)

Former Commissioner Mark McClellan told the Pink Sheet that while it was clear Got-tlieb cared about FDA and its mission, “it’s an always-on and very demanding job, and especially hard with a young family elsewhere.”

McClellan, whom Gottlieb served under during his first stint at the agency, may have set the template for a quick exit. McClellan was commis-sioner for less than 17 months, although he left for another

post in the George W. Bush administration (CMS administrator) while Gottlieb hasn’t announced any future plans.

Still, multiple stakeholders were shocked when the news broke March 5. Former FDA Chief Counsel Peter Barton Hutt, who now is senior counsel at Covington and Burling, said the departure was a huge loss and that Gottlieb was a brilliant commissioner.

“I wish he’d change his mind,” Hutt told the Pink Sheet. “He reached out and took hold of every part of the agency.”

Published online March 5, 2019

CLICKRely on the Pink Sheet to keep up

with the impact of Gottlieb’s resignation and next steps. More coverage already available online

includes:

Gottlieb Wants His US FDA Team To Stay Together After

He Departshttps://bit.ly/2EUglSs

Historic Output Of Disease-Specific Guidances Is Among

Gottlieb’s Legacies At US https://bit.ly/2C4j8GP

Gottlieb Worries Vaccine Policy Could Spark Federalism Debate

https://bit.ly/2J0GPGd

Gottlieb’s Tenure As Commissioner Relatively Short

Among recent US FDA commissioners, Gottlieb’s approximately 23-month term will be the second-quickest voluntary departure, after Mark McClellan. The two commissioners with shorter tenures were involuntary departures: Robert Califf left at the end of the Obama administration, and Lester Crawford resigned due to ethics violations involving stock ownership.

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Goodbye To All That: EMA Leaves London After 24 yearsIAN SCHOFIELD [email protected]

A fter 24 years in the Canary Wharf area of London, the Euro-pean Medicines Agency officially moved to a new building in the Dutch capital, Amsterdam, on Friday March 1. The

EMA, which was established in London as the European Medicines Evaluation Agency (EMEA) in 1995, is having to relocate because of the UK’s impending departure from the EU on March 29.

There had been some debate as to whether the EMA could le-gally have remained in the UK once it was no longer an EU member state, but that would have been pretty much untenable for both political and practical reasons.

The relocation has been a huge upheaval for the agency, not only in terms of continuity of its regulatory work and the techni-cal implications of the move, but also because it expects to lose some 25% of its staff who either do not wish to or cannot follow the agency to the Netherlands. In collaboration with the Dutch government, the agency has established a relocation program to help staff who do wish to move to Amsterdam.

Things have been further complicated by the fact that no suit-able permanent premises were available to house the agency from March 29. Instead, it is occupying the Spark building in Amster-dam’s Sloterdijk business district, which will serve as a temporary HQ until construction of a new permanent building in the Zuidas area of the city is completed at the end of this year.

To help pharmaceutical companies familiarize themselves with the Spark building, the EMA has issued an “orientation guide” to the premises covering aspects such as travel connections, building facilities and key EMA services.

The eight-storey building has eight conference rooms, audiovi-sual, IT, teleconferencing and wi-fi facilities as well as a “small in-dustry lounge.”

TIME MAKES A DIFFERENCEOne change that could have implications for regulatory submis-sions, is that the EMA will be changing its time zone from Green-

wich Mean Time (GMT) to Central European Time (CET).During its period of “reduced virtual presence” from March 4

to March 8 inclusive, the EMA’s working hours will continue to follow GMT. Then, from March 11 onwards, its working hours will switch from GMT to CET, “reflecting EMA’s physical relocation from London to Amsterdam.” The agency also has to change its servers from GMT to CET to “re-state the time zone of EMA data,” and this will take place on March 29 at midnight GMT, “immedi-ately following Brexit.”

The EMA will consider regulatory submissions to have met a deadline of March 29 “if they filed on that date by 23:59 and 59 sec-onds GMT.” This includes submissions via the e-submission Gate-way and the EudraVigilance Gateway, it notes.

In order to reduce the risk of complications, the agency “will seek to avoid applying a deadline of midnight on 29 March 2019 in areas such as procurement, job vacancies and regulatory submissions.” If this is unavoidable, it will “individually consider any cases where a third party considers their submission to have been negatively im-pacted by EMA’s change of time zone. EMA will also take account of the impact of its change of time zone wherever a question regard-ing compliance with deadlines arises.”

Relocation of EMA staff to the Spark building is due to be final-ized by March 30. The new building in Zuidas is expected to be fully operational by Nov. 15, with staff relocation being complete by the end of December 2019.

CLOSING THE DOORS ON “THE LONDON YEARS”For its part, the EMA tweeted that it was “closing our London offices after almost a quarter of a century” and thanked London “for being such a gracious host”. It has put together a slide show illustrating what it refers to as “The London years”.

From the editors of Scrip Regulatory Affairs. Published online March 1, 2019

B R E X I T

The new building in Zuidas is expected to be fully operational by Nov. 15, with staff relocation being complete by the end of December 2019.



UK Drug Pricing & IP Targeted As US Gears Up For Post-Brexit Trade Deal Talks IAN SCHOFIELD [email protected]

T he US Trade Representative has formally released its nego-tiating objectives for a post-Brexit UK-US trade deal, saying the negotiations present an opportunity to address the tar-

iff and non-tariff barriers that have “challenged US exporters in key sectors while the UK has been a member state of the EU.”

One of the aims in the “Summary of Specific Negotiating Ob-jectives” is to seek provisions on intellectual property rights that “reflect a standard of protection similar to that found in US law,” including patents and the protection of undisclosed test and other data. The US also wants to see standards that ensure UK drug and medical device reimbursement procedures are “transparent” and “fair” and provide “full market access for US products.”

The release of the summary of objectives has prompted concern that the US will be able to use its greater negotiating power, and the perception that the UK is in a weaker position because of its need to sign new trade deals after Brexit, to secure advantageous terms in areas such as healthcare and agriculture, particularly in a no-deal scenario.

For example, it will be seeking changes that could dilute the gatekeeper function of the UK health technology assessment (HTA) body, the National Institute for Health and Care Excellence (NICE), which could result in the National Health Service paying more for new medicines. UK media reports have portrayed the effect of such changes as “potentially ending National Health Service con-trols on drug costs in favour of US-style direct-marketing of drugs.”

And while the UK government has said that EU legislation on patents and exceptions from patent infringement for studies, tests and trials conducted by generics firms will be retained in a no-deal scenario, there is likely to be strong US pressure for an increase in patent protections and the length of regulatory data protection (RDP) for biologics.

