Pharma intelligence informa Sheet Pink pink.pharmaintelligence.informa.com Vol. 81 / No. 15 April 15, 2019 FROM THE EDITORS OF SCRIP REGULATORY AFFAIRS, THE RPM REPORT, GOLD SHEET, PINK SHEET DAILY AND PINK SHEET BIOSIMILARS Biosimilar Makers Take On ‘Huge’ Barriers To A Sustainable European Market, p. 7 NEW PRODUCTS Amgen’s Evenity Clears US FDA With Preferred Indication, Black Box Warning, p. 17 REGULATORY UPDATE Myeloma CAR T-Therapy Among New EMA PRIME Winners, p. 9 CONTINUED ON PAGE 4 Insulin Prices: House Hearing Displays Bipartisan Commitment To Rapid Reform CATHY KELLY [email protected]U S House Republicans and Democrats are frustrated with the measures pharmaceutical manufacturers and phar- macy benefit managers have taken to lower insulin pric- es and warned them at an April 10 hearing that a more radical solution is needed – and soon. “What we’re going to do is get together in a bipartisan way and we’re going to work with all of you, plus everyone else in the distribution system, to figure out how we can provide insu- lin to diabetics at a cost they can afford,” Energy & Commerce Oversight and Investigations Subcommittee Diana DeGette (D- Co), told a panel of pharmaceutical manufacturer and pharmacy benefit managers in her closing comments. “We’re going to do that as quickly as we can,” DeGette promised, adding: “We’re prepared to talk to you now and we’re prepared to bring you back in July or September to talk about the progress that we’ve made because this is not optional. It’s going to happen.” The hearing was the second to be held by the subcommittee as part of its work on insulin pricing but the first to feature mem- bers of the drug supply chain. (Also see “Insulin Manufacturers, PBMs To Face US House Subcommittee Grilling On Drug Pricing” - Pink Sheet, 2 Apr, 2019.) Although witnesses discussed a range of programs aimed at lowering insulin costs, members on both sides of the aisle agreed they don’t go far enough in helping all patients. (Also see “Insulin As- sistance Programs: Big Help Or Just A Band-Aid?” - Scrip, 10 Apr, 2019.) Testifyng were: Eli Lilly & Co. Insulins Global Business Unit Se- nior VP Mike Mason, Novo Nordisk AS Exec VP, North America Operations Doug Langa, Sanofi Executive VP for External Affairs Kathleen Tregoning, CVS Health Corp. Chief Policy and External Affairs Officer Thomas Moriarty, Express Scripts Holding Co. Se- nior VP, Supply Chain Amy Bricker and OptumRx Inc. Senior VP and Chief Medical Officer Sumit Dutta. “While these programs from manufacturers and PBMs are im- portant and useful in the short term, they are only a band-aid. We must work on a long-term, comprehensive solution,” Energy & Commerce Committee Ranking Member Greg Walden (R-OR) said in his opening statement. Rep. Brett Guthrie (R-KY), asked the witnesses to explain in a “While these programs from manufacturers and PBMs are important and useful in the short term, they are only a band-aid. We must work on a long-term, comprehensive solution.” – Rep. Walden
Transcript
Pharma intelligenceinforma
SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 15 April 15, 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
BIOSIMILARS
Biosimilar Makers Take On ‘Huge’ Barriers To A Sustainable European Market, p. 7
NEW PRODUCTS
Amgen’s Evenity Clears US FDA With Preferred Indication, Black Box Warning, p. 17
REGULATORY UPDATE
Myeloma CAR T-Therapy Among New EMA PRIME Winners, p. 9
CONTINUED ON PAGE 4
Insulin Prices: House Hearing Displays Bipartisan Commitment To Rapid ReformCATHY KELLY [email protected]
U S House Republicans and Democrats are frustrated with the measures pharmaceutical manufacturers and phar-macy benefit managers have taken to lower insulin pric-
es and warned them at an April 10 hearing that a more radical solution is needed – and soon.
“What we’re going to do is get together in a bipartisan way and we’re going to work with all of you, plus everyone else in the distribution system, to figure out how we can provide insu-lin to diabetics at a cost they can afford,” Energy & Commerce Oversight and Investigations Subcommittee Diana DeGette (D-Co), told a panel of pharmaceutical manufacturer and pharmacy benefit managers in her closing comments.
“We’re going to do that as quickly as we can,” DeGette promised, adding: “We’re prepared to talk to you now and we’re prepared to bring you back in July or September to talk about the progress that we’ve made because this is not optional. It’s going to happen.”
The hearing was the second to be held by the subcommittee as part of its work on insulin pricing but the first to feature mem-bers of the drug supply chain. (Also see “Insulin Manufacturers, PBMs To Face US House Subcommittee Grilling On Drug Pricing” - Pink Sheet, 2 Apr, 2019.)
Although witnesses discussed a range of programs aimed at lowering insulin costs, members on both sides of the aisle agreed they don’t go far enough in helping all patients. (Also see “Insulin As-sistance Programs: Big Help Or Just A Band-Aid?” - Scrip, 10 Apr, 2019.)
Testifyng were: Eli Lilly & Co. Insulins Global Business Unit Se-nior VP Mike Mason, Novo Nordisk AS Exec VP, North America Operations Doug Langa, Sanofi Executive VP for External Affairs Kathleen Tregoning, CVS Health Corp. Chief Policy and External Affairs Officer Thomas Moriarty, Express Scripts Holding Co. Se-nior VP, Supply Chain Amy Bricker and OptumRx Inc. Senior VP and Chief Medical Officer Sumit Dutta.
“While these programs from manufacturers and PBMs are im-portant and useful in the short term, they are only a band-aid. We must work on a long-term, comprehensive solution,” Energy & Commerce Committee Ranking Member Greg Walden (R-OR) said in his opening statement.
Rep. Brett Guthrie (R-KY), asked the witnesses to explain in a
“ While these programs from manufacturers and PBMs are important and useful in the short term, they are only a band-aid. We must work on a long-term, comprehensive solution.” – Rep. Walden
JN0000 GGB Awards 2019 Open for Entries Advert US Letter.indd 1 2019/03/20 18:27
pink.pharmaintelligence.informa.com April 15, 2019 | Pink Sheet | 3
exclusive online contentCO V E R Insulin Prices: House Hearing Displays Bipartisan
Commitment To Rapid Reform
D R U G P R I C I N G 4 PBMs Were On Capitol Hill, But Pharma
Still Took Some Heat
6 CMS Offers Part D Plans Financial Backstop If Rebates Eliminated In 2020
B I O S I M I L A R S 7 Biosimilar Makers Take On ‘Huge’ Barriers To A
Sustainable European Market
13 How Coherus Overcame FDA’s Doubts About Udenyca Immunogenicity
R E G U L ATO RY U P D AT E 9 Myeloma CAR T-Therapy Among New
EMA PRIME Winners
10 Industry Survey Lays Bare Huge Disparities In Access To New Drugs In Europe
11 What Can Korea Learn From The Invossa Trial And Error Case?
12 Patient Engagement In Clinical Trials Needs More FDA Guidance, Stakeholders Say
N E W P R O D U C T S 17 Amgen’s Evenity Clears US FDA With Preferred Indication,
Black Box Warning
A D V I S O RY CO M M I T T E E S 18 Recent And Upcoming FDA Advisory Committee Meetings
inside: 13 7 10
Further Brexit Delay Avoids No-Deal Impact For Pharma – For Nowhttps://pink.pharmaintelligence.informa.com/PS125096The EU has given the UK another extension, this time until 31 October, to find a solution to the Brexit impasse. In the meantime, things will stay pretty much as they are for the life sciences sector, although the possibility of a no-deal exit remains if a withdrawal agreement cannot be ratified.
Blow For Novartis As England’s NICE Says No To Kisqalihttps://pink.pharmaintelligence.informa.com/PS125087Novartis is having a harder time than Eli Lilly at getting health technology assessment body NICE to agree to make its breast cancer CDK4/6 inhibitor in combination with fulvestrant available on the National Health Service.
