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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

CLINICAL TRIALS

US FDA’s Complex Trial Design Pilot May Change ‘Ambitious’ Timelines, p. 7

BREXIT

Pharma Told To Maintain Drug Stockpiles Despite Six-Month Brexit Delay, p. 13

NEW PRODUCTS

NICE Says Yes To Akcea’s Tegsedi After ‘Improved’ Commercial Offer, p. 15

“Full Speed Ahead,” Says Acting US FDA Chief SharplessDERRICK GINGERY [email protected]

N ewly installed US FDA Acting Com-missioner Norman Sharpless plans to continue vigorous progress on the policy agenda initiated under his predecessor Scott Gottlieb. And while he now serves on an acting basis – pending the White House nomination and Senate confirmation of a new commissioner – Sharpless has made clear he will not ap-proach the top post like a temporary fill-in.

In his first FDA-wide speech, Sharpless said his appointment does not reflect an attempt by President Trump or Depart-ment of Health and Human Services Secre-tary Alex Azar to force FDA to change the direction set by Gottlieb. He said Trump

administration officials have made their support for FDA clear “and want to see this strong progress continue.”

“Let me reassure you, I am not planning any radical changes from what the FDA has been trying to accomplish,” Sharpless said April 16, according to remarks pre-pared for delivery. “Necessarily, there will be course adjustments as new facts emerge, but essentially, I feel I am walking into an organization on a good trajectory, and my main job is to figure out how to keep that going.”

Sharpless took over at the FDA on April 8. He said the agency would continue it efforts to fight the opioid crisis, increase

the efficiency of drug development and help lower drug costs, all staples of Got-

tlieb’s agenda.“I plan to maintain FDA’s current course

of action in every area and proceed full speed ahead,” Sharpless said. “I promise you, for example, that we’ll continue our important and successful work to increase competition and reign in prescription drug costs through advances in our generic drug and biosimilars programs.”

Gottlieb pushed FDA into the drug pric-ing debate upon taking office, an area it had typically not engaged. (Also see “Got-tlieb Places Drug Pricing Out Front In First Speech To US FDA Staff” - Pink Sheet, 16 May, 2017.) Upon his departure, agency watchers and stakeholders wondered whether Gottlieb’s replacement would continue working on the problem as force-fully. (Also see “Gottlieb’s Greatest Strength As US FDA Commissioner? Stability” - Pink Sheet, 27 Mar, 2019.)

Sharpless also suggested a strong inter-est in biologics, stating that he is “eager to support” FDA work on innovative cellular therapies and other complex biologics, such as gene therapies.

Gene therapy is a new and growing area for the Center for Biologics Evaluation and Research. While the agency already has ap-proved some products, the sector’s popular-ity growth is expected to require an infusion of new personnel. (Also see “US FDA’s Biolog-ics Center Director Expects It Soon Will See ‘Growth Spurt’” - Pink Sheet, 2 Jul, 2018.)

Sharpless also called the opioid crisis “one of the greatest public health trag-

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exclusive online contentCO V E R “Full Speed Ahead,” Says Acting US FDA

Chief Sharpless

R E G U L ATO RY U P D AT E 5 UK Legislators Get Involved In NICE’s Methods Review

5 Doubts Over Impartiality Trigger New EMA Estradiol Cream Safety Review

9 Italy’s Little-Known Early Access Program

10 Korea To Reform Reimbursement Management To Cut Expenditure

16 US FDA Guidance Production May Be Slowed By New OMB Review Requirement

C L I N I C A L T R I A L S 7 US FDA’s Complex Trial Design Pilot May Change

‘Ambitious’ Timelines

8 EU Clarifies Interplay Between CTR And GDPR

M A N U FAC T U R I N G Q UA L I T Y 11 The Quality Lowdown: Foreign Burden, Border

Destruction, Particles, Sterility

B R E X I T 13 Pharma Told To Maintain Drug Stockpiles Despite

Six-Month Brexit Delay

D I S T R I B U T I O N 14 WHO Consults On Remaining Shelf-Life Policy

For Medical Products

N E W P R O D U C T S 15 NICE Says Yes To Akcea’s Tegsedi After ‘Improved’

Commercial Offer

A D V I S O RY CO M M I T T E E S 18 Recent And Upcoming FDA Advisory Committees

inside: 11 7 8

Invossa Gene Therapy Controversy Grows As Government, Patients Take Actionhttps://pink.pharmaintelligence.informa.com/PS125123

While the eventual fate of Kolon Life’s gene therapy Invossa is still undecided after interim results from an ongoing probe into its composition, controversy over the product is growing as patients seek compensation from the company and government, and calls grow for a wider investigation.