Michael Johnson, a former senior official at the UK Department of Trade and Industry, said in a blog on the Trade Knowledge Ex-change website: “Negotiating dynamics between the UK and US on regulation are unlikely to be balanced. The US market is five times that of the UK. The primary objective of American negotia-tors would be to ensure that UK regulations were more aligned to products and practices in the US. Given the relative size of the UK and the US it is hard to imagine that UK negotiators would have much success in changing American practices.”

In the introduction to the summary, the USTR says that, “as the first and fifth biggest global economies, the US economic relation-ship with the UK is one of the largest and most complex in the world, with annual two-way trade totaling more than $230bn.”

Despite this significant trade volume, though, “multiple tariff and non-tariff barriers have challenged US exporters in key sectors while the UK has been a member state of the EU and therefore a

part of the common trade policy of the EU. The UK’s decision to leave the EU creates a new opportunity to expand and deepen the US-UK trade relationship,” the USTR says.

While the summary does not go into detail on exactly what the US is seeking from a future trade deal, the various industry sectors, including pharmaceuticals, already laid out their own wish-lists in the form of submissions to the USTR in advance of a public hearing at the end of January. (Also see “PhRMA Muscles In With Post-Brexit Trade Deal Wish List” - Pink Sheet, 1 Feb, 2019.) The hearing was partly based on written responses to a consultation on the draft negotiating objectives issued in November last year.

The objectives were fleshed out by US industry representatives at the hearing, including Matthew O’Mara of the Biotechnology Innovation Organization, Brian Toohey of the Pharmaceutical Re-search and Manufacturers of America (PhRMA), and Jeffrey Francer of the Association for Accessible Medicines (representing generic and biosimilar drug companies). A transcript of the hearing has just been published along with the summary of negotiating objectives.

Toohey said in his evidence that while the US and the UK both offer “strong IP protections”, the US should seek “IP protections that meet the highest global standards, including at least 12 years of regulatory data protection for biologics.”

The UK, as part of the EU regulatory network, currently offers 10 years of RDP (eight years of data exclusivity plus two years of mar-ket protection) for all pharmaceutical products including biologics.

T R A D E P O L I C Y

“ The US should seek IP protections that meet the highest global standards, including at least 12 years of regulatory data protection for biologics” – Brian Toohey, PhRMA




The US has introduced a 12-year RDP period for biologics, although the recently concluded US-Mexico-Canada trade deal (USMCA) of-fers a minimum 10-year period.

The US could “establish a significant precedent for other future agreements, and help pave the way for the next generation of treatments and cures,” Toohey declared. “We think this is a real op-portunity to create a new standard in intellectual property.”

The AAM’s Francer disagreed, saying that free trade agreements had to “foster a stronger generic and biosimilar industry to provide savings for patients here in the US.” The AAM, he told the hearing, “supports provisions in US trade agreements that deliver on the TPA [Trade Promotion Authority] mandate to ensure that IP rights foster innovation and promote access to medicines. Any trade agreement reached with the UK must maintain this careful bal-ance, which is also reflected conceptually in current US law.”

He said the association opposed the inclusion of IP provisions that “extend monopoly protection for branded pharmaceuticals, such as longer pharmaceutical data exclusivity periods or man-dates to extend a patent term based on delays in granting the pat-ent or obtaining marketing approval.”

The AAM “would also like to note that the US and UK already have strong protection of pharmaceutical IP and strong engines for innovation under existing provisions. Thus, it’s unclear whether there needs to be a pharma-specific IP chapter” in the US-UK agree-ment, according to Francer.

However, if there is an IP chapter, the AAM would like it to in-clude provisions to “facilitate the timely development of and pa-tient access to generic and biosimilar medicines in the US and the UK. These features are outlined in more detail in our written sub-mission and include a clear and robust regulatory review, or Bolar period; an incentive for promoting generic and biosimilar competi-tion as exists in current statute in the US; and requirements to dis-close the best mode for carrying out a new invention, also required by Congress here in the US,” he declared.

PRICING & REIMBURSEMENTThe US brand industry also wants changes to the way that the UK determines pricing of and access to new medicines.

In its submission to the USTR, PhRMA had roundly condemned the UK’s market access policies, claiming they were characterized by “rigid health technology assessments (HTA), government price controls, insufficient health care budgets, and increasingly punitive and proactive national procurement initiatives and local barriers to uptake.” It specifically attacked the methodology used by NICE to evaluate medicines for use on the NHS, saying it was a “blunt

cost-containment tool” that delayed patient access to medicines – something NICE vehemently rejected. (Also see “UK’s NICE Rejects US Industry Attack On Its HTA Methods” - Pink Sheet, 12 Feb, 2019.)

Taking this a step further, Toohey told the hearing that the UK government was a “primary payer” for medicines “and, in effect, dictates prices.” This “dominant position,” he declared, “often results in the UK failing to appropriately recognize the value of innovation in its pricing reimbursement systems, and, instead, engage in ac-tions that distort markets and artificially depress prices.”

He said the UK’s HTA system “significantly undervalues innova-tive medicines and restricts patient access to those medicines, in terms of overall access to the market, but also in terms of how they can be used. Many medicines that are standard of care in the Unit-ed States are third or fourth line as a result of a very restrictive qual-ity-based system that’s operated in the UK. PhRMA believes that medicines should be priced “either through a market-based sys-tem… or some type of equivalent system that can be developed.”

For Tooley, the negotiations provide “an important opportunity, consistent with TPA, to ensure government reimbursement re-gimes are transparent, non-discriminatory, and provide procedural fairness and full market access for US products, which includes the setting of reimbursement amount on competitive market-derived pricing, or an equivalent process, such as one that appropriately recognized the value of an innovative product.”

He said that PhRMA would like existing agreements, most no-tably the US-Korea deal, to “form the basis for the market access commitments in any US-UK agreement.”

More generally, BIO’s O’Mara said it was “extremely important that a path forward is found to ensure that there’s a clean exit from Europe.” However, he said that in regulatory terms it was “critical to avoid a no-deal scenario” because complicated supply chains, regulatory process, and international cooperation would be nega-tively impacted if the UK underwent a disorderly exit.

BIO strongly supports close regulatory cooperation, and would like to see US-UK collaboration “modeled on what has been achieved with Europe, including quickly re-establishing an MRA [mutual recognition agreement] on good manufacturing practic-es,” O’Mara added.


T R A D E P O L I C Y

“ Free trade agreements must foster a stronger generic and biosimilar industry to provide savings for patients” – Jeffrey Francer, AAM

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EU CHMP Backs Three Conditional Approvals & Several Treatment FirstsIAN SCHOFIELD [email protected]

A t its final monthly meeting in London, the European Medicines Agency’s drug evaluation com-

mittee, the CHMP, gave the all-clear to all eight of the new drugs that were up for an opinion on EU marketing approval.