US FDA’s Transfer Policy For Orphan Drug Designation Under Scrutinyhttps://pink.pharmaintelligence.informa.com/PS125090Braeburn Pharmaceuticals says awarding Indivior’s opioid use disorder treatment Sublocade seven-year orphan exclusivity that flows from a 1994 orphan drug designation for Subutex would be an abuse of the system. The US FDA said it is carefully considering whether Sublocade qualifies for exclusivity ‘within the context of the opioid public health emergency.’
Gottlieb’s Parting Words For US FDA: ‘Be Willing To Push’ For Major Policy Changeshttps://pink.pharmaintelligence.informa.com/PS125062Outgoing Commissioner tells staff, “No phrase bothered me more than when I heard people say to me they didn’t want to do something important because they wanted to ‘preserve their political capital.’” FDA should not to worry about spending political capital, Gottlieb argued, because it is replenished upon accomplishing important things.
China’s Draft Cell Therapy Guidelines Draws Concern From Industryhttps://pink.pharmaintelligence.informa.com/PS125048New draft guidelines could potentially create parallel clinical pathways for cell and gene therapies in China, and industry executives are worried about different standards for such emerging treatments in a country with the highest number of ongoing cell therapy trials in the world.
follow-up written statement why it makes sense to have a high list price that is reduced through rebates instead of a lower list price to begin with. It may be “better for the insurance company” but a “lower list price is better for consumers,” he suggested.
CONGRESS ‘HAS TO MAKE SOME DECISIONS’ ON INSULIN PRICING“Hopefully this is the beginning of a series of hearings and we appre-ciate your testimony and information,” he continued. “We do have to make some decisions and we don’t want unintended consequences because if you get into price controls, you get into rationing and you get into shortages. And that’s not where I want to go.”
Also bipartisan was frustration with the witnesses’ talking points about how rebates drive list price increases (repeated by the manu-facturers) and how list price increases prompt the need for rebates (the PBM party line).
Rep. Buddy Carter (R-GA) who is not a member of the commit-tee but nevertheless participated in the hearing, emphasized the broad support for insulin price reform among members in remarks directed to the witnesses.
“I want to congratulate all of you because you’ve done something here today that we’ve been trying to do in Congress in the four years and three months I’ve been here and that is to create bipartisanship – because what you’ve witnessed here today is bipartisanship.”
The current situation with insulin pricing “is going to end,” Carter maintained.
He added the HHS proposal to replace rebates with up front dis-
counts that would be passed through to patients at the point of sale “is going to happen. ... We’re going to make sure it happens. That’s going to bring transparency to the system. And we’re not going to stop there.”
The proposed rule, which would revise the anti-kickback safe harbor for rebates in Medicare Part D and Managed Medicaid, was released in late January. (Also see “No More Rebates: HHS Proposed Rule Revises Anti-Kickback Safe Harbor” - Pink Sheet, 31 Jan, 2019.) It is generally sup-ported by manufacturers but opposed by PBMs and insurers.
DeGette commented when Carter finished that he sounded like one of the more liberal firebrands on the panel. “I never thought I’d see the day when Buddy Carter was channeling [Rep.] Jan Scha-kowsky, [D-Ill.]. Congratulations,” she quipped.
Published online April 10, 2019
CONTINUED FROM COVER PBMs Were On Capitol Hill, But Pharma Still Took Some Heat JESSICA MERRILL [email protected]
P harmacy benefit managers had their turn on Capitol Hill, called into testify on drug pricing before the Sen-ate Finance Committee April 9, but drug makers got a
lot of the blame for high drug prices.Leaders from five PBMs testified in the third hearing held
by the Senate Finance Committee on drug pricing, about six weeks after seven pharmaceutical leaders similarly testified. Among the PBM participants were United Healthcare Ser-vices Inc.’s OptumRx CEO John Prince, CVS Health Corp. Exec VP and CVS Caremark President Derica Rice, Humana Inc. Healthcare Services Segment President William Fleming, Cigna Corp. Exec VP and Chief Clinical officer Steve Miller and Prime Therapeutics Interim CEO Mike Kolar.
The hearing went off without any big surprises, with the PBMs pushing back on pharma’s main lobbying message, that high list prices are powered by PBMs, who benefit financially through rebates charged as a percent of list price.
Senators appeared to be going through the motions, press-ing the pharmacy distributors on the role of rebates and fees and how they relate to drug costs, but without a lot of speci-ficity. Perhaps congressional leaders were as befuddled by the pharmacy middleman as the general public. As Ranking Member Ron Wyden, D-OR, quipped, “I’m of the view that PBMs guard their operations with greater secrecy than HBO is guarding the ending of Game of Thrones.”
Nonetheless, pharma still took a lot of heat. As Senator Sheldon Whitehouse, D-RI, spelled out, only $23bn of the $480bn the US spends on drugs, or 5%, goes to PBMs, while $323bn goes to pharmaceutical companies.
“It has to be interesting to you all to witness how the pharmaceutical industry has been able to take pressure
“ I want to congratulate all of you because you’ve done something here today that we’ve been trying to do in Congress in the four years and three months I’ve been here and that is to create bipartisanship.” – Rep. Carter
pink.pharmaintelligence.informa.com April 15, 2019 | Pink Sheet | 5
D R U G P R I C I N G
on their pricing and turn it into, with political jiu-jitzu of al-most magical variety, pressure on their greatest adversary, the most powerful force for pushing prices down,” Whitehouse said. “I hope you at least respect what they have been able to pull off here.”
Indeed, industry has been quite successful turning attention to PBMs in the debate over drug pricing and highlighting the growing rebates drug makers pay off list prices to negotiate for-
mulary access with payers. One of the pivotal changes being proposed by the Trump Administration to lower drug prices is a proposal to eliminate rebates or pass them on directly to con-sumers at the point of sale. Drug makers are broadly support-ive of the plan, but payers argue that the proposal will result in higher insurance premiums.
MAKING THE CASE FOR REBATESThat sentiment was one echoed by the PBM representatives dur-ing the roughly three hours of testimony at the hearing.
Humana’s Fleming gave some of the more powerful testimony against the Department of Health and Human Services’ rebate pro-posal, pointing to the potential impact on overall health care costs.
“All beneficiaries will pay higher premiums, while 12% will see savings of greater than $70 per year; 5% will see savings of less than $70 per year,” he said. Meanwhile, “83% will pay higher total costs given the premium increases.”
Cigna’s Miller, who joined the insurer with the acquisition of Ex-press Scripts, said he supports the sentiment behind the rule but believes the current proposal poses problems.
“When you make the rebates publicly known it will make our ability to negotiate for discounts that much less effective,” he said. “You will decrease our negotiations, you will take pressure off pharmaceutical companies, you will raise premiums for 100% of the beneficiaries while only helping a minority of the beneficiaries.”
The potential impact on premiums has been one of the big challenges with changing the current rebate model. Bernstein Research analysts Luke Wilkes and Ronny Gal speculated in a recent research note that the pharmaceutical industry could be asked to pick up some of the tab to buy down premiums, based on discussions with pharma leaders negotiating in the area. (Also
see “Rebate Reshuffle: Could Pharma Foot The Bill To Offset Higher Premiums?” - Scrip, 8 Apr, 2019.)
The proposed rule was released in January and industry is now awaiting a final proposal from HHS after the formal comment pe-riod closed April. 8. (Also see “No More Rebates: HHS Proposed Rule Revises Anti-Kickback Safe Harbor” - Scrip, 31 Jan, 2019.)
The PBM representatives generally highlighted other areas where improvements could be made, with a focus on limiting out-of-pocket costs for patients, supporting value-based reim-bursement initiatives and developing more biosimilar competi-tion in the US.
HIGH-PRICED SPECIALTY DRUGS ARE A THORN FOR PHARMAThe pharma industry also took hits for the high price of spe-cialty drugs – including cancer drugs – that can cost more than $100,000 and for which rebates usually don’t even come into play.
