drug pricing approvals us fda, but gene therapy ......pharma intelligence informa pinksheet...

CONTINUED ON PAGE 4

BROUGHT TO YOU BY THE EDITORS OF SCRIP REGULATORY AFFAIRS, THE RPM REPORT, TAN SHEET, GOLD SHEET, PINK SHEET DAILY AND PINK SHEET

Pharma intelligenceinforma

SheetPinkpink.pharmaintelligence.informa.com Vol. 81 / No. 3 January 21, 2019

US FDA

Shutdown Bite Tightens At US FDA, But Gene Therapy To Get 50 More Reviewers, p. 4

DRUG PRICING

House Oversight Drug Pricing Hearings Will Begin With Expert, Patient Witnesses, p. 8

APPROVALS

Japan Approvals Include World Firsts For Romosozumab, Spinal Injury Cell Therapy, p. 10

comparative pricing and intellectual prop-erty.” (Also see “Ensuring UK Medicines Sup-ply Under No-Deal Brexit “Just Got Harder”” - Pink Sheet, 10 Dec, 2018.)

Following the Jan. 15 vote, Mike Thomp-son, CEO of the ABPI, said: “The focus of pharmaceutical companies is on making sure that medicines and vaccines get to patients whatever the Brexit outcome. This includes stockpiling and duplicating man-ufacturing processes here and in Europe. We continue to work as closely as possible with Government on no deal planning.”

“But we reiterate that ‘no deal’ would prove to be extremely challenging,” Thompson continued. “With time running out we hope Parliament will come togeth-er and quickly find a solution to the stale-mate and reassure patients that medicines will not be disrupted come March 2019.”

Nathalie Moll, director of the European industry federation EFPIA, said: “Now is the time for policy makers in the UK and the EU to put politics aside and put mea-sures in place to prevent patients being harmed by the consequences of Brexit. In particular from disruption to the supply of medicines including from transport delays at the border and where the development, manufacture, packaging, safety testing and regulation of the medicine no longer benefits from mutual recognition.”

Just what kind of solution might be found is anyone’s guess. The first hurdle facing the government is winning a vote on a motion of no confidence tabled by the Labour party, which will be held in

After MPs Reject Brexit Deal, UK ABPI Wants Solution ‘Quickly’IAN SCHOFIELD [email protected]

T he Association of the British Pharma-ceutical Industry has called on UK parliamentarians to find a solution

“quickly” to avoid medicines shortages after parliament overwhelmingly rejected the Brexit deal agreed with the EU in November 2018, casting yet more doubt on the way forward for relations between the UK and the EU after the Brexit date of March 29.

The uncertainty generated by the vote, which took place in the evening of Jan. 15, will be anathema to the life sciences industry, which is desperate for some sort of clarity over the future trade and regula-

tory relationship between the UK and the EU. Its worst nightmare would be the UK falling out of the EU with no deal in place. This is effectively the default option in the absence of agreed alternatives, and it is supported by many Leave backers who want the UK to fall back on World Trade Or-ganization rules.

In December, Steve Bates, CEO of the BioIndustry Association, said that a no deal Brexit “would mean the biggest disintegra-tion of the complex regulated medicines market across Europe in terms of regula-tion, cross border movement of goods,

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exclusive online contentCO V E R After MPs Reject Brexit Deal, UK ABPI Wants

Solution ‘Quickly’

U S F D A 4 Shutdown Bite Tightens At US FDA, But Gene Therapy

To Get 50 More Reviewers

6 Shutdown Week Four: FDA Maintains Pre-Shutdown Output Pace In Some Cases

D R U G P R I C I N G 8 House Oversight Drug Pricing Hearings Will Begin

With Expert, Patient Witnesses

A P P R O VA L S 10 Japan Approvals Include World Firsts For Romosozumab,

Spinal Injury Cell Therapy

A D V I S O RY CO M M I T T E E S 12 Is There A REMS In Uloric’s Future? US FDA Panelists

Say Yes, Agency Says Not Likely

18 Recent And Upcoming FDA Advisory Committees

D R U G R E V I E W S 13 UK’s NICE Under Fire For New HTA Fees

M A N U FAC T U R I N G Q UA L I T Y 14 PIC/S Considers New System For Monitoring

Compliance By Members

15 Random Checks Now Routine: China To Inspect Your Factories Near And Far

R E G U L ATO RY U P D AT E 16 EMA To Bring Anticancer Drugs Guide Up To Speed

With Biomarker Development

inside: 15 9 10

CVS Medicare Part D Plan With Pass-Through Rebates Has Limited Uptakehttps://pink.pharmaintelligence.informa.com/PS124575

Low enrollment indicates that beneficiaries have trouble figuring out whether reductions in cost sharing would offset a much higher premium.

ICER’s ‘Unsupported Price Increase’ Report Due This Fallhttps://pink.pharmaintelligence.informa.com/PS124583

Report by the Institute for Clinical and Economic Review will seek to inform the public policy debate on price increases for prescription drugs.

Mexican Pharma Industry Joins Anti-Corruption Crackdownhttps://pink.pharmaintelligence.informa.com/PS124581

The Mexican research-based pharmaceutical industry has pledged to crack down on corruption as the country’s new president says the vice must be eliminated to deliver better health system.

Sanofi’s Sotagliflozin: Risk Of Ketoacidosis Divides US FDA Advisory Committeehttps://pink.pharmaintelligence.informa.com/PS124584

Some Endocrinologic and Metabolic Drugs Advisory Committee members said a REMS is sufficient, but others worried that proposed risk management plans were not proven effective.

NICE Clears Verzenios For Breast Cancer After Lilly Offers UK Discounthttps://pink.pharmaintelligence.informa.com/PS124585

Verzenios, Lilly’s new drug for metastatic breast cancer, is some way behind Pfizer’s Ibrance and Novartis’s Kisqali, but it has some clinical advantages that could allow it to gain uptake.

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B R E X I T

the evening of Jan. 16. If, as expected, the government wins that vote, prime min-ister Theresa May has said she hopes to meet parliamentarians from across the political spectrum to discuss some sort of deal that might be accepted by the House of Commons.

Her choices are limited, though Mrs May could seek more concessions from the EU to make the deal more palatable to MPs on both sides of the Brexit debate – or talk about some other package – but the EU has little room for manoeuvre given the “red lines” she has laid down, such as withdrawal from the EU customs union and single market, and ending freedom of movement and the jurisdic-tion of the Court of Justice of the EU. Should the prime minister relax those red lines, some other relationship – a form of “softer” Brexit, a customs union for example – could be negotiated with the EU. So far, though, she has refused to give ground on those stipulations.

One possibility for the government is to seek an extension of the Article 50 notification period, which is set to ex-pire on March 29, to remove some of the pressure building up as the Brexit dead-line approaches. Such an eventuality is thought to have been discussed, and the

EU would be expected to agree an exten-sion to at least July this year, but only to allow a significant event to take place, such as a fresh referendum on Brexit or a general election, not to try to renegoti-ate the agreed deal.