Baby Steps To Real-World Evidence Of Efficacy: External Controls Gain Popularity In Rare Disease Trialshttps://pink.pharmaintelligence.informa.com/PS125128

The Pink Sheet takes a closer look at recent clinical announcements showing how rare disease therapy sponsors are already increasingly reliant on natural history studies to guide drug development.

Vocabulary Change: CDER Eliminating ‘Review’ For NDAs And BLAshttps://pink.pharmaintelligence.informa.com/PS125086

Like ANDA evaluations, US FDA plans to use the word assessment to describe them for NDAs and BLAs.

Filling The Rebate Void: PBMs Versus Wholesalershttps://pink.pharmaintelligence.informa.com/PS125127

The proposal to eliminate rebates in the US raises important follow up questions, including who will be responsible for pharmacy transactions at the point of sale. PBMs say they should stay in that role to assure a smooth transition; independent pharmacies have other ideas.

EMA Restricts Sanofi’s Lemtrada Use, Initiates Risk-Benefit Reviewhttps://pink.pharmaintelligence.informa.com/PS125111

Labeling changes for the multiple sclerosis drug being mandated by European regulators were made to the US label in January.

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U S F D A

edies this nation has faced,” saying FDA would continue developing new solu-tions to the epidemic. Several already are in development, including new pack-aging standards for immediate release opioids and evidence-based prescribing guidelines. (Also see “Norman Sharpless Will Arrive At US FDA With Many Challenges Awaiting” - Pink Sheet, 27 Mar, 2019.)

‘NOT A TEMPORARY’ JOB In signaling that FDA would continue mov-ing forward with several ongoing initiatives, Sharpless added that he was “not acting as if this is a temporary or part-time job.”

For an acting commissioner, the state-ment makes sense in order to assure staff and stakeholders that he was not intend-ing only to be an agency caretaker until a long-term replacement is named.

But for Sharpless, the choice of words may carry more weight, as many have speculated since his appointment that Trump eventually would nominate him as permanent commissioner.

Indeed, Sharpless also said that not only did he look forward to meeting many em-ployees at the agency’s White Oak head-quarters in the coming months, but also that he planned to visit FDA field offices “and see first-hand what you do.”

Sharpless gave up a permanent posi-tion as director of the National Cancer

Institute to become acting head of FDA, a move likely not intended to last only a few months. Sharpless seems to believe his stay at White Oak to be a long one, whether it is in an acting or permanent capacity. (Also see “New Acting US FDA Commissioner Shares Agency’s Clinical Trial Reform Message” - Pink Sheet, 12 Mar, 2019.)

SHARPLESS HAS A LAUGH AT GOTTLIEB’S EXPENSE Sharpless also offered a humorous tone dur-ing the speech. One joke referenced Got-tlieb’s oft-mentioned sartorial style, as Sharpless admitted “there will of course be some letup from Gottlieb: for example, I

don’t have nearly as interesting socks from a wardrobe [point of view].”

“On the plus side, I am pretty sure I can beat his time in the FDA 5K coming up this May 3 (since I am told he never ran it),” Sharpless said. “In fact, I am planning on setting the commissioner’s record.”

Gottlieb often was photographed in public wearing flashy socks. He left Sharpless a pair of his signature socks with a skull and polka dots on them, which Sharpless tweeted he would wear to his first FDA hearing.

Sharpless also said that a revamped FDA website would launch next week, which he said was evidence he already was making a difference.