As Prime’s Kolar pointed out, “The fact that rebates are not of-fered on many of the highest cost drugs and that studies show no correlation between prices and rebates underscore that rebates are a key to mitigating rather than causing high drug prices.”
Humana’s Fleming discussed the increasingly common prac-tice of pricing drugs from $50,000 to $100,000. “Nearly one of ev-ery two specialty drugs results in members entering catastrophic coverage on their very first fill,” he said.
Cigna’s Miller pointed to expensive cancer treatments. “If you think about patients with cancer who have an enormous burden at the counter, because there are no rebates on those products, they don’t benefit at all from moving the rebate to the point of sale.”
He advocated in favor of more targeted approaches that could ad-dress specific groups of patients. “If you look at the category of drugs that are creating the pain for patients at the pharmacy counter, they fall into several buckets. It’s diabetic agents. It’s hepatitis C. It’s asthma,” he said. “If you had a targeted solution for those, you would actually relieve most of the patients that have the problem.”
Express Scripts recently announced a new program that would cap cost sharing for a 30-day supply of insulin at $25, a program Miller mentioned several times during the hearing, as the PBM leaders sought to put their best foot forward. (Also see “Express Scripts Insulin Program Lowers Cost Sharing With Supplemental Manufacturer Discounts” - Pink Sheet, 3 Apr, 2019.)
While there appears to be bipartisan support for legislation lowering drug prices, it’s still unclear what, if any, legislation will come out of the Senate Finance Committee hearings on drug pricing. Having heard from patients and pharmaco-economists, pharmaceutical manufactures, and now PBMs, the next move is in Congress’ court.
But with the 2020 election already on the horizon, it seems un-likely anything controversial will get done. Even the Administra-tion’s rebate rule may not be finalized for next year, in part be-cause of concern that the reg’s potential to raise premiums could hand a talking point to the opposition.
Published online April 9, 2019
Humana’s Fleming gave some of the more powerful testimony
against the HHS rebate proposal, pointing to the potential impact on
CMS Offers Part D Plans Financial Backstop If Rebates Eliminated In 2020CATHY KELLY [email protected]
M edicare Part D plans may be able to participate in a “demonstra-tion” over the next two years that
would help cushion the financial impact of an HHS rule to eliminate drug rebates by revising the anti-kickback safe harbor that currently protects them.
“If there is a change in the safe harbor rules effective in 2020, [the Centers for Medicare and Medicaid Services] will conduct a demonstration that would test an efficient transition for beneficia-ries and plans to such a change in the Part D program,” CMS told plan sponsors in an April 5 guidance.
The demonstration would involve a nar-rowing of the Part D risk corridors, which could lead CMS to pay more in reinsurance to the plan if costs exceed the amount pro-jected in the bid.
Elimination of rebates in Part D is expect-ed to have a major impact on the market but it’s not clear exactly what will happen because a lot depends on how manufactur-ers, pharmacy benefit managers and plans react. (Also see “HHS Rebate Plan A Leap Of Faith? Lower Costs Hinge On Drug Firm, Plan Response” - Pink Sheet, 2 Feb, 2019.)
Without rebates, plan costs could in-crease significantly, which could lead them to pass on some of the increase to benefi-ciaries. That’s the issue CMS is trying to ad-dress with the guidance.
“For 2020, under the demonstration, the government would bear or retain 95% of the deviation between the target amount … and the actual incurred costs …beyond the first 0.5%,” the notice explains. Partici-pation in the demonstration would be vol-untary but plans choosing to do so would have to participate for two years.
The approach would be “a softening of the blow to risk that plans would face be-cause they’re going into the unknown un-der this new rule,” health policy expert and former Medicare Payment Advisory Com-mission member Jack Hoadley said in an
interview with the Pink Sheet.On the other hand, he pointed out,
plans may worry that if they participate in the demonstration and the rule does not advance, they might find themselves in a position of returning more risk corridor
money to CMS than they would otherwise.“If you narrow the risk corridor under
this demonstration and nothing else changes, you’re going to be giving more money back to CMS because … you’re making profit beyond the amount the risk corridor called for. More of that profit is go-ing to be falling outside of that narrow cor-ridor,” Hoadley said.
BIDS FOR 2020 SHOULD INCLUDE REBATESAlthough the guidance could ease the transition for plans if the rule goes into effect, it also advises that bids for 2020 reflect the status quo and include rebates. In doing so, CMS acknowledges the diffi-culties posed by the way the timing of the rebate regulation interacts with the annual Part D plan bidding cycle.
The proposal was issued by HHS Office of Inspector General in late January and has a Jan. 1, 2020 effective date. It spent several months under review at the White House, which likely delayed its release lon-ger than HHS had expected. (Also see “HHS
Rebate Rule: At Least We Know Who Is In Charge” - Pink Sheet, 6 Feb, 2019.)
The comment deadline for the proposal is April 8 and a final rule could issue one to two months later. At the same time, Part D bids for the 2020 benefit year are due June 3. By then, plan sponsors either won’t know what’s in the final rule, or they would have little time to adapt to the rule (if it has come out).
CMS acknowledges it has “received questions about how plans should ac-count for the possibility of a change in the safe harbor rules.”
In response, the notice directs plans to submit bids for 2020 “in a form and man-ner that is consistent with the Anti-Kick-back Statute law and regulations in effect as of the bid submission deadline, includ-ing, for the purposes of bid development, the treatment of manufacturer rebates per our existing rules and guidance related to direct and indirect remuneration.”
Given the tight time frame, it would not be unexpected for HHS to delay the effective date of the rule to allow stake-holders “to absorb and try to respond in a more measured way,” Hoadley noted. However, the demonstration suggests there is still “an interest in trying to move forward in 2020.”
One reason to push ahead is that hav-ing the rule in place would make a good talking point for President Trump on the campaign trail. The rebate rule is gener-ally considered to be the most potentially impactful of the drug pricing policies ad-vanced by the Administration so far.
“It would be a couple of years before we fully understand those impacts,” Hoadley cautioned. However, “I suppose they could say, ‘Look, we’ve done it. We’ve trans-formed the world.’ And it would be hard for people to say either ‘that’s right’ or ‘that’s wrong’” based on the early evidence.
Published online April 5, 2019
Without rebates, plan costs could increase
significantly, which could lead them to pass on some of the increase
pink.pharmaintelligence.informa.com April 15, 2019 | Pink Sheet | 7
B I O S I M I L A R S
Biosimilar Makers Take On ‘Huge’ Barriers To A Sustainable European MarketIAN SCHOFIELD [email protected]
B iosimilar industry leaders are gear-ing up to tackle the threats to the longer-term sustainability of the
sector caused by divergences in biosimi-lar usage across Europe, a dearth of near-term biologic expiries, and a shift towards smaller patient populations. But they say the industry cannot solve these problems on its own, and later this year they will be pushing the new European Parliament and European Commission to look afresh at ways to promote a competitive and sus-tainable market.
In a wide-ranging interview with the Pink Sheet during last week’s Medicines for Europe biosimilars conference in Am-sterdam, Adrian van den Hoven and Marc-Alexander Mahl, the association’s direc-tor general and president respectively, discussed the challenges facing the sec-tor, not least the uneven penetration of biosimilar medicines in the different EU countries – an issue that was addressed by several speakers at the conference. (Also see “EU Countries Examine Reasons For Wide Differences In Biosimilar Usage” - Pink Sheet, 1 Apr, 2019.)
“Our difficulty is that we have to get those penetration rates up,” van den Hoven said. “It is not a straightforward model of encouraging competition, it is not generic substitution model, it is a prescription and procurement driven market. The only way it has worked for any molecule in any coun-try is via benefit sharing: where you have tenders, some or all of the savings are re-directed towards the hospital department, or more nurses. This has been almost ex-clusively the driver thus far. Unfortunately not all countries have adopted this model, so you don’t see a lot of penetration.”