They included treatments for rare dis-eases with no available therapies, while three products were recommended for a conditional marketing authorization (CMA), meaning the companies will have to provide more data once they are approved.

Among the products recommended by the committee was Akcea’s Waylivra (volanesorsen), for treating familial chy-lomicronemia syndrome (FCS), a rare con-dition for which there is no authorized treatment available. The product failed to secure approval in the US last year.

Other products green-lighted were Portola’s Ondexxya (andexanet alfa) for reversing the effects of anticoagulation drugs, BioMarin’s Palynziq (pegvaliase) for phenylketonuria (PKU), and AbbVie’s Sky-rizi (risankizumab) for psoriasis – Skyrizi’s EU approval within the coming months could be a world first.

Also cleared were Sanofi/Lexicon’s anti-diabetic Zynquista (sotagliflozin), Pfizer’s Lorviqua (lorlatinib) for NSCLC, GlaxoS-mithKline’s Dectova (zanamivir) for influ-enza, and a generic paclitaxel product from Teva for breast and lung cancer.

AKCEA’S WAYLIVRAIf approved by the European Commission, Akcea Therapeutics Inc.’s Waylivra will be the first product to become available for the treatment of FCS.

The CHMP’s positive opinion for a con-ditional marketing authorization is a wel-come boost for Akcea after the Food and Drug Administration rejected the drug last August. The US agency decided not to ap-prove the drug because of concerns over its efficacy, even though its advisory com-mittee recommended approval by 12-8. (Also see “2018 Complete Response Letters: Efficacy Issues Drove Most Product Rejec-tions” - Pink Sheet, 9 Jan, 2019.)

Akcea said the positive opinion was “a testament to the European Regulatory Authorities’ commitment to facilitating ac-cess to innovative medicines for patients in need,” adding that it was “working to con-

firm a path forward for Waylivra in the US and in Canada.”

The EU marketing authorization appli-cation was the subject of four sets of out-standing issues from the CHMP over the course of 2018, suggesting the committee was looking very closely at the application. As part of the CMA, Akcea and its partner Ionis will be required to conduct a non-interventional post-authorization safety study (PASS) based on a registry.

FCS is an ultra-rare disease caused by impaired function of the lipoprotein lipase (LPL) enzyme and is characterized by se-vere hypertriglyceridemia. Patients with the condition can develop potential fatal acute pancreatitis and experience symp-toms like abdominal pain, fatigue and im-paired cognition.

Waylivra works by reducing the produc-tion of ApoC-III, a protein produced in the liver that plays a central role in the regula-tion of plasma triglycerides and may also affect other metabolic parameters.

ONDEXXYAPortola Pharmaceuticals Inc.’s On-dexxya (andexanet alfa), which has also been recommended for a CMA, is the first specific antidote for reversal of the anticoagulant effects of the factor Xa inhibitors, apixaban and rivaroxaban, in patients experiencing uncontrolled or life-threatening bleeding. The company said a marketing authorization decision was expected in early May.

“Given the number of patients cur-rently taking Factor Xa inhibitors and the anticipated growth of their utilization in Europe, the medical community has been eagerly awaiting the availability of an antidote that, in case of emergencies, can rapidly reverse the anticoagulating effects of rivaroxaban or apixaban,” said Jan Beyer-Westendorf, head of throm-bosis research at the University Hospital Dresden, Germany.





Portola said the submission was based on data from two Phase III ANNEXA stud-ies looking at the product’s safety and efficacy, as well as adjudicated data from patients enrolled in the ANNEXA-4 Phase 3b/4 study, results of which were pub-lished in February.

“Given the consistency of the AN-NEXA-4 data and the significant unmet need for a Factor Xa inhibitor reversal agent, we believe Ondexxya has the po-tential to benefit thousands of patients and we look forward to the opportunity to expand patient access in Europe this year,” said the firm’s president and CEO, Scott Garland.

As part of the EU conditional approval process, Portola is required to provide final study reports for the ANNEXA-4 trial and a randomized controlled trial re-quested by the FDA, as well as additional pharmacokinetic data, the company said. The product was approved in May 2018 in the US, where it is marketed as Andexxa.

PALYNZIQBioMarin Pharmaceutical Inc.’s orphan drug Palynziq has been OKd by the CHMP for reducing blood phenylalanine (Phe) concentrations in PKU patients aged 16 and over who have inadequate Phe control despite prior use of other treatments. Bio-Marin said the CHMP had noted that data collected in the pivotal Phase 3 PRISM-2 trial and an ongoing open-label extension study were “suggestive of an improvement in inattention and mood symptoms.”

On its approval in the US in May last year, Palynziq became the first available enzyme substitution therapy to target the underlying cause of PKU, the company added. Hank Fuchs, president, worldwide research and development at BioMarin, said the product was “an important step forward in advancing the standard of care and in broadening available treatment op-tions for PKU patients.”

PKU is a rare genetic disease that mani-fests at birth and results in a variety of cu-mulative toxic effects on the brain, and is marked by an inability to break down Phe, an amino acid found in all forms of protein. Some 18,000 patients aged 16 and older are affected by PKU in Europe and the Mid-

dle East. Left untreated, high levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychiatric-related issues, the company noted.

FIRST FOR SKYRIZI?AbbVie Inc.’s risankizumab (Skyrizi) is a first-in-class humanized immunoglobulin monoclonal antibody designed to selec-tively inhibit IL-23 by binding to its p19 subunit. Indicated for moderate to severe plaque psoriasis, it is seen as a follow-up to the company’s blockbuster drug Humira (adalimumab), which has lost patent pro-tection in Europe and is facing biosimilar competition in the US from 2023.

AbbVie said Skyrizi is “under review with health authorities globally and is currently not approved by regulatory authorities.” That means that if the CHMP’s positive opinion is confirmed by the European Commission in a couple of months, it could be the product’s first approval worldwide – although the product has a PDUFA action date of April 25 in the US, so it could be a close race.

The EU filing for Skyrizi was supported by data from AbbVie’s global Phase 3 clini-cal program involving more than 2,000 pa-tients across four pivotal Phase 3 studies.

ZYNQUISTASanofi/Lexicon Pharmaceuticals Inc.’s Zynquista (sotagliflozin), a small molecule with dual inhibition activity on SGLT1 and

SGLT2, has been OKd as an adjunct to insu-lin to improve glycaemic control in adults with type 1 diabetes mellitus who have failed to achieve adequate glycaemic con-trol despite optimal insulin therapy.

The CHMP’s opinion was based on data from three Phase 3 studies including 1,853 patients with type 1 diabetes mellitus, according to the committee, which said the main benefit of treatment with sota-gliflozin diabetes was its ability to improve glycaemic control. Other effects include weight and blood pressure reductions and reduced variability of glucose levels.