“Not a bad start,” he remarked. “Just one week in and I’ve fixed the website.”

Employees and stakeholders alike com-plain about difficulties finding information on FDA.gov.

Sharpless also is showing some Twit-ter savvy, posting a selfie of himself with the crowd during the speech. (See photo above.) Humor aside, time will tell wheth-er Sharpless can match the level of com-munication and media savvy Gottlieb showed in raising the profile of FDA. (Also see “Gottlieb’s Short Tenure Will Be Felt Long After He Leaves US FDA” - Pink Sheet, 5 Mar, 2019.)

Published online April 16, 2019

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

UK Legislators Get Involved In NICE’s Methods ReviewVIBHA SHARMA [email protected]

A UK parliamentary group is invit-ing stakeholder feedback on what should be covered under the up-coming review of the methods used by health technology assessment body, NICE, for appraising new treatments.

The group will forward a report summa-rising the feedback to the National Institute for Health and Care Excellence (NICE), the HTA body for England and Wales, which is planning soon to initiate a much-awaited review of how it evaluates new drugs and devices for potential use on the National Health Service.

NICE has set up a working party to con-sider the scope of review into its method-ology. However, the institute has said that it does not intend to consult publicly on this. (Also see “UK NICE Review Will Look At Criteria For Appraising Highly Specialized Products” - Pink Sheet, 8 Apr, 2019.)

The All Party Parliamentary Group (APPG) on Access to Medicines and Medi-cal Devices, which is looking at pricing, funding and wider access issues, has taken it upon itself to invite written evidence from stakeholders on a broad range of

topics that stakeholders might want to be addressed under the review.

The APPG told the Pink Sheet that the written evidence, along with some oral evi-dence sessions to be held in May, would be published in a final report “to be finished and launched in June.” The oral evidence sessions will be with experts representing different stakeholder groups, who will be invited to give their opinions on the meth-ods review in person.

As part of its exercise, the APPG is asking:

• What issues should the NICE methods review consider, for both highly spe-cialized technologies (HST) evalua-tions and single technology apprais-als (STA), as a priority?

• How can NICE methods review bal-ance the budgetary constraints of the NHS with the need to deliver impor-tant treatments to patients?

• Are there any comments and sugges-tions about the governance of the NICE methods review?

• Whether stakeholders think NICE’s

current approval rate of 82% should be higher and if so how might that come about.

• How can NICE rebalance its overall approval rate across all disease areas, technologies, severity, rarity, etc?

• Are there any outstanding method-ological/process areas that should have been addressed in the UK government’s Accelerated Access Review or the Vol-untary Scheme for Branded Medicines Pricing and Access that can be ad-dressed in the NICE methods review?

Stakeholders have until April 29 to sub-mit written evidence. The APPG said it wel-comes all types of evidence - from data, including analysis or internal studies an or-ganization has carried out, to personal or organizational views on these issues.

The written evidence submitted will not be shared with NICE or made public and any references used in the final APPG re-port will be anonymous. The final report will be shared publicly and with NICE.


Doubts Over Impartiality Trigger New EMA Estradiol Cream Safety ReviewNEENA BRIZMOHUN [email protected]

T he European Medicines Agency is having to repeat a review into the risks associated with high-strength estradiol-containing creams for treating vaginal atrophy after a top European court decision rendered invalid some of the risk-minimizing recommendations the agency had previously made for th products.

The 27 March decision by the Court of Justice of the EU partially annulled on procedural grounds recommendations the EMA made in April 2014 and which

were subsequently adopted by the Eu-ropean Commission. The court did not question the agency’s scientific conclu-sions; basically, it said it was not possible to guarantee the impartiality of the key expert the EMA had appointed to draw up the recommendations.

The commission has now asked the EMA to reassess the risk of estradiol being ab-sorbed systemically from these creams, and to again recommend measures that should be put in place to protect patients.

Systemic absorption of estradiol from these products has been linked to side ef-fects that include venous thromboembo-lism, stroke and endometrial cancer.