One problem for the industry is that while the launch of biosimilars can serve to bring down prices, this often happens at the expense of the biosimilars themselves: for example, the originator company slash-es its own price, and the biosimilar fails to
gain market share.“People can say, well this is fair compe-
tition, but the difficulty with that is that if biosimilars don’t get any volume at all, and the companies have spent at least €100m on developing each product, it will narrow the scope of future develop-ment,” van den Hoven declared.
In such cases no one will want to invest in biosimilars, he said. “There have been cases where the biosimilar manufacturer has won the tender at, we suspect, a very good discount, but then something has happened and the hospital has remained on the reference product. None of our companies can sustain this… we cannot just be a tool to bring prices down, we have to get business,” he said.
“This is not happening everywhere, but there are enough cases for us to ex-press concern. Payers can gloat about the savings, that is fine, but if we don’t get any business, well, they won’t be gloating for very long.”
Mahl agreed, saying that, for some rea-son, countries that struggled most with their healthcare systems very often had the lowest biosimilar adoption rates. “In terms of utilizing the benefit of biosimi-lars, benefit sharing, the opportunity to save money and invest it in better health-
care, they do the least on this, and this is where our activities are focused.”
Central and eastern European coun-tries seem to have the biggest issues with biosimilar penetration so Medi-cines for Europe has set up a special task force to “try to drive discussions there and share the experience of more ad-vanced countries,” van den Hoven noted. “In some countries like Hungary there is some progress, in others like Romania there is much less. Then there are the other outliers, where it is only starting to happen now, like Belgium and Ireland.”
Ireland, he said, was “kind of stuck. The mistake they made was that as soon as a biosimilar enters the market the originator has to reduce their price so they get a saving, but they don’t get any biosimilar uptake.”
Another big worry for the sector is that following the spike in biosimilar approvals and launches in Europe in recent times, the next few years are looking much leaner.
In his presentation to the conference, Murray Aitken of biopharmaceutical ser-vices company IQVIA said that in the near term, new biosimilar opportunities would be fewer than in the past. Citing the recent “wave of biosimilars including adalimum-ab,” he said: “We are all reaping the benefits
of that from a payer and manufacturer per-spective, but it won’t last forever, because the next five years in particular will be quite thin in terms of new molecules that are going to lose exclusivity.”
Aitken also pointed out that more next-generation innovative treatment options are coming through pipeline that could “potentially reduce the use of the prior generation molecules which are also the ones that will be losing exclusivity.” In addi-tion, newer biologics are being developed for smaller patient populations. “So we are in a bit of a bubble from that perspective,” he observed.
Mahl said these were real problems. The biologics that will be coming off patent will be smaller in commercial terms, but manu-facturers wanting to produce biosimilar versions will still have to leap the same hurdles in investment and development costs, he noted. “All that creates additional entry barriers, and that means you have an unsustainable environment where there is no biosimilar uptake, where market shares stay low.”
Generics and biosimilars, he said, were the solution to making healthcare systems sustainable: “Without us, novel high-price medicines would not be fundable.” It was vital to ensure that “the policies and sys-tems in place, the regulatory environment, allow for a multi-player market, free com-petition, and efficient regulatory processes to make sure that the entry barriers are kept as low as possible. That way, in the second half of next decade and the early 2030s we would see a steady stream of new biosimilars coming onto the market.”
TAKING IT TO THE EUAs van den Hoven sees it, the problem is one that has to be addressed by those in charge of healthcare, and at the European level. “The stakeholders, patient communi-ties, are asking us to enter into small popu-lation follow-on developments: basically generic or biosimilar versions of orphan drugs. We have discussed that extensively within Medicines for Europe – what are the regulatory and IP hurdles, what are the market barriers – and there is no business case. So I can urge my members to do the right thing and help these people with ge-
neric or biosimilar orphan medicines, but there is only so much our members can get approval for in terms of investment if they know they are going to lose money.”
He said that EU policy makers needed to take action, but were not doing so. “The unfortunate thing is that we don’t have anyone in the EU institutions who see this
problem that Murray raised yesterday. And it is amazing because when the health ministers come to Brussels, the only thing they, the health commissioner and the par-liament are concerned about is the high price of new medicines. All they are talking about in Brussels is the growing share of drugs for small patient populations taking a bigger share of the healthcare budget.”
Van den Hoven said that among policy makers and politicians there was an as-sumption that biosimilar companies were going to “take care of this for everybody. And I’m afraid that if I look at what is happening on the IP side, no one even understands it. If I look at the market bar-riers, the defence strategies are clearly designed to keep us out of the market: as long as there are savings there is lim-ited action. And if I look on the regulatory side, there are legitimate scientific chal-lenges that the regulators need to get their heads around to address something like a small-population biosimilar – you can’t get patients for clinical studies, so what do you do? There are theories and ideas but no strategy, there is no pathway for any of this, so it is difficult for us. This is going to be a huge challenge.”
CAMPAIGN LAUNCHMedicines for Europe’s latest initiative is a campaign dubbed “Together for Health,” which has just been launched and out-lines four key priorities for the sector: eq-uitable access to medicines, a responsible industry and regulatory framework, lead-ership in manufacturing, and empower-ing the healthcare community.
It plans to take its case to the highest level, and says it is ready to engage with the EU, national governments and stake-holders. Its particular focus is on the new European Parliament that will be elected in May, and the new European Commis-sion to be appointed in October.
The aim of the campaign is to make sure that equitable access to health is in the fo-cus of sustainable healthcare systems, but also to support a strong and robust Euro-pean biosimilars and generics industry and manufacturing base, Mahl said.
“The EU can’t fix everything,” added van den Hoven, “but if it decides to tackle this and make sure it doesn’t create any ad-ditional barriers, it is already a change in mindset.”
He said there was a whole range of other issues that needed addressing: the fact that the EU regulatory system is “based on an originator industry model,” with biosimilars firms being required to carry out a lot of duplicative work, partic-ularly on clinical trials; the way that na-tional procurement systems work, which often results in a “race to the bottom” in terms of price; and building up a sustain-able biosimilar manufacturing base in Europe, on the back of the manufactur-ing waiver that is about to get formal ap-proval. (Also see “Monitoring To Start As EU SPC Waiver Nears Finishing Line” - Pink Sheet, 4 Apr, 2019.)
“These are the key things we want to take forward in discussions with the next parliament and commission,” van den Hoven said. “I think ours is one of the rare industries that can prove it can deliver, on generics, biosimilars. I challenge anyone to deliver more access than we do, in Europe. I think we have the credibility, but I guess we need to have a stronger voice.”
Published online April 5, 2019
“ The next five years
in particular will be
quite thin in terms of
new molecules that
are going to lose
exclusivity.”
– Murray Aitken, IQVIA
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Myeloma CAR T-Therapy Among New EMA PRIME WinnersNEENA BRIZMOHUN [email protected]
J anssen’s CAR T-cell therapy, JNJ-68284528, for multiple myeloma is one of three new investigational prod-
ucts that have secured a place on the Eu-ropean Medicines Agency’s priority medi-cines (PRIME) scheme for getting drugs for unmet medical needs through the review process and to patients faster.
The PRIME designation for Janssen’s B-cell maturation antigen (BCMA) CAR T-ther-apy is expected to help the company keep pace with its primary competitor, Celgene/bluebird bio, and the product the two com-panies are co-developing, bb2121.
The two other recent additions to the scheme are Krystal Biotech’s topical gene therapy for dystrophic epidermolysis bul-losa, KB103 (bercolagene telserpavec), and Takeda Pharmaceutical’s Zika virus vac-cine, TAK-426.
The Janssen, Krystal and Takeda appli-cations for entry onto the scheme were reviewed and accepted during the 25-28 March meeting of the EMA’s Committee for Medicinal Products for Human Use. The committee rejected four other applications.