However, the CHMP cautioned that despite precautionary measures during treatment with sotagliflozin, there was “a considerable increase in the risk of dia-betic ketoacidosis (DKA), a potentially life-threatening complication.” Therefore it said that treatment should only be considered in overweight or obese patients with a BMI higher than 27kg/m2 and that its use was not recommended in type 1 diabetes mellitus patients with low insulin require-ments. “During treatment with Zynquista, insulin therapy should be continuously optimised to prevent ketosis and DKA and the insulin dose should only be reduced to avoid hypoglycaemia.”

DECTOVAGlaxoSmithKline PLC’s Dectova (zana-mivir), which the CHMP has recom-mended for use in complicated and po-tentially life-threatening influenza A or B infection in adults and children over six months of age, is a new infusion solution form of zanamivir, which the company already markets in inhalation form as Relenza. The product was submitted for an “exceptional circumstances” approval, the company noted.

The committee said Dectova’s ben-efits were its “ability to speed resolution of clinical signs and recovery in patients with complicated and potentially life-threatening influenza” and that the most common side-effects were diarrhea, he-patic transaminase elevations, hepato-cellular injury, and rash.

The company declined to give any more information about its filing and launch strategy for the product, which is

AbbVie’s Skyrizi is a first-in-

class humanized immunoglobulin

monoclonal antibody that is seen as a follow-up to the

company’s blockbuster Humira.



not thought to have been approved by any other regulatory authority, or about the commercial relevance of the product to GSK.

LORVIQUALorviqua (lorlatinib), Pfizer Inc.’s ana-plastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has also been recommended for a CMA. It is intended for use in patients with ALK-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after alectinib or ceritinib as the first ALK TKI therapy, or crizotinib and at least one other ALK TKI.

Conversion to a standard marketing authorization would be contingent on the company providing comprehensive data showing that the product’s bene-fit-risk balance is positive, Pfizer noted.

It said the MAA was based on results from a non-randomized, dose-ranging and activity-estimating, multi-cohort, multi-center Phase 1/2 study, B7461001, which enrolled a total of 229 patients with ALK-positive metastatic NSCLC across various subgroups based on prior treatment. The product is already approved as Lorbrena in the US, where it received an accelerated approval.

GENERIC PACLITAXELTeva Pharmaceutical Industries Ltd.’s Pazenir, previously known as Paclitaxel Teva Pharma, is a nanoparticle formula-tion of paclitaxel for metastatic breast cancer and NSCLC. It is a generic ver-sion of Abraxane, another nanoparticle albumin-bound paclitaxel product that has been approved in the EU since 2008.

“Studies have demonstrated the sat-isfactory quality of Pazenir,” the CHMP said, adding that a bioequivalence study was not required. This is because the product is administered intrave-nously and the nanoparticles dissoci-ate rapidly, and “also because of the qualitative and quantitative composi-tions and the nature and behaviour of the products.”


US FDA EXPANDS PATIENT INPUT TO NEW AREA: Orphan Grant Applications DERRICK GINGERY [email protected]

O utside experts will help the US FDA’s Office of Orphan Products Development review grant applications and patient views will be given to the grant review staff to incorporate into decisions. Both should offer the rare disease commu-

nity more power over trial designs and FDA’s orphan drug research agenda.OOPD Director Janet Maynard and FDA Patient Affairs Staff Director Andrea Furia-

Helms said in a Feb. 28 blog post celebrating Rare Disease Day that the additional pa-tient input will help the agency shift the grant programs to prioritize more innovative and efficient trial designs and features, such as adaptive and seamless trials and basket and umbrella studies looking at multiple rare diseases and products. Grantees also are encouraged to use modeling and simulations and real-world data, they wrote.

OOPD administers the orphan products grants programs, which give awards intended to encourage development of new medical products for rare diseases. The program in-cludes clinical trial and natural history study grants, as well as the pediatric device con-sortia grants program.

In 2018, OOPD gave more than $15m in grants supporting about 60 ongoing and 12 new clinical trials. Another $2m in grants funded ongoing natural history studies and the Center for Devices and Radiological Health gave $6m in pediatric device consortia grants, according to the blog post.

The agency signed a memorandum of understanding with the National Organization for Rare Disorders in 2018, allowing the two to collaborate on workshops, training and listening sessions, where patients could relay their experience to FDA staff. The goal of the project is to increase agency understanding of various rare diseases. (Also see “US FDA/NORD Partnership Will Further Increase Patient Involvement In Drug Development” - Pink Sheet, 27 Feb, 2018.)

FDA said grant reviewers are receiving summaries of the listening sessions as well as Voice of the Patient reports, which are the final product of each patient-focused drug development meeting conducted over the past several years.

“OOPD expects this information to be useful when preparing critiques related to pa-tient input, feasibility and study impact,” the agency told the Pink Sheet. “Although not all diseases will be represented, issues that were brought up by patients and others at these patient focused initiatives may be of use in their assessments by providing more aware-ness of these perspectives.”

FDA also has implemented “revised review criteria specific to the goals” of the orphan grants program. The agency told the Pink Sheet that scoring criteria for the natural his-tory grant program was simplified and increased focus on incorporating “patient input and infrastructure.”

Maynard and Helms wrote in the blog post that the first Orphan Products Grants Inter-nal Review Committee was established and includes agency regulatory and rare disease experts, as well as external rare disease experts, who will “determine the likelihood for the project to exert a sustained, powerful influence on the research fields involved.”

FDA said the experts that peer review applications include clinicians and academics in the subject area.

Maynard became acting OOPD director in October after a year of leadership chang-es. She was named the permanent director on Feb. 17. Capt. Nicole Wolanski also was named permanent deputy director after a stint in the acting role. (Also see “US FDA Ap-points Another Orphan Products Development Office Head Amid Growth Expectations” - Pink Sheet, 15 Oct, 2018.)

R E G U L AT O R Y U P D AT E




R E G U L AT O R Y U P D AT E

THE LATEST IN FDA’S PATIENT-FOCUSED EFFORTS Patient influence on the grant process is the latest evolution of FDA’s effort to include patient input in its activities.

FDA began its patient-focused drug development initiative as part of the 2012 prescription drug user fee renewal. The agency hosted several disease-focused meetings for patients and advocates to give insights on treatments and unmet needs. (Also see “FDA Ends Regu-larly Scheduled Patient-Focused Drug Development Meetings” - Pink Sheet, 28 Sep, 2017.) Many patient groups also conducted their own meetings using a similar format to provide more rare disease infor-mation to the agency. (Also see “FDA’s Patient-Focused Drug Develop-ment Meetings Inspire Imitators” - Pink Sheet, 19 May, 2014.)