The new review will take into account both the original data and any new data that have become available since the previous review. It is being conducted by the EMA’s pharmacovigilance committee, the PRAC, and will focus on high-strength estradiol-containing creams (0.01% by weight) that are used inside the vagina to

pink.pharmamedtechbi.commailto:[email protected]:[email protected]



treat post-menopausal women with vagi-nal atrophy.

The PRAC has been given until July to release a list of outstanding issues or rec-ommend measures that should be put in place to protect patients.

14-YEAR-OLD LEGAL CASEThe CJEU ruling last month follows a drawn out legal case that started in Ger-many 14 years ago.

It began when the marketing authori-zation holder for Linoladiol N, Dr August Wolff GmbH & Co KG Arzneimittel, brought an action before the Administrative Court of Cologne after Germany’s Federal Insti-tute for Drugs and Medical Devices, BfArM, refused to renew the marketing authoriza-tion for the product in 2005.

The administrative court dismissed the case, but its judgement was subsequently repealed by the Higher Administrative Court of Münster, and the marketing authoriza-tion was renewed in March 2013, explained Oppenhoff & Partner, the law firm that has been representing Dr August Wolff.

Meanwhile in 2012, the German regu-lators had asked the EMA to carry out a full assessment of the benefit-risk bal-ance of topical estradiol-containing medicines Linoladiol N and Linoladiol HN, under Article 31 of the EU medicines directive, Directive 2001/83/EC.

In 2014, the EMA completed its review of the risk of systemic absorption with these creams and recommended measures to minimize it, including limiting the use of the creams to a maximum duration of four weeks. It also said that Linoladiol N cream should only to be used inside the vagina for treating postmenopausal women with vaginal atrophy due to a lack of estrogen, while Linoladiol HN cream should only be used for postmenopausal women with mild, inflammatory skin conditions around the genital area. In addition, it said that Linoladiol HN was no longer to be used to treat lichen sclerosus, a skin con-dition that commonly affects the genital area and that the pack size of Linoladiol N should be reduced to prevent patients from using them for longer than recom-mended. The commission endorsed the agency’s recommendation and issued a fi-

nal, legally binding decision valid through-out the EU on 19 August 2014.

Dr August Wolff appealed against the commission’s endorsement before the

General Court of the European Union on the grounds that, among other things, an expert opinion on which the EMA’s deci-sion had been based had not been drawn up objectively, Oppenhoff & Partner ex-plained in a statement this month. The rap-porteur-general had acted in a dual capac-ity, as she was also a staff member of BfArM – the authority that had asked the EMA to initiate the review procedure on Linoladiol N and that had initially not renewed the marketing authorization for Linoladiol N, the law firm said. The court dismissed the action in the first instance and Dr August Wolff appealed against this to the CJEU.

In the latest ruling, the CJEU shared the opinion of Dr August Wolff. “It considered the appointment of the BfArM employee as rapporteur-general to be a violation of the principle of careful and impartial ex-amination anchored in Article 41 of the Charter of Fundamental Rights of the Euro-

pean Union,” the law firm said. “It therefore repealed the ruling of the [General Court of the European Union] of October 2016 and declared the decision of the EU Commis-sion null and void. Linoladiol N may now continue to be used as before.”

Oppenhoff & Partner clarified that the ECJU declared the commission’s order “null and void, with the exception of intravagi-nal application,” which had not been at-tacked by the client and which, therefore, was not at issue. “All other measures or-dered by the [commission] were revoked,” Peter Klappich, a partner at the law firm told the Pink Sheet. Klappich noted that the costs of the litigation must be borne by the commission in full.

THE CREAMS CONCERNEDHigh-strength estradiol-containing creams have been authorized in the EU for the treatment of vaginal atrophy in post-menopausal women through national procedures for over 40 years. They are mar-keted in Austria, Bulgaria, Croatia, Czech Republic, Estonia, Germany, Hungary, Lat-via, Lithuania and Slovakia under the fol-lowing trade names: Linoladiol, Linoladiol N, Linoladiol Estradiol, Estradiol Wolff and Montadiol. As well as Dr August Wolff, the EMA notes that Pharmazeutische Fabrik Montavit Ges MBH is also a marketing au-thorization holder of these types of creams.