While the idea of a new referendum has many supporters among the public, politically it would be very controversial, and it is not clear how much backing it would have in parliament. But if the gov-ernment wins the confidence motion, Labour members in favour of Remain are expected to increase the pressure on the party’s leader, Jeremy Corbyn, to back a new referendum.

A further option is to revoke the Ar-ticle 50 notification altogether, a scenario backed by London First, an organization representing around 200 businesses across the capital. It said: “With the Prime Minister’s deal dead in the water, we need to stop the clock and revoke Article 50 to avoid a disastrous no deal Brexit. A vote of no confidence is unlikely to achieve much apart from further delay. We urge the Government and parliamentarians on all sides to step back from the brink and agree a way forward quickly. If the Gov-ernment can’t come up with a plan that commands Parliamentary support, the decision should go back to the people.”

EU VIEW Speaking after the vote, the EU’s lead ne-gotiator Michel Barnier said that there was a “crystal clear majority” against the with-drawal agreement. While it was too early to assess all the consequences of the vote and he would not speculate on the different sce-narios, he noted that the vote “showed that political conditions are not yet there in Lon-don” for accepting the negotiated deal. But he added: “The EU will remain united and determined to find a deal.”

The EU is prepared to consider any al-ternative plan the UK can offer, but has stressed that the ball is now in the UK’s court. European Commission President Jean-Claude Juncker said time was run-ning out. “I urge the United Kingdom to clarify its intentions as soon as possible. Time is almost up,” he said.

Among some at EU level, the vote seems to have generated the impression that things are edging towards a “softer” Brexit, or perhaps even a “no-Brexit” outcome. European Council president Donald Tusk tweeted: “If a deal is impossible, and no one wants no deal, then who will finally have the courage to say what the only pos-itive solution is?

From the editors of Scrip Regulatory Affairs. Published online January 16, 2019

CONTINUED FROM COVER

U S F D A

Shutdown Bite Tightens At US FDA, But Gene Therapy To Get 50 More ReviewersMICHAEL CIPRIANO [email protected]

I n anticipating a glut of new investiga-tional new drug (IND) applications for cell and gene therapies in the coming

years, the US FDA announced its goal to add 50 additional clinical reviewers to deal with the growing workload.

In a Jan. 15 statement from FDA Com-missioner Scott Gottlieb and Center for Biologics Evaluation and Research (CBER) Director Peter Marks, the regulators pre-dicted that the agency will be receiving

more than 200 INDs per year by 2020. FDA already has more than 800 active cell-based or directly administered gene thera-py INDs on file, the officials noted.

Gottlieb and Marks further predicted that FDA will be approving 10 to 20 cell and gene therapy products a year by 2025 “based on an assessment of the current pipeline and the clinical success rates of these products.”

According to the statement, the 50 new clinical reviewers would be added “to the

group charged with overseeing the clinical investigation, development, and review of these products.”

BUSINESS AS USUAL, BUT STRAINS SHOWINGThe new CBER announcement comes as FDA trudges through its fourth week of the government shutdown. (Also see “Shutdown Week Four: FDA Maintains Pre-Shutdown Output Pace In Some Cases” -



Pink Sheet, 14 Jan, 2019.)The agency has done its best to main-

tain its muscular communications strategy and convey an appearance of business as usual. (Also see “Drug Safety Announcement Blitz Highlights Gottlieb’s PR Savvy As Shut-down Drags On “ - Pink Sheet, 9 Jan, 2019.) Gottlieb has kept up a near-constant Twit-ter presence on a variety of issues through-out the shutdown, including updates on the status of FDA’s user fee funding.

But strains are starting to show. Some furloughed staffers have had to return to work unpaid to inspect high-risk facili-ties, and Aimmune Therapeutics Inc. an-nounced that the agency cannot begin review of AR101, its oral immunotherapy for peanut allergy, even though the BLA was submitted before the shutdown. The application is being handled by CBER.

Perhaps most ominously, Gottlieb an-nounced the agency was reducing its “burn rate” to extend its user-fee funded activities for a few more weeks.

HIRING TIMELINE UNCLEAR Against that backdrop, the announcement of anticipated staff expansion probably seemed at least a little incongruous. A larger staff has been anticipated for CBER, as Marks had previously said that the center will need more personnel handle the increasing pop-ularity of gene therapies. (Also see “US FDA’s Biologics Center Director Expects It Soon Will See ‘Growth Spurt’” - Pink Sheet, 2 Jul, 2018.)

But the timing for CBER’s expected hires remains unclear. An FDA spokesperson told the Pink Sheet that the agency does not have an update on a specific timeline at this time.

FDA has historically struggled with hir-ing staff to fill vacancies. But the agency re-cently restarted a pilot program intended to streamline the process.

POLICIES REMAIN ON TRACK Gottlieb and Marks reiterated that the agency “will work with sponsors to make maximum use of our expedited programs including regenerative medicine ad-vanced therapy (RMAT) designation and accelerated approval.”

The FDA spokesperson pointed to the informal meetings from the agency’s Ini-

tial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) pro-gram, which she said “provide sponsors with early interactions with the agency, and allow the FDA to encourage sponsors with products that show promising safety and efficacy to apply for use of the expedit-

ed programs, including RMAT designation.” (Also see “CBER Implements Pre-Clinical Meeting Program For Biologics, Gene Ther-apy Sponsors” - Pink Sheet, 22 Jun, 2018.)

Gottlieb has also previously trumpeted his support for gene therapy sponsors to pursue the accelerated approval pathway. (Also see “Gottlieb On Gene Therapies: ‘Very Seductive’ To Think About Accelerated Ap-proval Pathway “ - Pink Sheet, 7 May, 2018.) He and Marks echoed that sentiment in the Jan. 15 statement.

“For one thing, the accelerated approval pathway may offer a faster route to approv-al for new treatments, including potentially curative benefits in significant, unmet med-ical needs,” the officials said. “But the path-way also offers additional authorities for FDA to require postmarket follow-up stud-ies. Since many of the risks associated with gene therapy products relate to questions about the product’s durability and potential for rare instances of off-target effects, it may not be feasible to conduct pre-market trials that address all these theoretical risks in any reasonably sized study.”

The statement also mentions that a slew of guidance documents on product devel-opment is in the works, including for inher-ited blood disorders such as hemophilia. FDA already released draft guidance on the

development of gene therapies for hemo-philia in July 2018 amid a trove of others. (Also see “Hemophilia Gene Therapy Studies Could Use Non-Inferiority Design, US FDA Sug-gests “ - Pink Sheet, 16 Jul, 2018.) and (Also see “Gene Therapies Need Long-Term Follow-Up Plan From Outset Or Risk Clinical Hold “ - Pink Sheet, 11 Jul, 2018.) The agency spokeswom-an indicated that the hemophilia guidance mentioned in the announcement would be a finalized guidance.