The PDUFA VI agreement with industry also required integration of FDA rare disease staff into the review divisions to ensure more con-sistent application of the agency’s flexible review approach. (Also see “Rare Disease Integration Into FDA Reviews Will Grow Under PDUFA VI” - Pink Sheet, 18 Jul, 2016.)

At the same time, FDA and industry are working to systematically collect patient data so it may be used in regulatory decision-mak-ing. (Also see “From Listening To Advising: The Maturation Of US FDA’s Patient-Focused Drug Development Program” - Pink Sheet, 8 Jan, 2018.)

SHIFT TO NOVEL TRIAL DESIGNS REFLECTS WOODCOCK’S VISION OOPD’s shift of the grant program focus on master protocol and other trial designs appears to mirror Center for Drug Evaluation and Research Director Janet Woodcock’s oft-repeated clinical trial reform message.

Woodcock has implored industry and other stakeholders to adopt master protocol and basket designs, as well as use real-world data, to streamline the drug development process. (Also see “Master Protocols Are Both Welcome And Inevitable – US FDA’s Wood-

cock” - Pink Sheet, 6 Jul, 2017.)Woodcock also has said that an overhaul of the clinical trial sys-

tem is necessary to help lower development costs. (Also see “Re-liance On ‘Digitized Paper’ Is Slowing Drug Development – US FDA’s Woodcock” - Pink Sheet, 14 Nov, 2018.)

MEETING ON RARE DISEASE ‘COMMONALITIES’ SCHEDULED FDA also plans another public meeting to gather patient perspec-tives on rare diseases, this time in search of common ground to help drug development.

The April 29 meeting at FDA’s White Oak headquarters will solicit patient and caregiver opinions on the impact of rare diseases on daily life and “assess commonalities that may help the agency and medical product developers further understand and advance” drug develop-ment, according to a Federal Register notice announcing the event.

FDA wants to find “common issues and symptoms” in rare diseases that could help create novel trial endpoints or designs that can focus on a variety of rare diseases.

The meeting is open to any patient with a rare disease and their caregivers. Agency officials want to hear about disease symptoms, treatment considerations, and factors relevant to participating in a clinical study or registry, according to the notice. Written comments also may be submitted to the docket.

The agency already is encouraging development of clinical out-come assessments that include patient-, clinician- and observer-reported outcomes, which may be applied across multiple dis-eases. (Also see “US FDA Targets Migraine, Schizophrenia And Opioid Sparing Drugs For Clinical Outcome Assessment Development” - Pink Sheet, 25 Feb, 2019.)


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Janssen’s Spravato Enters US Market With Enhanced REMS And Plans For A Monotherapy TrialSUE SUTTER [email protected]

The US FDA approved Janssen R&D LLC’s antidepressant Spravato (esketamine) March 5 with an enhanced Risk Eval-uation and Mitigation Strategy (REMS) but also a postmar-

keting commitment for a monotherapy study that the agency itself has suggested would be difficult to conduct.

Esketamine nasal spray is indicated for use in conjunction with an oral antidepressant for treatment-resistant depression in adults. The FDA action marks the first US approval for esketamine and the first drug approval for treatment-resistant depression in 10 years.

Esketamine is not a new molecular entity but, rather, an enantio-mer of ketamine, an approved drug that is used off-label intrave-nously and intranasally to treat depression. Ketamine is also recre-ationally abused for its dissociative effects.

The approval came one day after the drug’s priority review user fee goal date of March 4. Esketamine also received breakthrough therapy designation based on the potential for rapid treatment.

The approval aligns with an FDA advisory committee’s endorse-ment, with 14 of 17 panelists concluding at a Feb. 12 meeting that the drug’s benefits outweighed its risks.

Labeling includes a boxed warning on the risks of sedation and dissociation, and the potential for abuse and misuse. It also in-cludes the antidepressant class warning on suicidality.

‘LONG-STANDING NEED’ FOR NEW TREATMENTSThe only other drug approved for treatment-resistant depression is Eli Lilly & Co.’s Symbyax (olanzapine/fluoxetine), which added the indication in 2009.

“There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition,” said Tiffany Farchione, acting director of FDA’s Division of Psychiatry Products.

“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug ap-proval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment,” Farchione said. “Because of safety concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the healthcare provider can monitor the patient.”

Prescribing and distribution will be limited under a restrictive REMS with elements to assure safe use, and the risk manage-ment program must be fully operational before Spravato is in-troduced into interstate commerce, FDA’s approval letter states.

Janssen said it expects to launch esketamine around March 18, and the company is working quickly to educate and certify treatment centers under the REMS. “We are exploring several ways to educate and certify additional treatment centers over time, including maximizing access for patients across the coun-try,” Janssen told the Pink Sheet. “Our hope is to have hundreds of centers open within the first year across the country.”

A product website, www.Spravato.com, will include a tool for locating certified healthcare facilities.

Importantly, launch will not be held up by the need for con-trolled substance scheduling. Esketamine is a Schedule III drug because the Drug Enforcement Agency placed ketamine and all of its salts, isomers, and salts of isomers into Schedule III of the Controlled Substances Act in 1999, Janssen said.

Spravato’s wholesale acquisition cost will range from $4,720-$6,785 for the one-month induction phase, to $2,360–$3,540 for monthly maintenance therapy, Janssen said, noting that these estimates do not include the costs for administration and monitoring required under the REMS.

Janssen is manufacturing Spravato in anticipation of a US roll-out starting in mid-March.

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Janssen hopes to have hundreds of REMS-certified Spravato treatment centers

open across the country within a year.



www.Spravato.com



REQUIREMENTS FOR CERTIFIED HEALTHCARE FACILITIESJanssen had proposed a REMS that would limit esketamine distri-bution and dispensing to certified hospitals, pharmacies and out-patient care centers and ensure the drug is not dispensed for pa-tients to use at home. Certified facilities would be required to have procedures in place to monitor patients when they self-administer esketamine for transient dissociative and blood pressure changes until the individual is stable and ready to leave the healthcare set-ting based on clinical judgment. (Also see “Janssen’s Esketamine: US FDA Panel To Weigh Efficacy, REMS Restrictions For Treatment-Resistant Depression” - Pink Sheet, 10 Feb, 2019.)

However, FDA said that patients should be monitored for se-dation, dissociation and blood pressure changes for at least two hours after dosing and should not drive or operate heavy machin-ery for the rest of the day. The agency also pushed for a manda-tory patient registry to better characterize the drug’s risks. The final REMS reflects FDA’s preferences.