As these medicines are all authorized nationally and not through the centralized procedure, the PRAC recommendations will be forwarded to the EU’s Co-ordina-tion Group for Mutual Recognition and De-centralised Procedures – Human (CMDh), which will adopt a position.

The EMA has been approached for comment.


The PRAC has been given until July to

release a list of outstanding issues or

recommend measures that should be put in place to protect

patients.

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C L I N I C A L T R I A L S

US FDA’s Complex Trial Design Pilot May Change ‘Ambitious’ Timelines DERRICK GINGERY [email protected]

T he timeline for FDA’s complex in-novative trial designs (CID) pilot program may require adjustment amid worries the eight-month timeline is too long to fit plans for advancing a product to market.

Dionne Price, acting deputy director of the Center for Drug Evaluation and Re-search’s Office of Biostatistics, said spon-sors should consider the timeline when applying to the CID program. But she also indicated that conventional routes for acceptance of complex trial designs may not save time.

“Even if you were to go the traditional route, some of the divisions that are busy and probably those that would likely re-ceive a lot of these innovative designs, their calendars are full,” Price said dur-ing the Drug Information Association/FDA Biostatistics Industry and Regula-tor Forum earlier this month. “You’re al-ready looking at months of just getting on their general calendars and that’s not counting a second meeting.”

The CID program, which launched in August, is intended to help sponsors cre-ate and implement new study designs and end misperceptions that FDA will not accept them. The trials to be con-sidered are expected to be so innova-tive that they may require simulations to determine operating characteristics. FDA and industry included the program in the 2017 prescription drug user fee re-authorization.

Participating sponsors are allowed two meetings with the agency. The process begins when FDA evaluates a CID meet-ing request. Assuming both sides reach a disclosure agreement, the first meeting would be four months after submission, followed by the second meeting after another four months.

Price said the process may seem like a long time, but deadlines have proven dif-ficult to meet for sponsors as well as FDA.

“The program has very ambitious timelines for both FDA and industry,” she said. “This has been evident from the submissions and meetings that we have had thus far.”

Price also said that FDA may consider changing the timelines, if necessary, but is still working out best practices for the young program.

“At least for this first year, we’re try-ing to see how it goes,” she said. “We are open to feedback. If we need to adjust the timeframes we will.”

Sponsors also are concerned that the four-month lag between the CID meet-ings may be problematic, suggesting more interactions may be necessary. Price said FDA will entertain alternative meeting schedules if needed.

“We are being flexible so if there is a genuine rationale and need for addition-al interactions if we have the resources available, we are trying to be flexible in that regard,” she said. “The 120-day span was specified in the PDUFA VI goals letter so that at least for the first year is what we are trying to stick with again with flexibil-ity if resources allow, and that could even be longer if asked by some chance.”

STILL NO CID CASE STUDIES AVAILABLE The timeline is only the latest problem that sponsors have raised about the CID program. FDA also wants to publicize some aspects of the trials approved for the program to help the industry at large. Sponsors were reluctant to allow their program details to be revealed, however. (Also see “US FDA Offers Sponsors More At-tention For Sharing Complex Innovative Trial Designs” - Pink Sheet, 3 Apr, 2018.)

Price made clear during the confer-ence that FDA does not want to release the sponsor name, product name and molecular structure, subject level data, recruitment strategies, adverse events

or a complete description of eligibility criteria.

However, a disclosure negotiation is part of the timeline before any CID meet-ings are scheduled. Between day 45 and day 80, both sides are scheduled to dis-cuss the items that can be released pub-licly. The agency then tells the sponsor whether the meetings will be conducted.

Price said that the agency was unable to use any submissions received so far as program case examples “due to where we are in the process.”

The disclosure requirement and legal wrangling required was thought to po-tentially limit participation. (Also see “US

The CID program, which launched in August, is intended to help

sponsors create and implement new

study designs and end misperceptions

that FDA will not accept them.

pink.pharmamedtechbi.commailto:[email protected]


FDA’s Complex Trial Design Pilot Might Be Handicapped By Disclosure Requirements” - Pink Sheet, 16 May, 2018.)