Gottlieb and Marks additionally re-hashed FDA’s intention to issue guidance on the development of gene therapies for certain neurodegenerative diseases. Just as Gottlieb recently explained to the J.P. Morgan conference in San Francisco, the regulators noted in their announce-ment that the accelerated approval path-way would only be applicable for certain neurodegenerative drugs. (Also see “Gene Therapies: Accelerated Approval Open For Some, But Not All, Neurodegenerative Dis-ease Treatments” - Pink Sheet, 8 Jan, 2019.)

“For example, we intend to propose guidance to address how the accelerated approval pathway may be used when the target of the gene therapy product is an underlying monogenetic change that causes a serious disorder not addressed by available therapy,” the statement reads. “In these cases, the gene therapy could offer the potential to alter or cure the underly-ing genetic defect that gives rise to, and causes the advance of, a disease.”

However, the regulators continue, “a more traditional approach to drug devel-opment may be more appropriate if the gene therapy creates a genetic alteration aimed at treating the symptoms of a neu-rodegenerative disease, or potentially al-tering its course by altering the expression of a protein or enzyme believed to play a role in the advance of a disease.”

An additional forthcoming guidance “will recommend parameters for how innovators can introduce advances in manufacturing that promote the more efficient development and application of CAR-T therapies without necessarily re-quiring costly new clinical investigations,” the announcement adds.

Published online January 15, 2019

U S F D A

The timing for CBER’s expected hires remains unclear. FDA

recently restarted a pilot program

intended to improve the hiring process.



SHUTDOWN WEEK FOUR: FDA Maintains Pre-Shutdown Output Pace In Some CasesDERRICK GINGERY [email protected]

T he US FDA has managed to main-tain and sometimes exceed prior output levels during the weeks

since the start of the partial government shutdown, although it appears that pace soon may diminish.

The agency has been using carryover user fee revenue to continue reviewing pending applications and perform other functions since congressional Democrats and the White House failed to reach a funding agreement.

Carryover-fueled production in some cases has been robust since the shut-down began Dec. 21. FDA has approved about as many ANDAs per day since the shutdown began as during the three weeks leading up to it. Tentative applica-tion approvals during the shutdown were ahead of the pre-shutdown pace, accord-ing to data as of Jan. 11.

However, production on the new drug side of FDA’s operation has dropped dra-matically. No original NDAs or BLAs were approved from Dec. 21 through Jan. 11 and supplement output has slowed com-pared to before the shutdown. The agen-cy hasn’t missed any user fee deadlines, however, and the absence of any full ap-provals could simply reflect a lull follow-ing 2018’s record-breaking pace.

Sponsors and other stakeholders who continue to work with the agency have said that business largely remains as usu-al: reviews are continuing and questions are being answered.

Sponsor and public meetings also are remaining as scheduled. The agency conducted its Jan. 11 advisory commit-tee meeting on cardiovascular safety and regulatory options for Takeda Pharma-ceutical Co. Ltd.’s Uloric (febuxostat) (Also see “Is There A REMS In Uloric’s Future? US FDA Panelists Say Yes, Agency Says Not Like-ly” - Pink Sheet, 12 Jan, 2019.) and released documents in advance of a Jan. 16 advi-sory committee meeting on Amgen Inc.’s

romosozumab.But an output decrease seems all but

inevitable given FDA priority changes and a dwindling pot of money.

Commissioner Scott Gottlieb tweeted Jan. 8 that he intended to “re-allocate user fee money from certain pre-market drug review work to postmarket drug safety surveillance.” (Also see “Drug Safety An-nouncement Blitz Highlights Gottlieb’s PR Savvy As Shutdown Drags On “ - Pink Sheet, 9 Jan, 2019.)

“We’re systematically reviewing our portfolio and making sure that our safety functions remain resourced as best they can, for as long as they can,” Gottlieb tweeted. “Our consumer protection role is our most critical mission.”

“All of our work at the FDA is critical, so nothing we stand down is unimport-ant,” he added. “But the functions that can most directly impact consumer safety will continue, to the best of our abilities, sub-ject to the legal and financial limitations of the current circumstances.”

Gottlieb also tweeted Jan. 13 that more facility surveillance inspections, surveil-lance sampling of high-risk imports, as well as more recall-related activities, should be considered exempt during the shutdown, meaning related staff would continue working without pay, because they are considered essential to public

health and safety.“It is not business as usual at FDA,” Got-

tlieb said in a tweet. “Many key functions aren’t getting done. But we’re focused on maintaining core activities that directly impact consumer safety and save lives.”

Gottlieb said Jan. 14 the prescription drug user fee carryover had about five weeks of funds remaining thanks to re-ductions in overhead, an increase from Jan. 5, when there was about a month of carryover remaining. He said Jan. 8 that the medical device user fee program has two to three months of funding and the generic user fee program has between one and three months of funding.

FDA retained about 59% of its staff during the shutdown, the majority of which with carryover funds. The agency is expected to furlough more employees as user fee funds run out. (Also see “As US FDA Shutdown Continues, What Will Be The Cost Of Not Spending?” - Pink Sheet, 28 Dec, 2018.)

ANDA, SUPPLEMENT APPROVALS CONTINUE… With carryover balances diminishing, FDA also may try to clear as much of its pend-ing work as possible.

Attorney Frank Sasinowski, a director at Hyman, Phelps and McNamara, told the Pink Sheet that he expects FDA will calcu-

U S F D A

“We’re systematically reviewing our portfolio and making sure that our safety functions remain resourced as best they

can, for as long as they can.” – Commissioner Gottlieb



late a date that carryover funds will run out and “likely reach to finish actions that are within the penumbra of that date,” such that goals approaching soon after the cutoff may be accelerated.

Agency data suggests that review staff-ers made a final push to complete as much work as possible both as the shutdown approached and as it appeared user fee funds would be directed elsewhere.

FDA approved 172 NDA/BLA supple-ments from Dec. 1-Dec. 21, including 92 from Dec. 18 through Dec. 21, the final four work days before funding lapsed. The total over the final four days repre-sented about 53% of all the supplements approved in December before the shut-down began.

FDA posted another 89 supplement ap-provals from Dec. 22-Jan. 11, including a sodium-chloride labeling supplement that was signed and posted Dec. 29, a Sat-urday. (See charts.)

The post-shutdown total included 42 approvals, about 47%, that were posted Jan. 9 through Jan. 11, after Gottlieb an-nounced his shift of funds to postmarket surveillance.

Supplement output has decreased dur-ing the lapse period. The agency is aver-aging about seven supplement approvals per day, compared to about 11 per day from Dec. 1-21.

FDA is approving about the same num-ber of ANDAs per day since the shutdown began as compared to the three weeks leading up to it. The agency is averaging 3.3 ANDA approvals per work day since funding lapsed, compared to 3.4 ANDA approvals per day from Dec. 1-21.

During the three weeks in December before the shutdown, FDA approved 51 ANDAs, including 10 posted Dec. 21, its largest daily output of the month. From Dec. 22-Jan. 11, the agency approved 40 ANDAs.