Members of FDA’s Psychopharmacologic Drugs Advisory Com-mittee and Drug Safety and Risk Management Advisory Committee supported these enhancements but also sought greater specificity on the types of healthcare facilities that could be certified under the REMS due to concerns about the development of the esketamine equivalent of opioid “pill mills.” (Also see “Janssen’s Esketamine Needs

Better Defined REMS, US FDA Panel Says” - Pink Sheet, 12 Feb, 2019.)The approved REMS does not specifically provide a definition of

a certified healthcare facility but rather the requirements for certi-fication, FDA said.

The Spravato REMS Healthcare Setting Enrollment Form requires that facilities have a prescriber onsite during esketamine adminis-tration and monitoring, and that a healthcare provider be on site to monitor each patient for at least two hours following administration for resolution of sedation and dissociation, and changes in vital signs.

Certified facilities must train all relevant staff involved in pre-scribing, dispensing and administering the drug and establish processes and procedures to ensure that the following take place in the healthcare setting:

• A healthcare provider counsels the patient on the need for enrollment, monitoring, and risks of sedation and dissociation, and changes in vital signs prior to receiving Spravato;

• All patients are enrolled in the Spravato REMS by completing and submitting the Patient Enrollment Form;

• Verify the patient is enrolled in the REMS before dispensing Spravato for patient self-administration;

• The patient self-administers Spravato under the direct supervi-sion of a healthcare provider;

• A healthcare provider monitors every patient for at least two hours for resolution of sedation and dissociation and changes in vital signs after every dose;

• A Patient Monitoring Form is submitted to the Spravato REMS for every patient within seven calendar days following ad-ministration of every dose; and

• Spravato is not dispensed for use outside the healthcare setting.

SIMPLIFIED PACKAGING PRESENTATIONJanssen simplified the drug’s packaging presentation from its origi-nal proposal.

Each nasal spray device delivers two sprays containing a total of 28 mg esketamine. During the first four weeks of treatment, the recommended dose is 56 mg (two bottles) or 84 mg (three bottles) twice a week, followed by maintenance doses of 56 mg or 84 mg once a week or every two weeks.

Janssen had proposed a 28 mg starting dose in patients ages 65 years and older, but that dosing recommendation is not included in labeling.

The company also had proposed to supply esketamine in car-tons containing one, two or three devices. However, FDA said the proposed packaging could lead to confusion and medication er-rors, concerns that were echoed by some advisory committee members. FDA suggested a single packaging configuration with one device.

However, FDA and Janssen ultimately settled for two packag-ing presentations comprising two or three nasal spray devices and doing away with the single device package presentation.

MONOTHERAPY STUDY COMMITMENTLabeling includes clinical efficacy data from two positive stud-ies: a short-term, randomized, placebo-controlled trial and a ran-domized withdrawal, maintenance-of-effect study. The approval marks the first time Division of Psychiatry Products has consid-ered a randomized withdrawal trial as one of the two adequate and well-controlled trials needed to demonstrate substantial evi-dence of effectiveness.

Janssen’s Phase III program included initiation of a new oral an-tidepressant as background therapy in both the esketamine and placebo vehicle arms because FDA concluded it would not be ap-propriate to study the drug as monotherapy in a randomized trial of treatment-resistant depression patients who had already failed at least two prior antidepressants.

At the advisory committee meeting, Farchione said that since the target patient population is seriously ill and failed a number of treatments, it would be hard for the agency to stomach the idea

FDA’s Division of Psychiatry Products must agree to Janssen’s monotherapy study design before

the trial begins.



of having patients in a randomized trial in which they receive no active treatment. Having all subjects start on a new antidepressant seemed like a good way to deal with that concern, especially given that one would not expect to see much effect from an oral antide-pressant in the first few weeks of a study, she said.

However, advisory committee members urged Janssen to con-duct a monotherapy trial because the drug is likely to be used that way in the real world by patients who have failed multiple oral antidepressants. They also raised concerns that labeling the drug only for concomitant use with an oral antidepressant would limit reimbursement. (Also see “Janssen’s Esketamine Gets US FDA Panel Endorsement, But With Pricing, Access And Diversion Concerns” - Scrip, 14 Feb, 2019.)

FDA’s approval letter includes a postmarketing commitment for Janssen to study esketamine’s efficacy as monotherapy in treatment-resistant depression. “The study design must be agreed to by the division prior to initiating the study,” the letter states. A final study protocol is due in September, with study completion targeted for March 2022.

Janssen said that when a draft protocol for the monotherapy study is developed, the company will seek input from the FDA, in-stitutional review boards, principal investigators and other experts. “We are always committed to working in the most ethical manner possible while exploring clinical trial design and research, and we

understand fully the challenges in doing clinical research of this nature,” the company said.

“There are a number of potential study designs that could ad-dress this question,” FDA told the Pink Sheet. “We intend to engage in further discussion with the applicant on the design of the study. For it to fulfill the PMC, we have to agree on the final protocol.”

The approval also includes two postmarketing study requirements:

• A three-year, open-label safety study to characterize the long-term effects of esketamine on cognitive function and urinary symptoms (ongoing trial TRD 3008 will be adapted to meet this requirement); and

• Analysis of bloodbank samples from patents who participated in two Phase IIII studies to further characterize the potential risk of increasing thyroid stimulating hormone levels.

FDA’s near-miss of the user fee goal date for esketamine may have resulted, in part, from the five-week partial government shut-down that began in late December.

The shutdown delayed formal announcement of the advisory committee meeting in the Federal Register, and Farchione told the panel the meeting “almost didn’t happen.”


B R E X I T

MHRA Reinforces Brexit Road-Map, Indian Firms Expect Tough Transition

ANJU GHANGURDE [email protected]

T he UK Medicines and Healthcare Products Regula-tory Agency (MHRA) underlined at a recent conference in Mumbai, India, a range of revised regulatory requirements

and its ongoing preparedness to ensure a smooth transition after March 29, when the UK is due to exit the EU. Indian firms, however, anticipate a number of near-term challenges.

A significant part of preparation underway at the MHRA is cur-rently geared towards ensuring that the UK is ready for a “no-deal” Brexit, in case that happens. Revised legislation, a raft of detailed technical guidance – estimated to be of the order of around 50 dif-ferent pieces of guidance across the sectors that the MHRA regu-lates – and a new IT system are being readied ahead of the planned exit on March 29.

Any changes in legislation are intended to “untangle” the UK’s leg-islation from the European network to ensure that the UK legislation functions without any reliance on European directives, the MHRA in-dicated at the recently concluded India Pharmaceutical Forum.

In a presentation at the meeting, David Churchward, expert GMDP inspector at the MHRA, highlighted a range of key changes

in store for industry including in areas such as market authoriza-tions (MAs) as well as plans to provide new MA assessment proce-dures – namely ‘targeted, accelerated and rolling’ - alongside the existing national licensing route in the event of a no-deal Brexit.