The new additions to PRIME bring to 53 the total number of products to have made it onto the three-year-old scheme; applica-tions for 183 products have failed. (Also see “Only One In Seven PRIME Applications Meet EMA Test” - Pink Sheet, 21 Mar, 2019.)
The scheme offers developers enhanced scientific and regulatory support from the EMA to help optimize their development plans, and the likelihood of having their product reviewed under the EU’s acceler-ated assessment procedure when it is even-tually filed for regulatory review.
PROMISING EARLY CLINICAL STUDIESAcceptance on PRIME means that an ap-plicant has managed to convince the EMA that its product has the potential to benefit patients with an unmet medical need based on early clinical data.
Janssen’s designation was based on clinical study results – from the Phase I/II
LEGEND-2 study and the Phase Ib/II CAR-TITUDE-1 study – evaluating the safety and efficacy of its BCMA CAR T-therapy in the treatment of patients with advanced re-lapsed or refractory multiple myeloma.
According to Datamonitor healthcare an-alyst Hardik Patel, the designation will help Janssen “keep pace with” bb2121, the BCMA CAR-T therapy that Celgene and bluebird are co-developing for the treatment of patients with relapsed/refractory multiple myeloma.
“Celgene will likely aim to file for approval of bb2121 in the US and the EU this year,” Pa-tel told the Pink Sheet.
bb2121 has also benefited from PRIME, having been granted entry onto the scheme in November 2017. At around the same time, it received breakthrough therapy des-ignation (BTD) in the US. Janssen told the Pink Sheet that it had not received BTD. “Cur-rently, we remain focused on advancing the clinical development program for JNJ-4528, globally, together with Legend Biotech, a spokesperson for the company said.*
JNJ-68284528, also known as JNJ-4528, is classed as an advanced tissue medical prod-uct (ATMP). It is currently being investigated for the treatment of patients with multiple myeloma who have received at least three prior regimens, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and have documented disease progression within 12 months of starting the most recent therapy, or are double refractory to an IMiD and PI. These patients have few available treat-ment options and are often faced with poor outcomes, the company said.
KRYSTAL’S FIRST-IN-CLASS TREATMENTKrystal’s application for PRIME designation was supported by clinical data to date from the ongoing GEM-1 Phase I/II study coupled with non-clinical data.
KB103, which is also classed an ATMP, is the company’s lead product candidate. Krystal said it was a first-in-class topical gene therapy for the treatment of dystrophic epi-dermolysis bullosa and “a truly transforma-tive treatment” for the condition.
KB103 is a replication-defective, non-inte-grating viral vector that has been engineered using Krystal’s STAR-D platform to deliver functional human COL7A1 genes directly to the patients’ dividing and non-dividing skin cells. “HSV-1 is Krystal’s replication-deficient, non-integrating viral vector that can pen-etrate skin cells more efficiently than other viral vectors,” the company said. “Its high payload capacity allows it to accommodate large or multiple genes and its low immuno-genicity makes it a suitable choice for direct and repeat delivery to the skin.”
Takeda, meanwhile, has been testing TAK-426 – a purified, inactivated, alum-adjuvant-ed, whole Zika virus vaccine – in a Phase I trial. In January 2018, the company said that the US Food and Drug Administration had granted the product fast track designation.
FOUR THAT MISSED THE MARKOne of the four applications that were re-jected was for a product under develop-ment that aims to increase the chance of an ongoing pregnancy in women under-going fresh single blastocyst transfer fol-lowing in vitro fertilization. The other three covered products for treating recent on-set Type 1 autoimmune diabetes patients with evidence of residual β-cell function, primary biliary cholangitis in patients with an inadequate response to ursodeoxycho-lic acid (UDCA) or unable to tolerate UDCA, and chronic kidney disease-associated pruritus in patients on hemodialysis.
Industry Survey Lays Bare Huge Disparities In Access To New Drugs In EuropeIAN SCHOFIELD [email protected]
T he wide disparities in patient access to medicines in Europe have come under scrutiny again after updated industry data showed that patients in some European countries some-
times have to wait seven time longer than those in other countries to obtain the same medicine, with access problems being notice-ably more acute in the southern and eastern European markets.
In terms of average speed to patient access after marketing ap-proval, Germany topped the rankings, followed by Denmark and Switzerland. The worst performers under this measure was Serbia, followed by Lithuania and Portugal. In terms of the “rate of availabil-ity”, ie, the number of medicines actually available to patients under a reimbursement scheme in European countries, the UK leads the field.
The “Patient WAIT Indicator” survey was published by the Eu-ropean pharmaceutical industry federation EFPIA. Nathalie Moll, EFPIA’s director general, said the reasons for the disparities were often multi-factorial but were almost never clinical.
The survey found that the average delay between a product be-ing authorized for marketing and its availability to patients “can vary by a factor greater than X 7 across Europe, with patients in Northern/Western Europe accessing new products 100-200 days after market authorization and patients mainly in Southern/East-ern Europe between 600-1,000 days.”
Moll said that whatever the reasons for the disparities in access, they were “at the expense of patients’ health and it’s time all actors in the healthcare system come together to address Europe’s access
to medicines challenges.”The survey, which was produced for EFPIA by the biopharma-
ceutical services company IQVIA, covers 121 new products that gained a centralized EU marketing authorization between January 2015 and December 2017, with the cut-off point for availability be-ing Dec. 19, 2018.
It measures the average time between marketing authorization and access, as well as the rate of availability. A total of 30 countries (24 EU countries plus Iceland, Macedonia, Norway, Serbia, Switzer-land and Turkey) were included in the study.
In terms of average speed to patient access after marketing ap-proval, Germany came first at 119 days, followed by Denmark (146 days), Switzerland (171) , the UK (209) and the Netherlands (220). The worst performers were Portugal (634 days), Lithuania (726) and Serbia (925). As for the rate of availability, the UK led the field, followed by Germany, Austria, Denmark and Italy, while bringing up the rear were Lithuania, Latvia, Serbia and Macedonia.
ORPHANS, ONCOLOGYThe survey found that the rate of availability for orphan medi-cines in more than 80% of the countries was lower than for all products between 2015 and 2017, and that the average delay between marketing authorization and patient access ranged from four months to three years.
By contrast, the rate of availability of cancer drugs was higher than that for all products in 73% of the countries, while the aver-age time to patient access varied from two months to more than 2.5 years.
Even within countries there are large variations in speed of pa-tient access to newly approved medicines. “In fact in many cases,” Moll observed, “the level of variation within a country is greater than between countries. For example, in Estonia the shortest delay was 21 days and the longest 1,443 days, in Ireland the variance was 0 days to 1,321 days and in Austria 33 days vs. 1,383 days.”
The reasons behind these delays are often “multi-factorial, root-ed in the medicines access systems and processes in the EU mem-ber states,” Moll said. “These can range from duplicative clinical as-sessments to the length of an HTA process, reimbursement delays, local formulary decisions, even IT processes. Access delays are not simply a question of economics but concerns over affordability of new medicines and the sustainability of healthcare play a part. De-lays in access can also be used as a cost containment measure.”
The high prices of some new drugs, particularly biologic medi-cines, have indeed been causing concern among national pay-ers and health technology assessment bodies, as typified by products such as Vertex’s Orkambi in the UK. (Also see “‘Extreme Outlier’ Vertex Slammed For Orkambi Pricing Approach In England”
“The reasons behind these delays are often multi-factorial, rooted in the
medicines access systems and processes in the EU member states.”
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- Pink Sheet, 8 Mar, 2019.)But as Moll points out, the reasons for the disparities in access are
“almost never clinical.” She says that “patients in one part of Europe should not have to wait seven times longer for a new medicine than citizens in another country. Patients living with one condition in a country should not have to wait longer than a patient living with a different condition. Access to medicines should be based on your clinical need not your post code.”
IRELAND SLUGGISHCommenting on the survey, Irish industry body the IPHA noted that Ireland ranked 20th for speed of access to new medicines, with patients waiting on average 486 days for some drugs. “By contrast, Denmark, with a population size similar to our own, has a wait time of 146 days. Last year, their figure was 155 days,” IPHA commented. The average wait time across Europe countries was 413 days, it added.