Tentative application approvals, al-though much smaller in number, have a higher post-shutdown rate than the pre-shutdown period. As of Jan. 11, the agen-cy issued more tentative approvals during the 12 work days since the shutdown be-gan, 15, compared to the 15 work days in December before the shutdown, 14.

…BUT WHAT ABOUT NDA-BLA APPROVALS? The supplement, ANDA and tentative ap-plication approval totals illustrate the work FDA still could accomplish with carryover

funds, which garnered praise from Gott-lieb and others.

The lack of an original NDA-BLA approval since the shutdown began potentially illus-trates what is to come if the shutdown is not

U S F D A

Full ANDA Approvals Pre- And Post-Shutdown

NDA/BLA Supplement Approvals Pre- And Post-Shutdown

*Indicates approval was issued on a non-work day (Saturday)

Note: Pink bars indicate pre-shutdown daily approval totals, crimson bars post-shutdown approval totals.

FDA approved many applications in the days leading up to the Dec. 21 govern-ment shutdown, but also has been able to keep pace with outputs despite the funding lapse thanks to carryover user fees. No original NDAs or BLAs were ap-proved between the start of the shutdown and Jan. 11.

Source: FDA’s Drugs@FDA website

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U S F D A

resolved before carryover funds run out.There also are more than 10 products

with user fee goals in January, including some new molecular entities, whose re-views could be delayed. (Also see “User Fee Goal Dates” - Pink Sheet, 7 Feb, 2017.)

Among them is Immunomedics Inc., whose proposed breast cancer treatment Sacituzumab govitecan (IMMU-132) has a Jan. 18 user fee goal. The company told the Pink Sheet that conversations with FDA are progressing and there is no reason to an-ticipate a delay.

Many more NDA goals arrive in Febru-ary and if the shutdown continues, spon-sors of those products also face potential delays in their approval decisions. (Also see “Shutdown Week Three: Sponsors With Up-coming User Fee Dates Should Start Sweat-ing “ - Pink Sheet, 7 Jan, 2019.)


Tentative Approvals Pre- And Post-Shutdown

Note: Pink bars indicate pre-shutdown daily approval totals, crimson bars postshutdown approval totals.

Source: FDA’s Drugs@FDA website

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D R U G P R I C I N G

House Oversight Drug Pricing Hearings Will Begin With Expert, Patient WitnessesCATHY KELLY [email protected]

T he US House Oversight and Reform Committee’s Jan. 29 hearing on drug pricing will include testimony

from experts and patients affected by ris-ing prices, according to the panel.

The hearing will be the first of “several” to tackle the issue, the committee said. As a first step in the committee’s investigation into drug pricing, Chairman Elijah Cum-mings, D-MD, also sent letters to 12 bio-pharma companies requesting informa-tion on the reasons behind price increases.

The letters seek information and com-pany communications on price increases, investments in research and development and corporate strategies to preserve mar-ket share and pricing power. They focus on drugs that are among the costliest to Medicare Part D, among the costliest per beneficiary, or had the largest price in-creases over a five-year period.

Companies receiving letters include:

• AbbVie Inc. (for Humira, Imbruvica);

• Amgen Inc. (Enbrel, Sensipar);

• AstraZeneca PLC (Crestor);

• Celgene Corp. (Revlimid);

• Eli Lilly & Co. (Humalog Qwikpen);

• Johnson & Johnson (Imbruvica);

• Mallinckrodt PLC (H.P. Acthar);

• Novartis AG (Gleevec);

• Novo Nordisk AS (Novolog Flexpen, Victoza 3-Pak);

• Pfizer Inc. (Lyrica, Nexium);

• Sanofi (Lantus, Renvela); and

• Teva Pharmaceutical Industries Ltd. (Copaxone).

“The Committee on Oversight and Re-form is investigating the actions of drug companies in raising prescription drug prices in the United States, as well as the ef-fects of these actions on federal and state budgets and on American families,” Cum-mings says in the letters.

“For years, drug companies have been aggressively increasing prices on existing drugs and setting higher launch prices for new drugs while recording windfall profits. The goals of this investigation are to deter-mine why drug companies are increasing prices so dramatically, how drug com-panies are using the proceeds, and what steps can be taken to reduce prescription drug prices,” he explains.

The letters acknowledge that “research and development efforts on groundbreak-ing medications have made immeasurable contributions to the health of Americans,



including new treatments and cures for diseases that have affected people for cen-turies.” But Cummings adds, “the ongoing escalation of prices by drug companies is unsustainable.”

The investigation is a priority initiative for the committee and represents the kind of activity that can be expected from the House now that Democrats are in charge. (Also see “Democrat-Controlled House Will Turn Up The Volume On Drug Pricing” - Pink Sheet, 7 Nov, 2018.)

However, it’s unclear whether the in-vestigation will lead to legislation that would find traction in the Republican-controlled Senate. House Democrats re-cently unveiled a package of bills with ideas that are unlikely to generate much Republican support. (Also see “Demo-crats’ Drug Pricing Bills Echo Trump Ideas But Broad Republican Support Unlikely” - Pink Sheet, 10 Jan, 2019.)

LEGISLATION ON REBATE REFORM MAY BE NEEDED, SEN. COLLINS SAYSHowever, some Senate Republicans are also pushing for results on drug pricing. Sen. Susan Collins, R-Me., wrote to HHS Secretary Alex Azar Jan. 10 urging admin-istrative action on rebate reform and sug-gesting legislation may be necessary.

HHS has taken steps to explore different approaches to rebate reform but has yet to announce any action. The government first looked into the feasibility of requiring point-of-sale rebates in Medicare Part D. It ran into concerns that the practice would lead to higher spending for Medicare but has not publicly abandoned the idea. (Also see “Part D Point-Of-Sale Rebates Los-ing Appeal? CBO Confirms Big Cost To Medi-care” - Pink Sheet, 30 May, 2018.)

The department has also sent a pro-posed rule to the Office of Management

and Budget for approval that would re-vise the current anti-kickback safe harbor for rebates, which could create a major disruption in the rebating system. The proposal has been pending since July. (Also see “Pfizer Price Increases Underscore Rebate Problem, HHS’ Hargan Says” - Pink Sheet, 12 Dec, 2018.)

The Administration’s drug pricing blue-print “appropriately identifies the need for rebate reform as an opportunity to in-centivize lower list prices,” Collins says. “I encourage HHS to take action quickly on this initiative.”

Collins noted the Senate Aging Com-mittee, which she chairs, conducted an investigation into price increases for in-sulin in 2018 and heard from manufactur-ers that increasing rebate demands from pharmacy benefit managers help drive up list prices.

“Although rebates are certainly not the only cause of rising drug prices, it is clear that they warrant greater attention from both the Administration and Congress,” she maintains. “Rebates calculated as a percentage of list prices create an especial-ly perverse incentive for supply chain par-ticipants to encourage higher list prices.”