Churchward explained that the new norms would require a marketing authorization holder (MAH) for a UK MA to be located in the UK; currently the holder of a UK MA may be based any-where within the EU.

In a no-deal scenario “we will continue to accept an MAH locat-ed in the EU until the end of 2020 but there must be a UK point of contact and that may be a legal representative, a consultant per-haps on behalf of that European MAH; they must be located in the UK and registered with us within four weeks of exit,” Churchward told a packed house on Feb. 28.

MA ASSESSMENT PROCEDURESGoing forward the MHRA also expects to provide new MA assess-ment procedures for products containing new active substances and biosimilars alongside the current national licensing route in a




no-deal scenario. Churchward explained to delegates that

under a new targeted process for a product with a new active substance or a biosimilar that has been submitted to the EMA and re-ceived a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), the UK reg-ulator will assess that data within 67 days of submission of the UK application.

For the accelerated authorization program, the MHRA will aim to complete the assess-ment within 150 days while the ‘rolling re-view’ for new active substances and biosimi-lars, will allow firms to make an application in stages during the product’s development.

“We will assess that data as you develop the product, so it reduces your regulatory risk and also enables you to get products to market more quickly,” he added.

For active substances manufactured in the UK, post-exit, the UK will be a third country to the EU and will need to provide a written confirmation of GMP compliance for impor-tation to the EU, just as others like the Indian government are required to for active sub-stances manufactured in India, Churchward explained. Around 30% of APIs sold in the EU come from India.

Churchward also outlined the UK regula-tor’s plans for readying its own IT systems. The UK currently uses a number of European IT systems such as the EudraGMDP, but a no-deal Brexit would cut off access to those sys-tems. The new UK IT systems are expected to be ready by March 29 to enable the MHRA interact with industry, Churchward said.

“So we will have a UK national replacement for the EudraGMDP data base as one example,” he added.

SHORT-TERM CHALLENGESSome leading Indian firms with operations in Europe, however, anticipate challenges, at least in the initial period after Brexit.

“It’s a huge exercise and will slow things down and many of us will struggle to ensure consistent supplies. In the near-term Eu-rope [business] will be challenging,” the CEO of a frontline Indian firm told the Pink Sheet.

The regulatory head of another Indian firm said that while most companies have been gearing up to handle Brexit-related changes, the burden of duplication and add-on work cannot be wished away.

“Wherever our MA has the UK as a RMS [reference member state] , I have now to identify a new RMS in the EU,” the official cited as an example.

The official also noted that the UK was, in general, the “driver” at the EMA in terms of scientific advice and related aspects, but that would no longer hold.

“Now if we want to go for scientific advice, we’d probably have to go to Germany or some other European nation,” the official not-ed, adding that the task on hand was “huge” but things should settle in due course. (Also see “Goodbye To All That: EMA Leaves London After 24 years” - Pink Sheet, 1 Mar, 2019.)

A leading Indian firm with operations in Eu-rope told the Pink Sheet that with Brexit, com-panies will need to establish “two separate quality and regulatory systems”, one for the EU and one for the UK, but added that fortunately the company has a “robust affiliate” in each re-gion and already has strong QP and regulatory functions within each affiliate.

The company claims to have made the tran-sitions that will be required for Brexit; how-ever, it admits that Brexit has had an impact in “redistributing” various activities within its German and UK affiliates as well as an overall impact on increased UK QP focus, transition-ing all decentralized procedures where UK was a Concerned Member State (CMS) into national registrations, with the UK as MAH and dedicated QP and regulatory resources to manage the separation.

“Because of the specific situation of the company having an affiliate in the UK and in the EU [Germany], the Brexit require-ments may be less daunting than a com-pany not having such dual affiliates in each

region,” the firm’s vice president, regulatory and quality affairs, told the Pink Sheet.

TRANSITIONING OF EXISTING MRAS Meanwhile, changes appear limited, at least for now, in some other areas and the forum heard that the MHRA expects to maintain its inspections program – it will continue to be based on risk as before and will continue to include UK and third countries.

“We will continue to work on integration into PIC/S [Pharmaceu-tical Inspection Convention and Pharmaceutical Inspection Co-op-eration Scheme] and ICMRA [International Coalition of Medicines Regulatory Authorities] work sharing initiatives, where we recog-nize and take into account the outcomes of inspection findings from our partners,” Churchward said.

Several Indian firms have over the past few years faced flak over GMP deviations, though US Food And Drug Administration data presented by McKinsey & Co at the forum suggested that inspec-tion outcomes in India had improved in 2018 and were now “more in line” with global outcomes.

B R E X I T

“We will continue to work on integration

into PIC/S and ICMRA work sharing

initiatives, where we recognize and take into account the outcomes of

inspection findings from our partners.”

– MHRA’s Churchward


B R E X I T

On how things may play out for the UK in the event of a no-deal Brexit with respect to the mutual recognition agreement which allows the FDA and the EMA to share inspection data and make sure certain resources are better focused, the MHRA told the Pink Sheet that it is working with partner countries to seek to ensure that the existing MRAs are “transitioned into UK agreements” in time for a potential no-deal Brexit.

“This would ensure that trading partners would continue to ac-cept UK results and certificates as they currently do today. Some discussions are more advanced than others [for example, the UK has already signed an agreement with the US] and businesses should familiarize themselves with the detailed EU Exit guidance available on www.gov.uk to understand how to prepare if some MRAs are not in place by exit day,” the UK regulator explained.

Churchward, however, also emphasized that the British gov-ernment has made it clear that even after the UK leaves the EU, it wishes to maintain, in future, a very close relationship with the European medicines regulatory network and to preserve its partnerships with those authorities that it had been working with for decades and with which it had built up a “significant level of trust.”

If a deal is reached, the UK will leave the EU on March 29 but there will be an implementation period until the end of 2020, which essentially is expected to mean that, in practice, there will be no change in the regulatory framework for pharma until the end of that period.


Sanofi’s Dengvaxia: US FDA Panel Finds Pediatric Use More Acceptable Than Broader Target PopulationSUE SUTTER [email protected]

S anofi’s hopes for US FDA approval of its dengue vaccine Dengvaxia may hinge upon a pediatric indication following a strongly negative advisory committee review, particularly

regarding licensure for a broader age group.However, even a more limited label may not be enough to over-

come what advisory committee members saw as a key obstacle to the vaccine’s near-term use – the lack of a readily available and reliable point-of-care diagnostic for screening potential vaccine re-cipients for previous dengue infection.

At a March 7 meeting, FDA’s Vaccines and Related Biological Products Advisory Committee rendered split votes on efficacy and safety of Dengvaxia in persons ages nine to 45 years old with laboratory-confirmed previous dengue infection and liv-ing in endemic areas. The nine to 45 age group is Sanofi’s re-quested target population.