IPHA also said that when it came to the availability of new medi-
cines (ie, the number of drugs available to patients), Ireland “con-tinues to be in a poor position, ranking 16th out of the 27 coun-tries.” Only 42% of the new medicines licensed for prescription to patients in the EU in 2015, 2016 and 2017 “were available and reim-bursed in the health services here at the end of 2018.”
Oliver O’Connor, IPHA chief executive, said the data were part of a growing trend of evidence showing that Ireland has a “severe problem” accessing new medicines.
“We rightly aspire to be among the best in Europe,” O’Connor said. “For example, government policy is to achieve cancer survival rates among the top seven countries in Europe. Our speed of ac-cess to medicines needs to be the same to deliver that. Ireland ac-tually has income per capita comparable with, or even higher than, countries like Germany, Belgium, Denmark and Spain. Yet, we lag these and many other countries in speed of access to new medi-cines.”
Published online April 9, 2019
What Can Korea Learn From The Invossa Trial And Error Case?JUNG WON SHIN [email protected]
T rial and error is frequently, if not always, an accompaniment to the introduction of new technologies. As one example, in South Korea there was huge controversy a decade ago relat-
ing to a stem cell research scandal involving a local cloning scientist. Gene therapies have also been controversial as the approach
was seen by some as “playing god”, and concerns over the safety and bioethics of such cutting-edge therapies have been raised worldwide as technology has yet to stabilize.
However, it remains a fact that global pharma firms will continue to race towards the development of these and other pioneering approaches, and against this background, South Korea should ac-tively pursue and even lead the development of these drugs to be-come a major player, according to one local observer.
NEW TECHNOLOGIES COME WITH TRIAL AND ERRORIn this regard, Kolon Life Science Inc.’s gene therapy Invossa (TG-C) may be just another example of the trial and error involved in the development of novel medical treatments, Yun-Taek Jung, presi-dent of South Korea’s Pharmaceutical Strategy Institute (PSI), said in an interview with Scrip.
The first approved gene therapy in the country, Invossa was re-cently suspended from sale and distribution in South Korea, while recruitment in an ongoing US Phase III trial program has been tem-porarily halted, following findings that an active cell component may differ from the data submitted at the time of approval.
“The latest unprecedented incident could just be limited to this company’s issue. It could just be an issue of the difference in tech-nology advancement between 2004 and present, or an error that is
now unveiled, or could be another issue,” commented Jung. “In any case, there is definitely trial and error in such a new technology.”
South Korea’s drug authorities are slated to disclose the result of their ongoing probe into the product in mid-April, while the FDA in the US is to discuss the matter with the company.
Invossa, approved in South Korea in 2017, has been under the spotlight due to the advancement to commercialization of a gene therapy and its use of advanced technology, although it did not get the disease-modifying status Kolon had hoped for. The com-pany is instead aiming to establish this in the Phase III US trials.
CUTTING-EDGE BIOLOGICS LAW DELAYEDA recent delay in the political passage by parliament of a new act to support and ensure the safety of cutting-edge regenerative medi-cines and biologics may also have been directly or indirectly affect-ed by the Invossa incident, given that this is likely to have raised concerns over such innovative therapies.
The bill for the proposed act aims to give priority to the review of biologics for treating rare diseases, and to grant conditional approvals to such drugs once their efficacy is sufficiently proven. Such a system usually involves the postmarketing surveillance of safety and efficacy in actual use for a certain period before a full approval is given.
South Korea has also been trying to come up with detailed guide-lines for a fast-track review and approval system to provide the in-dustry with a clearer understanding of the process, as it has been unclear which medicines are eligible for the scheme and how this actually works in practice. (Also see “Korea To Introduce Fast-Track Re-view For Cutting-Edge Biologics, Devices” - Pink Sheet, 25 Jan, 2018.)
NEED FOR CLEARER GUIDELINES Although gene therapies may require continued long-term moni-toring to determine possible side-effects, so far Kolon’s clinical tri-al and real world data for Invossa in more than 3,400 patients over the past 11 years do not point to any major safety issues or risks.
“New therapies will continue to face various challenges and there will certainly be trial and error in the beginning. But based on this experience [with Invossa], new therapeutics should con-tinue to be developed,” Jung stressed. “The parliament is saying that more discussions may be needed to pass the cutting-edge biologics act, but it is essential to act pre-emptively to prepare and establish these guidelines.”
If South Korea can have clearer guidelines on the development of pioneering drugs, this could help authorities better deal with these and lead to more stable results in granting their approvals, he said.
Jung pointed to the 21st Century Cures Act in the US and the Regenerative Medicine Act in Japan as examples of efforts to get in a better position to handle new technologies. “These laws were also introduced for the safety management of these drugs and such laws support both the industry and regulators in these coun-tries, but not in South Korea,” he noted.
This may not mean that South Korea’s ministry of food and drug safety handled the approval of Invossa inappropriately, Jung ob-served, but the incident will be further reviewed and investigated by the ministry and the US FDA to make more precise judgments and decisions. It appears that the discrepancies in cell type may not have been confirmed just by the approval documents submit-ted to the ministry, the PSI president said.
“What it [the Invossa affair] suggests is that this should be a good opportunity for South Korea to learn from this experience and better handle such issues going forward, as more and more cutting edge medicines are developed and launched in the country,” Jung said.
PSI, a pharma industry research and consulting institute in South Korea, provides solutions across the pharma value chain to support the advancement of the industry into the global market, and enhances new drug development capabilities by exploring innovative and sustainable business models. Jung is also an ad-junct professor of the department of pharmaceutical industry at the country’s Chung-Ang University.
Published online April 10, 2019
Patient Engagement In Clinical Trials Needs More FDA Guidance, Stakeholders SayMICHAEL CIPRIANO [email protected]
S takeholders agree that it is going to take a collaborative ef-fort to improve the incorporation of patient perspectives into the clinical trial process, and one area they have point-
ed to is more guidance from the US FDA.One specific area of guidance that was discussed at a March
19 public workshop hosted by FDA and the Clinical Trials Trans-formation Initiative was related to the development of plain language summaries of clinical trial data, which involves con-veying the results of a trial so that the participating patients can understand them.
Jessica Scott, head of R&D patient engagement at Takeda Pharmaceutical Co. Ltd.,alluded to a collaboration between the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT Center) and TransCelerate BioPhar-ma Inc., which submitted a draft guidance on the issue for FDA’s consideration in 2017.
“What we’ve done as an industry, part of the TransCelerate work was even to develop the first set of recommendations, that what is nonpromotional language in this space, how do we know what would be thought of as nonpromotional when we write a plain language summary?” Scott explained. “What format and emphasis? What content and word choice? There was no guidance yet, and we worked together to figure out what might work from an industry perspective and a patient perspective, and it was the first attempt.”
Plain language summaries in the European Union will soon be mandatory, likely in 2020, when the EU Clinical Trials Regulation (No 536/2014) is expected to come into effect. The regulation re-quires that companies provide lay person summaries of their clini-cal trial results to the EU portal within a year of the trial ending.
The goal of the proposal submitted to FDA, Scott explained, was a first attempt “to consider for harmonization of regulations across the regions so that what is a what is required and expected in the EU is also their clear guidances and guardrails for industry to feel that doing the same thing in the U.S. would be an accepted prac-tice per our regulatory system.”
David Leventhal, senior director of clinical innovation at Pfizer Inc., noted that, “The issue of there not being FDA guidance I think for some sponsors is a problem. ... There’s I think an attitude by some that unless it’s explicitly stated as a requirement by the agency, that some research sponsors won’t do it.”
Contract research organizations have noticed the phenomenon
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as well and are asking FDA to strengthen a recent draft guidance on risk-based monitoring (RBM) to ensure greater adoption of the prac-tice. (Also see “Clinical Trials: US FDA Should Frame Risk-Based Monitor-ing As Best Practice, ACRO Says” - Pink Sheet, 19 Mar, 2019.)