Legislation “may well be necessary and I would appreciate the opportunity to work with you and your staff on legislative re-forms,” she adds.


D R U G P R I C I N G

Republican Sen. Susan Collins wrote to HHS Jan. 10 urging administrative action on rebate reform and suggesting legislation may be necessary.

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Japan Approvals Include World Firsts For Romosozumab, Spinal Injury Cell Therapy IAN HAYDOCK [email protected]

J apan’s Ministry of Health, Labour and Welfare has granted formal marketing authorizations to a group of new products, including the first such regulatory nods globally for several

novel therapies. The Tokyo-based Amgen Astellas BioPharma KK joint venture

secured the first approval worldwide in early January for its anti-sclerostin antibody Evenity (romosozumab), for the treatment of osteoporosis in patients at high risk of fracture.

The Japanese medical device, packaging and equipment group Nipro Corp. meanwhile was granted a conditional approval at the end of December for regenerative medicine Stemirac (STR01), a breakthrough autologous bone marrow mesenchymal stem cell (MSCs) therapy for the treatment of patients with spinal cord injuries.

Co-developed in Japan with Astellas Pharma Inc. and UCB Group, Evenity acts as an anabolic therapy to promote bone for-mation and reduces bone resorption to increase bone mineral density and reduce hip and other fracture risk, one of the main causes in Japan of loss of independence and nursing care among the country’s estimated 12 million osteoporosis sufferers.

Astellas noted that patients with a prior fracture are around twice as likely to suffer another one if undiagnosed and untreat-ed, and as such the new therapy may help to address a major cause of disability.

The Japanese approval was based on two Phase III trials; FRAME

in 7,180 postmenopausal women with osteoporosis and BRIDGE in 245 men with osteoporosis, which showed significant reductions in both vertebral and clinical fractures, and significant increases in bone mineral density.

The country’s regulatory agency, the PMDA, also reviewed car-diovascular safety data from the 4,093-patient ARCH trial, conduct-ed in high fracture risk postmenopausal women with osteoporosis.

Romosozumab - which is still under approval review in the US and EU - is now awaiting a reimbursement price listing under Ja-pan’s national health insurance (NHI) system, which will allow na-tionwide launch, and will be co-promoted by Amgen Astellas (51% owned by Amgen Inc.) and Astellas, with UCB to conduct disease awareness activities.

A US FDA advisory committee on romosozumab is currently scheduled for Jan. 16, following the refiling last July by Amgen of a BLA in the wake of a July 2017 Complete Response Letter. (Also see “Amgen Puts Evenity Filing Back On Track With TIMI Cardiovascular Risk Review” - Scrip, 13 Jul, 2018.)

Evenity will enter an osteoporosis biologics market in Japan that already includes Amgen’s RANK ligand antibody denosumab, ap-proved locally as Pralia in 2013 through local partner Daiichi San-kyo Co. Ltd., and Eli Lilly & Co.’s recombinant parathyroid hormone Forteo (teriparatide), approved locally in 2010.

Datamonitor Healthcare forecasts a contraction in the country’s total osteoporosis market to $791m by 2025, however, affected by Foreto’s loss of exclusivity and the availability of the relatively cheaper anabolic therapies such as Evenity.

WORLD-FIRST CELL THERAPY NODNipro’s Stemirac was granted a conditional approval by the min-istry in late December, following a late June 2018 filing that was given expedited review under Japan’s “sakigake” scheme for pio-neering breakthrough therapies.

This status was granted for the Nipro product in 2016, for the treatment of neurological symptoms and disabilities in spinal cord injury patients, and the recent clearance (which followed a positive recommendation in November) is the first in the world for a stem cell-based therapy in this indication.

Jointly developed with a specialist at Sapporo Medical University in Japan, the treatment involves the extraction of MSCs from pa-tients’ marrow within a few weeks of the injury. These are then cul-tivated and a “dose” of 50-200 million cells injected intravenously back into the patient within several months of injury, to help re-duce inflammation and promote regeneration of bone and blood vessels and the restoration of damaged nerve connections.

While the approval was supported by a small clinical trial in 13 patients that showed improvement in motor function in some

A P P R O VA L S

Spongy bone tissue affected by osteoporosis



cases, the ministry has requested a comprehensive all-patient sur-veillance program to confirm safety and efficacy as a condition of approval, while still enabling early access.

The therapy is also expected to be granted reimbursement un-der Japan’s NHI scheme, which has a precedent of paying for sever-al earlier regenerative medicines in other indications, and the fact

that the country has a highly supportive policy framework for such therapies, with dedicated regulations enacted in late 2014.

Other activity in the spinal cord injury field in Japan includes a planned small clinical trial with induced pluripotent stem cell-de-rived neuronal cells.

TARLIGE, VIZIMPRO, OTHERS The group of early January approvals also included Daiichi San-kyo’s Tarlige for peripheral neuropathic pain (PNP), and Gilead Sciences Inc.’s Epclusa for chronic hepatitis C virus infection.

Tarlige (mirogabalin besylate), an alpha 2 delta ligand that binds to subunits of voltage-dependent calcium channels, was filed in February last year on the basis of Asian trials (including Japan) in diabetic PNP and postherpetic neuralgia. The first of these conditions is estimated to affect 9-22% of the more than 10 million diabetes patients in Japan, Daiichi noted. The approv-al is the first worldwide for the drug.

Epclusa (sofosbuvir 400mg plus velpatasvir 100mg), a once-daily oral therapy, becomes the first product to be approved in Japan for adults with chronic HCV infections with decompen-sated cirrhosis, with a 12-week course.

It was also cleared for chronic HCV without cirrhosis, or pa-tients with compensated cirrhosis who have had prior treatment with a direct-acting antiviral (DAA), both of which have limited treatment options and will require a longer 24-week regimen in combination with ribavirin.

Sofosbuvir, an NS5B polymerase inhibitor, was approved alone as Sovaldi for HCV in Japan in 2015, while velpatasvir is an NS5A inhibitor.

Gilead noted the approval was supported by a Japanese trial in which 92% of those were “cured”, reaching SVR12 (undetect-able HCV RNA after 12 weeks). A separate Japanese trial in geno-type 1 or 2 patients failing DAA treatment gave an SVR12 rate (with ribavirin) of 97%.

Also approved by the health ministry was Otsuka Pharmaceu-tical Co. Ltd.’s Selincro (nalmefene; licensed from Lundbeck Inc.), an oral small molecule therapy to reduce alcohol consumption in

alcohol-dependent patients, Daiichi Sankyo’s Minnebro (esaxer-enone) for hypertension, and Pfizer Inc.’s Vizimpro (dacomitinib) for non-small cell lung cancer (NSCLC).

Nalmefene was approved in Europe for the indication in 2013, and acts as an antagonist to certain brain opioid receptors, helping to reduce craving. Esaxerenone blocks activation of mineralocorti-coid receptors and was identified under a 2006 research collabora-tion in this field with US firm Exelixis Inc., which led to a Japanese filing in February 2018, based on the local Phase III ESAX-HTN trial versus eplerenone.