After the votes on efficacy and safety in this age group, FDA added two new voting questions on efficacy and safety limit-ed to persons ages nine to 17 years with laboratory-confirmed previous dengue infection and living in endemic areas. This population drew favorable votes from a majority of the panel-ists. (See box, p. 18.)

Sanofi’s clinical package includes data from three randomized, placebo-controlled, clinical endpoint studies that evaluated vac-cine safety and efficacy in subjects ages nine to 16 years old, as well as three immunogenicity and safety studies intended to sup-port use in adults.

Sanofi is seeking to limit the vaccine’s use to individuals with previous dengue infection because long-term clinical data sug-gest Dengvaxia increases the risk of hospitalized virologically-con-

firmed dengue among individuals who have never been infected with any of the four virus serotypes.

This finding was based on a retrospective analysis using an ELI-SA assay on stored sera to determine whether vaccinated subjects who were hospitalized with virologically confirmed dengue were immune or non-immune at the beginning of study.

DIAGNOSTIC ISSUES POSE A CHALLENGEThe advisory committee discussion was more negative than might have been expected given the neutral-to-positive tenor of FDA’s briefing documents, which did not raise any major red flags. (Also see “Sanofi’s Dengvaxia Postmarket Monitoring Plan Targets Vac-cine’s Safety Concerns” - Pink Sheet, 5 Mar, 2019.)

Panelists raised several concerns about moving Dengvaxia for-

A D V I S O R Y C O M M I T T E E S


www.gov.uk




ward for the proposed indication, including:

• Lack of a reliable, point-of-care diagnostic for screening for dengue infection;

• Operational challenges to screening for previous dengue infection;

• Retrospective analysis that led to the screening recommendation; and

• Limited amount of immunological data in adults.

Currently, laboratory-based tests are used to detect prior den-gue infection. However, no serologic tests are cleared by FDA for establishing prior exposure to dengue, and currently available IgG ELISA tests may lead to false positive results because of low speci-ficity and the potential for detecting cross-reactive antibodies to other flaviviruses.

Sanofi said it is working to co-develop a point-of-care test that could be used to screen for prior infection, which would enable screening and vaccination to take place in a single visit. The company expects such a test would be ready for FDA registration in late 2020.

However, uncertainties about the reliability and availability of exist-ing lab-based tests in endemic areas and the absence of a point-of-care screening assay led some panelists to conclude that Dengvaxia is not ready for US licensure given the safety concerns about vaccinat-

ing individuals who are naïve to all dengue virus serotypes.“The diagnostics are really absolutely critical here,” said Michael Ku-

rilla, director of the Division of Clinical Innovation at the National Insti-tutes of Health’s National Center for Advancing Translation Sciences.

“I think it is incumbent to really define not just what’s out there already, but to define … the sort of minimum sensitivity and specificity, combined with the available seroprevalence data, that really allow public health officials in general to make a decision as to whether this is the vaccine they want to implement in their region, as to whether it’s going to have an overall effect on the population,” he said.

Melinda Wharton, director of the Immunization Services Divi-sion at the Centers for Disease Control and Prevention’s National Center for Immunization and Respiratory Diseases, said the data for the populations studied in the efficacy trials are compelling in demonstrating that Dengvaxia prevents severe outcomes in seropositive individuals. However, she acknowledged the limita-tions of available lab tests and pointed to the “signficant opera-tional challenges” to routinely conducting serological assays prior to vaccination. “It’s just operationally a really difficult thing to do.”

“I don’t believe we have a test available to allow us to deter-mine whether or not this would be safe in the field and in light of that I have serious concerns,” said Tammy Beckham, acting direc-tor of the National Vaccine Program Office.

William Messer, assistant professor in the Department of Mo-lecular Microbiology and Immunology at Oregon Health and Sci-ence University, raised concerns about the retrospective nature of the analysis on individuals’ pre-existing exposure to dengue.

Although there was a lot of evidence demonstrating that Dengvaxia is effective in seropositive individuals, “this is a retro-spective analysis of a vaccine trial that was designed to test a dif-ferent question,” Messer said. “Many times we have been burned in the medical field by applying retrospective analyses and data and making prospective assumptions about whether or not the retrospective analysis really reflects what a prospective study” would have.

LIMITED BRIDGING DATAPanelists also were uncomfortable with what they viewed as the limited amount of data in adults.

Sanofi submitted three studies that provided descriptive immu-nogenicity data in individuals ages 18-45 years that were intended to support immune bridging from the Phase III study results in pe-diatric patients to adults.

However, these studies were conducted in India, Singapore and Vietnam, and panelists questioned whether the data could be ex-trapolated to adults in Puerto Rico and other US territories where dengue is endemic.

Sanofi submitted the biologics license application on Aug. 31; the application is undergoing a priority review, with a May 1 user fee goal date. Sanofi said it has applied for a tropical disease prior-ity review voucher.


A D V I S O R Y CO M M I T T E E V OT E S

• Are the available data adequate to support the ef-fectiveness of Dengvaxia for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in persons nine through 45 years of age with laborato-ry-confirmed previous dengue infection and living in endemic areas? Y – 6, N – 7, A – 1

• Are the available data adequate to support the safety of Dengvaxia when administered to persons nine through 45 years of age with laboratory-confirmed previous dengue infection and living in endemic areas? Y – 7, N – 7

• Are the available data adequate to support the ef-fectiveness of Dengvaxia for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4 in persons nine to <17 years of age with laboratory-confirmed previous dengue infection and living in endemic areas? Y – 13, N – 1

• Are the available data adequate to support the safety of Dengvaxia when administered to persons nine to <17 years of age with laboratory-confirmed previous den-gue infection and living in endemic areas? Y – 10, N – 4



EDITORS IN CHIEF Ian Haydock (Asia)Eleanor Malone (Europe)Denise Peterson (US)

EXECUTIVE EDITORSPOLICY AND REGULATORYMaureen Kenny (Europe) Nielsen Hobbs (US)

COMMERCIALAlex Shimmings (Europe)Mary Jo Laffler (US)

ASIAAnju GhangurdeJung Won ShinBrian Yang

EUROPENeena Brizmohun Francesca BruceAndrea Charles

John DavisKevin GroganIan SchofieldVibha Sharma Jo ShorthouseSten Stovall

USMichael CiprianoBowman CoxJoanne EglovitchEileen FrancisDerrick GingeryJoseph HaasEmily HayesMandy JacksonCathy KellyJessica Merrill Brenda SandburgBridget SilvermanMalcolm SpicerSue Sutter

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Sanofi Pasteur’s Dengvaxia, a live, attenuated tetravalent vaccine for dengue

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