Pfizer individually offers plain language summaries to its clini-cal trial participants through a community called “Pfizer Link,” Leventhal explained, although he added that “if any one com-pany is not doing this well, I think it reflects badly on the entire clinical research enterprise.”
Scott also mentioned that many in industry have concerns that journal editors will consider a plain language summary prior publi-cation if it is released before an article on a clinical trial is published.
“We’ve tried to get clarity from journals,” Scott said. “I’ve pre-sented at conferences where journal editors were present, to try to understand if they, having the sole judgment to determine whether a summary is, to them, something they would consider prior publication, therefore deny the publication of a trial manu-script. It’s not up to us, and they have discretion, and we have not been able to get a position on this. So that’s a barrier for many sponsors moving forward until we do.”
A ‘CULTURE OF TRIALS’ More broadly, Peter Saltonstall, president and CEO of the National Organization for Rare Diseases, broadly endorsed the publication of FDA guidance to help build “a culture of trials.”
A culture of trials, Saltonstall explained, “keeps the patient at the center, but it talks about all those other ancillary supporting pieces that need to go into being able to deliver an effective trial, and I’m talking about everything from signing up, to technology, to report-
ing results back [to patients].”“I actually think [guidance is] something that would be helpful
to the community, and it’s something that we ought to work to-ward. … I think it would be really helpful because of all the dispa-rate views we’ve been hearing today, the guidance may really help us coalesce and come together to help build that culture of trials moving forward,” Saltonstall said.
Several patients at the meeting said they have never seen the results for trials they have participated in, which Saltonstall said surprised him.
A PLACE FOR MORE REGULATION? Although perhaps not a direct endorsement, one industry speaker at the meeting teased the idea of more regulation.
Joseph Kim, a senior advisor in patient experience and design innovation at Eli Lilly & Co., specifically mentioned that, “I think there’s a lot that can be done already to help patients transition back to standard of care, but that being mandated by regulations might be an interesting way to look at it.”
The comment came as something of a surprise to Theresa Mul-lin, Associate Director for Strategic Initiatives in the Center for Drug Evaluation and Research. Later in the meeting, Mullin noted that “I can’t believe that I heard that more regulatory requirements were desirable. But I did hear something to that effect today.”
Saltonstall commented that “I’m not one to have more regulation necessarily,” but he reiterated generally that FDA guidance could be helpful to sponsors in improving the patient engagement process.
Published online April 8, 2019
How Coherus Overcame FDA’s Doubts About Udenyca ImmunogenicityBOWMAN COX [email protected]
It was after Coherus BioSciences Inc. shared clinical immunogenicity results with the US FDA that the agency began
to question the biosimilarity of its Udenyca to Amgen Inc.’s Neulasta (pegfilgrastim).
Ultimately, FDA’s doubts would delay ap-proval by nearly a year, to November 2018. (Also see “Keeping Track: FDA Starts November With A Bang” - Pink Sheet, 2 Nov, 2018.)
Details of the biosimilar immunogenic-ity study, the concerns it raised in FDA’s chemistry, manufacturing and controls review, and how the applicant overcame
those concerns were disclosed in partially redacted drug review documents FDA re-cently posted.
A little over seven months into the re-view of what was then called CHS-1701, re-viewers Haoheng Yan and Fred Mills of the Office of Biotechnology Products in FDA’s Center for Drug Evaluation and Research saw a problem in one of four parallel-arm studies, the one that primarily focused on immunogenicity.
For study CHS-1701-04 to be successful, it would have to convince FDA it could be
95% sure that anti-drug antibodies would not emerge in 10% more of the patients treated with Udenyca than with the US-licensed version of Neulasta, a pegylated recombinant granulocyte colony-stimu-lating factor used to reduce the incidence of febrile neutropenia in patients receiv-ing myelosuppressive anti-cancer drugs.
It would also have to show, with the same degree of assurance, that neutraliz-ing antibodies would not emerge in 3.7% more of the patients treated with Udeny-ca than with the US version of Neulasta.
Coherus reported a 9.8% incidence of anti-drug antibodies in the CHS-1701 arm and a 5.0% incidence, which FDA adjust-ed to 5.8% after identifying an additional positive subject, in the US-licensed Neu-lasta arm, for the 271 healthy volunteers who completed the study.
The difference in the incidence of anti-drug antibodies was only 4% in the study population, but the FDA reviewers fig-ured that statistically, this only provided 95% assurance of a 10.97% difference in treated patients.
Coherus did its own statistical analysis and came up with a 10% figure for the max-imum difference, called a one-sided upper bound of the 95% confidence interval.
Either way, it failed the success criteria, even if just barely.
‘RESIDUAL UNCERTAINTY’ WORRIED FDA“There was extensive discussion of these data within OBP,” FDA’s memorandum on the immunogenicity review said.
Eventually, a consensus emerged in that office, a part of CDER’s Office of Pharma-ceutical Quality, “that the difference cre-ated unacceptable uncertainty regarding the similarity of CHS-1701 and US-Neulas-ta,” the memorandum said.
The agency concluded that the observed difference in anti-drug antibody emer-gence “may not be sufficient to support a demonstration that there are no clinically meaningful differences” with Neulasta.
The difference seen “creates residual uncertainty regarding biosimilarity,” FDA added, particularly given that the base-line immunogenicity rate was expected to be lower, not higher, and the 10% threshold had been chosen just to sup-port a feasible study design.
But FDA went on to suggest that fur-ther study might show the difference was not as bad as it looked. Coherus could examine factors such as titers, persistence and whether the antibodies were responding to the supportive poly-ethylene glycol part of the pegfilgrastim molecule, or the active granulocyte colo-ny-stimulating factor part of it.
The OBP team lead and acting review chief agreed with the reviewers in a May 1, 2017, memorandum to recommend against approval due to the immunoge-nicity concerns.
THE COMPLETE RESPONSEFDA’s June 9, 2017, complete response let-ter led with the immunogenicity concerns arising from OBP’s analysis of the March 21, 2017, study data. (Also see “Neulasta Biosimilar From Coherus Needs Better Immu-nogenicity Assay After Stumble At US FDA” - Pink Sheet, 12 Jun, 2017.)
The letter relayed the concerns raised in the immunological review memo to the applicant, requested the additional infor-mation sought on titers, persistence and antibody targets, and warned that de-pending on what the information shows, Coherus might have to conduct addition-al clinical studies.
The CRL also asked for a fully validated
neutralizing antibody assay, saying that the one submitted with the August 2016 appli-cation and another submitted in a January 2017 amendment were inadequate. The letter referred the company to FDA’s April 2016 draft guidance on developing and validating assays for immunogenicity test-ing of therapeutic protein products.
FDA also requested new potency data. The agency said Coherus had failed to eval-uate potency in its forced degradation stud-ies of CHS-1701 and US-licensed Neulasta.
FDA also requested potency data for the lot used in the immunogenicity clinical study, CHS-1701-04, which Coherus didn’t include due to material limitations, but promised to provide upon request.
There were 10 or 11 pages on release and stability specifications and their justi-fication that FDA redacted from the public version of the complete response letter.
FDA criticized the quality portion of Co-herus’ BLA, called Module 3, saying it was “not well prepared.” Although it was not an approvability issue, the agency asked the firm to include an informative summary regarding information referenced from numerous reports on topics like process characterization and in-process controls, saying that “your summaries with interpre-tations and conclusions form the basis for the agency’s review.”
THE RESUBMISSIONIt was a different story after Coherus re-submitted the BLA on May 3, 2018, as FDA spelled out in a Sept. 21, 2018, immunoge-nicity review memorandum.