Exelixis said it would receive a $20m milestone payment on the first commercial sales in Japan, adding to a milestone of the same amount last year upon the approval application. It is also eligible to “substantial” commercial milestones and low double-digit sales royalty payments under the deal, under which Daiichi holds global development and sales rights.

The new Japanese approval is another first worldwide for the drug, which is also in Phase III development in Japan for diabetic nephropathy.

The Japanese approval of Vizimpro was for EGFR gene mutation-positive, inoperable or recurrent NSCLC, a form of the disease which has a generally higher incidence in Asian patient popula-tions, and came just around seven months after the regulatory fil-ing in late May 2018. The oral kinase inhibitor was approved for first-line use by the US FDA last September for patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations, and has been submitted in the EU.

As in the US, the Japanese approval was supported by the 452-patient, Phase III ARCHER1050 comparative first-line study conducted in Japan and South Korea (co funded with SFJ Phar-maceuticals Inc.), which showed a statistically significant improve-ment in the primary endpoint of median progression-free survival versus gefitinib (AstraZeneca PLC’s Iressa), which was 14.7 months versus 9.2 months respectively.

From the editors of PharmAsia News. Published online January 16, 2019

A P P R O VA L S

The early January approvals also included Daiichi’s Tarlige for peripheral neuropathic pain (PNP), and Gilead’s Epclusa for chronic hepatitis C virus infection.

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

Is There A REMS In Uloric’s Future? US FDA Panelists Say Yes, Agency Says Not LikelySUE SUTTER [email protected]

A US FDA advisory committee said Jan. 11 that Takeda Pharmaceuticals USA Inc.’s gout drug Uloric (febuxo-

stat) should stay on the market, but with more restrictive labeling and possibly even a Risk Evaluation and Mitigation Strategy (REMS) – a remedy that the agency suggest-ed would be challenging if not unworkable.

Members of the Arthritis Advisory Com-mittee and Drug Safety and Risk Manage-ment Committee overwhelmingly voted that there is a gout patient population for which febuxostat’s benefit/risk profile is fa-vorable, despite an increased cardiovascular (CV) mortality risk seen in the CARES post-marketing study. (See box.)

That population, most panelists agreed, comprises patients who are intolerant to, or who fail on, allopurinol, which is the most frequently prescribed first-line treat-ment for gout.

Most committee members supported stronger label warnings on CV events, or even a boxed warning on CV death, as well as restricting the xanthine oxidase inhibitor’s indication to second-line use. Only two pan-elists supported market withdrawal under certain circumstances.

PANELISTS SEE REMS AS ALTERNATIVE TO WITHDRAWALFDA convened the advisory committee to consider regulatory options for febuxostat, which was approved in 2009 albeit with CV safety concerns. In the CARES postmarket-ing study required under that approval, febuxostat did not show an increased risk of major adverse cardiovascular events (MACE) but was associated with a 34% in-creased risk of CV death.

Although the agency presented five reg-ulatory options for committee discussion in its draft questions, FDA took one option – REMS – off the table in its final questions for the panel. (Also see “Takeda’s Uloric: CV Mor-tality Signal Leads US FDA To Ponder Regula-tory Options” - Pink Sheet, 9 Jan, 2019.)

However, it was an option that found favor with about one-third of the com-mittee members, who said a REMS would help ensure that providers are educated about the CARES data and that they have a conversation with their patients about the drug’s CV risks.

Cleveland Clinic Department of Cardio-vascular Medicine Chair Steven Nissen, who voted no on the question, called for a highly restrictive REMS in which the drug is distributed only through a centralized pharmacy and available only to prescrib-ers and patients who sign an informed consent. Such a restrictive program is necessary because changes in labeling, even boxed warnings, rarely result in ma-jor utilization challenges, Nissen said.

However, his proposal drew pushback from committee members who worried about putting up hurdles to treatment for gout patients, who already are undertreated.

“I’m quite nervous about what’s been suggested,” said David Felson, professor of

medicine and epidemiology at Boston Uni-versity. “The majority of patients with treat-able gout, many of whom have disability, are currently not receiving long-term ther-apy in the US, and I don’t really want to put more scary barriers in front of them.”

Bruce Psaty, co-director of the cardiovas-cular health research unit at the University of Washington, said he agreed with Nissen that a boxed warning is likely to have a lim-ited effect. But “I’m not sure I would go quite as far as Steve. I wouldn’t recommend with-drawing febuxostat, but it clearly should be a second-line agent in a way that can be convincingly conveyed by the FDA.”

Had the CARES data been available 11 years ago, febuxostat – which was the sub-ject of two complete response letters citing CV safety concerns – never would have got-ten approved, said Steven Meisel, system director of medication safety at Fairview Health Services in Minneapolis.

“But it is on the market, and I think it’s clear that there is a small subset of pa-tients for whom there is a benefit, and withdrawing it from the market is too ex-treme,” Meisel said. However, merely up-dating the labeling will be “pretty useless,” he added.

Patients should understand what the drug’s potential CV risks are and decide for themselves whether to assume those risks, Meisel said. “We have to empower the pa-tients to make their own decisions on an informed basis on this, and we can do that through an effective REMS program, prop-erly designed. But I wouldn’t go so far as to pull this drug into a specialty pharmacy. I think that’s a barrier too far.”

FDA PUSHES BACKHowever, the discussion about REMS prompted Jamie Wilkins, deputy director of FDA’s Division of Risk Management, to discuss the challenges of creating a REMS to address febuxostat’s CV risks.

“In the postmarketing setting, the

“The majority of patients with treatable gout, many of whom

have disability, are currently not receiving long-term therapy in the US, and I don’t

really want to put more scary barriers in front

of them.” – Boston University’s Felson




threshold to place a REMS on a product is that we would otherwise be considering taking a product off the market without the REMS in place,” Wilkins said.

“Additionally, REMS, although they may suppress the use of a product, that’s not their intention. Their intention is to miti-gate a risk. And here, we would be mitigat-ing the risk of MACE. How would we actu-ally measure that outcome here if the only program we would be putting together would be informative?”

Although the panel wants to ensure that the benefit/risk conversation between a prescriber and a patient actually takes place, “unless you’re otherwise suggesting to withdraw the product from the market,

then a REMS is not going to be put in place from a regulatory perspective to achieve that goal,” Wilkins said.

FDA lacks the ability to adequately mea-sure the mitigation of MACE risk or moni-tor it, she said. “It’s such a broad term that putting a REMS in place is very difficult to actually quantify and assess whether or not it’s successful in the setting of MACE.”

However, panelists suggested they were unswayed by FDA’s concerns.

“The only way to require [patients] be informed is through a REMS type of program,” Meisel said. “I frankly reject the notion that the FDA is powerless to put a REMS in.”

“I think there are many people here

today who voted yes because they be-lieve the drug ought to be available for this limited population. But we know the risks. And if you’re giving us the choice of take it off the market or do nothing or we just put in a black box warning, well maybe we take it off the market,” Meisel said. “There’s got to be a middle ground here with some sort of a REMS with an in-formed consent.”

The advisory committee meeting took place despite the ongoing partial federal government shutdown that has left FDA relying solely on user fees to review drug applications. (Also see “Shutdown Week Three: Sponsors With Upcoming User Fee Dates Should Start Sweating “ - Pink Sheet, 7 Jan, 2019.)

The last panel review to take place dur-ing a shutdown affecting FDA was an October 2013 review of an expanded in-dication for Amarin Corp. PLC’s Vascepa (icosapent ethyl).


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

Based upon the available data, is there a patient population in which the ben-efit/risk profile for febuxostat is favorable for the treatment of hyperuricemia in patients with gout? Y - 19 , N - 2, Abstain - 1

UK’s NICE Under Fire For New HTA FeesFRANCESCA BRUCE [email protected]

F ees for health technology appraisals conducted by NICE, the National Insti-tute for Health and Care Excellence in

the UK, could be bigger than the revenues that some medicines with smaller indica-tions bring in, Paul Catchpole, director of value and access at the Association of the British Pharmaceutical Industry has warned.

From April 1, companies will have to pay for technology appraisals undertaken by NICE. A single technology appraisal and highly specialized technology evaluations will cost £126,000 ($161,175), while fast-track appraisals and rapid reviews will cost £88,000. Standard multiple technology appraisals will cost £188,000 and complex multiple technology appraisals will cost £251,000.

England’s department of health con-sulted on plans to introduce the fees last

August, when it proposed a 25% discount for smaller companies. (Also see “UK: NICE Fees Plan Would Cost Life Sciences Industry £10m Each Year “ - Pink Sheet, 27 Aug, 2018.) However, this discount was increased to 75% after consultation responses high-lighted concern about the impact of fees on smaller companies.

The pharmaceutical industry made “strong representations” to underscore the difficulties smaller companies would face when paying the fees, said Catchpole, speak-ing last week at the Westminster Health Fo-rum Keynote Seminar – Next Steps for NICE: developing future guidelines, measuring output and supporting market access.

Nevertheless, according to Catchpole, there remain issues around smaller indica-tions, such as rare disease indications “where potentially the annual sales that might ac-

crue might be less than the charge for the appraisal in the first place,” he said. “There are definitely business case issues here that have not been addressed,” he said, adding that the situation would be monitored for any “unintended consequences.”

Catchpole’s comments came in response to a delegate from the pharmaceutical in-dustry who cautioned that the fees may deter some companies “from taking their products through the NICE process.” This would have negative consequences, for example for patients “unfortunate enough to have a rare disease,” the delegate said.

Meanwhile, another delegate from in-dustry told speakers that the fees were “exorbitant”.


D R U G R E V I E W S




M A N U FA C T U R I N G Q U A L I T Y

PIC/S Considers New System For Monitoring Compliance By MembersVIBHA SHARMA [email protected]

T he international Pharmaceutical Inspection and Co-opera-tion Scheme (PIC/S) has announced plans for a new annual reporting system to monitor whether its existing members

are continuously complying with the requirements of the scheme.In its 2019 workplan, the PIC/S states that its Sub-Committee on

Compliance will discuss the “possible introduction” of an annual reporting system to check continued compliance of existing par-ticipating authorities with PIC/S requirements.

A total of 52 competent authorities currently participate in the PIC/S scheme, which is a non-binding, informal co-operative arrange-ment between regulatory authorities in the field of good manufactur-ing practice (GMP) of medicinal products for human or veterinary use.

Every year, more competent authorities apply for membership to the scheme and they are allowed to participate only if they have a comparable inspection system. Having a comparable GMP in-spection scheme is one of the essential requirements for accession to the scheme.

The PIC/S also has a Joint Reassessment Programme in place since 2000 under which all existing PIC/S participating authorities are reas-sessed for equivalence with the PIC/S scheme on a regular basis.

In 2019, for example, five participating authorities are to be re-assessed under the JRP – Argentina’s Instituto Nacional de Medi-camentos (INAME), Canada’s Regulatory Operations and Regions Branch, the South African Health Products Regulatory Authority, Switzerland’s Swissmedic and the State Service of Ukraine on Med-icines and Drugs Control.

Also in 2019, PIC/S plans to evaluate accession and pre-accession applications from eight competent authorities – Armenia’s Scien-tific Center of Drug/Medical Technology Expertise, Brazil’s National Health Surveillance Agency (ANVISA), the Bulgarian Drug Agency, Italy’s Directorate General for Animal Health and Veterinary Medici-nal Products (DGSAF), the Jordan Food and Drug Administration, Pakistan’s Drug Regulatory Authority of Pakistan, the Russian Fed-eration/Minpromtorg State Institute of Drugs and Good Practices (FSI SID&GP) and the Saudi Food and Drug Authority.

In addition, this year, the PIC/S intends to work on “establishing a basis” for co-operating with the Association of Southeast Asian Nations’ Pharmaceutical Product Working Group. Also, PIC/S plans to establish and maintain close contact with non-member com-petent authorities that have “signaled an interest to join PIC/S,” in particular those from China and India.

Moreover, subject to the PIC/S committee’s agreement, there are plans to revise the PIC scheme (PIC/S’ constitution) in 2019 to clarify the definition of members as well as the legal status of the PIC/S. The review process will be undertaken by the PIC/S Sub-Committee on Strategic Development and is expected to be completed by Q4.

In addition, the SCSD will work on implementing the recently

adopted PIC/S guidance on GMP Inspection Reliance (PI 048-1) and monitor its voluntary implementation, as requested by the International Coalition of Medicines Regulatory Authorities, by collecting statistics on the application of the guidance through its three working groups on unique facility identifiers, inspector travel safety and whistle-blowers/confidential informants. (Also see “New PIC/S Guide Offers Framework For Voluntary Reliance On Foreign GMP Inspections” - Pink Sheet, 18 May, 2018.)

Also in 2019, the PIC/S data integrity working group will review the comments it received from the public on its draft guidance on “Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1 (Draft 3),” which was issued for consultation last year. (Also see “PIC/S To Guide Member Inspector-ates On Harmonizing GMP Deficiency Classifications” - Pink Sheet, 1 Nov, 2018.) Additional guidance documents for inspectors on data integrity will also be finalized.

Moreover, there are plans to finalize this year an aide-memoire on inspection of manufacturers and wholesale distributors for compliance with good distribution practice (GDP) and a Q&A doc-ument relating to the PIC/S GDP Guide.