FDA said that the company had devel-oped suitable immunogenicity assays, ob-tained serum samples from clinical study subjects and tested those samples for anti-body incidence, titer, specificity for polyeth-ylene glycol and granulocyte colony-stimu-
Udenyca BLA Timeline
August 9 2016
March 212017
June 9 2017
May 32018
November 22018
Coherus submits Udenyca BLA
Coherus submits immunological
study results
FDA answers with complete response letter
Coherus resubmits BLA
FDA approves Udenyca
(pegfilgrastim-cbqv)
✪
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lating factor, and neutralizing activity.When Yan and Mills, the OBP review-
ers, looked over the resulting data set, it showed “no significant difference be-tween CHS-1701 and US-licensed Neu-lasta,” the memo said.
The memo discusses the third neutraliz-ing antibody assay that Coherus developed with a contractor’s help, an anti-G-CSF anti-body titer assay, an immunodepletion NAb confirmatory assay, screening and titer cut point determination, titer assay precision, assay selectivity and sensitivity, matrix in-terference, drug tolerance, stability, and NAb assay precision. Everything was found to be acceptable.
The new assays put the clinical study data in a new light, showing FDA it could approve the biosimilar.
NO NEW NEUTRALIZING ANTIBODIES FOUNDThe new results showed no treatment-emergent neutralizing antibodies in any of the four clinical studies.
Four clinical study subjects had pre-exist-ing polyethylene-glycol-reactive anti-drug antibodies, including two in the immunoge-nicity study behind the complete response.
Yan agreed with Coherus “that their studies provide no evidence for treatment-emergent NAb, and therefore meet this co-primary endpoint.”
G-CSF TITER RESULTS WERE FAVORABLEYan explained that antibodies reactive to pegfilgrastim’s G-CSF moiety could have a critical impact on efficacy by blocking binding to the G-CSF receptor, and that they could impact safety if they cross-react with endogenous G-CSF.
Antibodies that react to polyethylene
glycol “are of less concern, as they are pres-ent at relatively high concentrations in nor-mal individuals without apparent effect,” she commented.
The new results showed six subjects al-ready had antibodies that reacted to G-CSF prior to treatment – five in the CHS-1701 arm and one in the US-Neulasta arm. An-other 16 subjects had treatment-emergent G-CSF-reactive antibodies – nine in the CHS-1701 arm and seven in the US-Neu-lasta arm. However, Coherus said some of those had antibody titers that were too low to measure or were unreliable.
Yan agreed with Coherus that “reliable titers show a low absolute incidence: two in CHS-1701 vs. one in US-Neulasta.”
Coherus concluded from the new data that non-neutralizing, low-titer, PEG-reac-tive anti-drug antibodies were behind the difference in anti-drug antibody incidence seen before but were unlikely to be clini-cally relevant.
Yan agreed that with the lack of treat-ment emergent neutralizing antibodies and the low incidence of anti-G-CSF titers, “from an immunogenicity standpoint, there appear to be no important differenc-es between CHS-1701 and US-Neulasta.”
THE APPROVALBuoyed by these results, Udenyca became the second Neulasta biosimilar approved for the US market, after Mylan NV’s Ful-phila. (Also see “Mylan’s Fulphila: First Neu-lasta Biosimilar’s Road To US Market Slowed Only By Product Quality, GMP Deficiencies” - Pink Sheet, 7 Nov, 2018.) Udenyca’s FDA approval came Nov. 2, 2018, along with the randomly suffixed chemical name of pegfilgrastim-cbqv.
Published online April 5, 2019
Highly SimilarBut Better
On a side note, forced degrada-
tion studies showed Udenyca to
be highly similar to Neulasta, but
also better:
• Chromatograms showed
similar degradation under
photo exposure, except
that Udenyca was more
photo-stable.
• Potency decreased under
photo exposure, but at a
slightly lower rate for
Udenyca.
• Udenyca’s response to heat
stress was similar to
Neulasta’s, but with less
oligomerization.
• Likewise, acid exposure
induced a highly similar
response, but with less oli-
gomerization and
deamidation for Udenyca.
• Base exposure also caused
oligomerization at a highly
similar but slightly lower rate
for Udenyca.
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pink.pharmaintelligence.informa.com April 15, 2019 | Pink Sheet | 17
N E W P R O D U C T S
Amgen’s Evenity Clears US FDA With Preferred Indication, Black Box WarningMICHAEL CIPRIANO [email protected]
W ith the US FDA’s April 9 approval of Evenity (romoso-zumab-aqqg), Amgen Inc. appears to have gotten ex-actly the label it wanted.
Evenity, a first-in-class sclerostin inhibitor, is specifically labeled for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
FDA had been mulling whether to narrow the indication even further to patients at low cardiovascular (CV) risk as a result from the ARCH and BRIDGE trials. (Also see “Amgen’s Evenity Faces CV Safety Gauntlet At US FDA Advisory Cmte. “ - Pink Sheet, 14 Jan, 2019.)
The indication that was eventually approved appears to have been assisted by an endorsement from the Bone, Reproductive and Urologic Drugs Advisory Committee, as a majority of panel-ists supported Amgen’s proposal. (Also see “Evenity Likely Headed For Approval With Amgen’s Proposed Indication, But Postmarketing Requirements Remain Unclear” - Pink Sheet, 16 Jan, 2019.)
The two trials, which were meant to support approval in the Eu-ropean Union, helped to derail Amgen’s initial July 2016 biologics license application (BLA) submission in the US, where it was seek-ing a broad approval for the treatment of osteoporosis in post-menopausal women. ARCH and BRIDGE were completed in the middle of the first review cycle, with the data revealing a higher incidence of positively adjudicated cardiovascular serious adverse events (CV SAEs) during the year-long treatment regimen of Eve-nity. (Also see “ARCH CV Signal Scuppers Blockbuster Hopes For Am-gen/UCB’s Evenity” - Scrip, 22 May, 2017.)
The data prompted FDA to issue a complete response letter in July 2017 with instructions to evaluate the cardiovascular safety findings.
In July 2018, Amgen resubmitted the BLA with a fuller dataset from the ARCH and BRIDGE trials and an external analysis of CV risk, while proposing a new indication for the treatment of osteoporosis in postmenopausal women at high risk of fracture and a black box warning for CV risk. (Also see “Amgen Puts Evenity Filing Back On Track With TIMI Cardiovascular Risk Review” - Scrip, 13 Jul, 2018.)
The company got the black box it desired in lieu of an even narrower indication for patients at low CV risk. The black box notes that Evenity may increase the risk of myocardial infarction, stroke and CV death.
“Evenity should not be initiated in patients who have had a myo-cardial infarction or stroke within the preceding year,” the warning states. “Consider whether the benefits outweigh the risks in pa-tients with other cardiovascular risk factors.”
In terms of postmarketing requirements, FDA is requiring Am-gen to conduct “a five-year observational feasibility study, poten-
tially followed by a comparative safety study or trial,” according to an April 9 release from the drugmaker.
The postmarketing requirement appears to be something of a compromise. Advisory committee members were split on whether FDA should require an observational study or randomized trial to further assess the magnitude of the CV risk. Amgen itself pushed for an observational study, but not a randomized trial, and it won’t have to do one – if the observational study turns out well.
Evenity lowered the risk of a vertebral fracture by 73% in the placebo-controlled FRAME trial, which did not demonstrate a CV risk. In the ARCH trial, which featured alendronate as an active comparator, Evenity reduced the risk of a vertebral fracture by 50% compared to two years of alendronate alone.
The company noted in its release that Evenity is “the first and only bone builder with a unique dual effect that both increases bone formation and to a lesser extent reduces bone resorption (or bone loss) to rapidly reduce the risk of fracture.” Amgen added that it will disclose the list price upon the launch of the drug, which is expected in approximately one week.
Published online April 9, 2019
The earlier advisory committee discussion debated an observational study versus a randomized trial. The postmarketing requirement appears to be something of a compromise.
Pink SheetLEADERSHIPPhil Jarvis, Mike Ward, Karen Coleman
SUBSCRIPTIONSDan Simmons, Shinbo Hidenaga
ADVERTISINGChristopher Keeling
DESIGNJean Marie Smith
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