Other elements in PIC/S 2019 workplan include further revis-ing the:

• PIC/S GMP guide in close co-operation with the European Medicines Agency’s inspectors working party on good manu-facturing practice and good distribution practice (GMDP);

• PIC/S GMP Guide for Blood Establishments (PE 005-3) and the PIC/S Guide to Inspections of Source Plasma Establishment and Plasma Warehouses (PE 008-3)

• PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments (to add annex on guidance on total parenteral nutrition;

• Revision of PIC/S Recommendations on Validation Master Plan; Installation and Operational Qualification; Non-Sterile Process Validation; and Cleaning Validation;

• PIC/S Guidance on Good Practices for Computerised Systems in Regulated GxP Environments;

• Aide Memoire on Inspection of Quality Control Laboratories; and

• Aide-Memoire on the Inspection of active pharmaceutical ingredients.

The PIC/S says it will also continue to provide training to GMDP inspectors and organize discussions on various related topics.




M A N U FA C T U R I N G Q U A L I T Y

Random Checks Now Routine: China To Inspect Your Factories Near And Far BRIAN YANG [email protected]

A new regulation on inspections of foreign manufacturing facilities issued by China’s National Medical Product Ad-ministration (NMPA) a day after Christmas has many im-

plications for drug and device makers who are already marketing products on, or are eyeing, the Chinese market.

The scope of the inspections includes the R&D and manufactur-ing process of all drugs and devices that are currently marketed, or intended to be marketed, in China, the aim being to ensure that overseas sites supplying China adhere to Chinese quality and safe-ty standards.

The backdrop to the new move is a steady increase in such over-seas inspections by Chinese authorities over the past few years, noted Ropes & Gray’s China healthcare partner Katherine Wang; initiated in 2011 for drug manufacturers, these have since been extended to medical device makers.

So far, China’s Center for Food and Drug Inspection (CFDI) has increased the number of checks from an initial seven products in 2011 nearly five-fold, to 33 products in 2018, with a total of 131 drugs having already gone through the process. The center ex-tended the inspections to medical devices in 2015, and has so far looked at 90 products in this field.

Out of 51 products inspected during 2017, chemical drugs accounted for 36, and nine were deemed to have failed due to GMP non-compliance, noted the CFDI in its annual report. While Europe and North America are the major regions for the inspec-tions so far, India is increasingly becoming another hot spot for the checks, the center said.

“The inspections covering products’ complete cycle is becoming more routine, and drug inspections are increasingly becoming one of the most important technical tools for regulators,” noted CFDI director Dong Jiangping in early 2018.

RISK-BASED INSPECTIONThe new regulation outlines several risk factors for the inspec-tions to be initiated, including: potential pitfalls identified during the product registration process; adverse events; risks identified by testing agencies; whistle-blower tips; Marketing Authorization Holder violations; violations noted by other regulatory agencies; and repeat violations and other situations.

The agency will issue an inspection notice and holders of the product registration should then fill in and send back an inspection authorization and product information sheet within 20 work days. Master file and other required documents must be provided within 40 work days, and holders should cooperate fully and not delay, deter, avoid or refuse the inspections, the NMPA notes.

Manufacturers’ sites aside, other relevant parties are also

subject to the possible inspections including R&D partners, suppliers of active ingredients, excipients, and packaging materials, and the registration holder should coordinate and communicate with these.

All parties are expected to be consistent in following the manu-facturing manual outlined in product registration files submitted to the NMPA, and to comply with China GMP standards.

During the inspections, manufacturers should maintain normal real-time production processes, open relevant areas to inspectors, and provide relevant files, records and digital data as required.

The agency may then issue one of three decisions - pass, pass with corrective actions, or fail - and can issue penalties for products that fail, ranging from meetings and warning letters to suspension of importation, import bans and product recalls, or in the worst case a sales ban and revocation of the Product Import Certificate. [Click here for the NMPA Overseas Inspection regulation]

COOPERATION KEYThe success of the expanded overseas inspections will hinge on cooperation from manufacturers and sufficient communication, noted the NMPA. Overall, the agency’s grip over drug and device production compliance is tightening, noted Cui Hao, director of its

Drug and Cosmetics Regulatory Bureau. The agency also said it will step up its own information sharing and disclo-sure of firm that do not cooperate with the inspections.

In such cases, the new regulation warns that companies will be issued with a failure notice.

From the editors of PharmAsia News. Published online January 16, 2019

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

EMA To Bring Anticancer Drugs Guide Up To Speed With Biomarker DevelopmentVIBHA SHARMA [email protected]

The European Medicines Agency is inviting stakeholder feedback on its proposal to update its guideline on

the clinical evaluation of anticancer me-dicinal products so that it better addresses aspects relating to the use of biomarkers and corresponding study designs.

Since the guideline was last revised in 2017, the use of biomarkers in oncology and hematology has evolved and pro-gressed considerably, resulting in novel development strategies as well as new definitions of therapeutic indications based on biomarkers. “The current guid-ance does not adequately address these new aspects,” the agency says.

The EMA’s proposal is outlined in a con-cept paper. The revisions, if and when they come into effect, are expected to have an impact on: the content of regulatory sub-missions by sponsors, including those to support anticancer agents based on bio-markers; and the content of scientific ad-vice issued by the EMA’s human medicines evaluation committee, the CHMP.

The concept paper explains that bio-marker-based developments often focus on narrow subgroups identified within larger populations and their develop-ment is, therefore, closer to designs used for small populations.

“Another specific aspect of biomark-ers in oncology is the possibility that the presence of a common pathological mechanism (detected by a biomarker) could predict the benefits associated to a treatment with an improved accu-racy, across the traditional anatomy- or histology-defined diseases,” the paper adds. “New corresponding study designs (mainly basket trials and umbrella trials)

are not discussed in the current version of the guideline.”

The agency’s Oncology Working Party (ONCWP) suggests updating the current guideline to:

• Expand the section on biomarkers to address the evolving scientific con-cepts, explain the place of biomark-ers in the development pathway, and address the main questions to be answered/solved during a standard development.

• Better describe the expected stan-dards in the context of rare cancers.

• Present the main features and prin-ciples of new designs (mainly basket trials). As the regulatory experience in this field is limited at present, the guidance on this topic will only focus on main aspects and principles.

Comments on the concept paper will be accepted until April 14.

A draft version of the revised anticancer medicines guideline is expected to be issued for stakeholder consultation by Q2 2019.


The use of biomarkers has evolved considerably, resulting in novel development strategies and new definitions of therapeutic indications and the current guidance “does not adequately address these new aspects.”

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Recent And Upcoming FDA Advisory Committee Meetings TOPICS ADVISORY COMMITTEE DATE

Results from the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial of Takeda’s Uloric (febuxostat), the drug’s ben-efit/risk assessment, and potential regulatory actions

Arthritis/Drug Safety and Risk Management

Jan. 11

Amgen’s romosozumab for treatment of osteoporosis in postmenopausal women at high risk for fracture or who have failed or are intolerant of other available osteoporosis therapy

Bone, Reproductive and Urologic Drugs

Jan. 16

Sanofi’s sotagliflozin as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes

Endocrinologic and Metabolic Drugs

Jan. 17


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