DMD CANDIDATE FIRST TO JOIN PROGRAM Price said a submission from Wave Life Sciences Ltd. was accepted in January. She was authorized to disclose details of the submission because the compa-ny issued a press release announcing its participation in the program.

Wave’s Phase II/III efficacy and safety trial for its Duchenne muscular dystro-phy candidate suvodirsen (WVE-210201), which is intended for DMD patients ame-nable to exon 51 skipping, was accepted. The trial is expected to launch this year and will measure dystrophin expression and product efficacy.

The company plans to leverage histori-cal control data on DMD to augment the trial’s placebo arm and potentially reduce the number of patients needed for the study, which could allow for faster com-pletion, according to its press release.

Wave also plans to use the CID meet-ings with FDA to consider the use of Bayesian statistical methods to adapt the trial and “allow for more efficient and productive clinical determinations,” according to the release. More informa-tion on the trial design was scheduled to be presented during the April 13-17 Muscular Dystrophy Association Clinical and Scientific Conference.

Wave also has signed a deal with Takeda Pharmaceutical Co. Ltd. to de-velop treatments for amyotrophic later-al sclerosis (ALS) and Huntington’s dis-ease. (Also see “Finance Watch: Gossamer Works Around The Shutdown To Price Its $230m IPO” - Scrip, 25 Jan, 2019.)

The CID program launched shortly after FDA’s model-informed drug devel-opment pilot program, a similar idea in-tended to allow sponsors time to discuss related development ideas, although not Bayesian or complex methods. (Also see “Complex Innovative Designs Pilot Likely Satisfies Industry’s Disclosure Wor-ries” - Pink Sheet, 29 Aug, 2018.)


C L I N I C A L T R I A L S

EU Clarifies Interplay Between CTR And GDPRVIBHA SHARMA [email protected]

T he European Commission’s much-awaited question-and-answer document on the interplay be-tween the Clinical Trial Regulation and the General Data Protection Regulation clarifies that informed consent obtained under both these legislative instruments serves different purposes.

Informed consent under the CTR must not be confused with consent as a legal ground for processing personal data un-der the GDPR, the commission states in the Q&A document published on April 10. The document underlines the im-portance of distinguishing between the requirement for consent for a subject to participate in a clinical trial and the re-quirement for the lawful processing of personal data under the GDPR.

Informed consent under the CTR is the fundamental condition under which a person can be included into a clinical trial, and it should be seen as an ethical standard and a procedural obligation. Informed consent under regulation was not conceived as an instrument for data processing compliance and should not be used as a legal basis for data process-ing, the commission clarifies.

The Q&A document elaborates on which alternative legal bases are appro-priate for processing personal data in the context of clinical trials under the GDPR – a topic that has prompted much debate to date. These can include, for example, when a task is carried out in the “public interest,” or where there are legitimate

interests of the data controller (eg trial sponsor) or under specific circumstances.

The commission published the Q&A document after securing the opinion of the European Data Protection Board on the matter. Specifically, the EDPB told the commission to amend the document to reduce its focus on consent and to better reflect alternative legal bases in the GDPR for the processing of trial data.

Ever since the GDPR came into force in May 2018, various EU member states have taken contradictory approaches to how the regulation’s provisions should be applied to clinical trials. The European Federation of Pharmaceutical Industries and Associations has previously told the Pink Sheet that it is worried that it may take years to fully implement this large and complex piece of legislation, while “those using personal health data to ad-vance science need legal certainty now.”

When the EDPB’s opinion on the mat-ter was first published this January, EFPIA said that while it provided clarity on the legal basis under which trial data may be processed in compliance with the GDPR, “a great deal more needs to be done” on this front.

The commission said the Q&A docu-ment will come into force when the CTR becomes applicable in 2020, except for the section on how sponsors should pro-ceed with ongoing trials under the Clini-cal Trials Directive.


mailto:[email protected]



Italy’s Little-Known Early Access ProgramIAN SCHOFIELD [email protected]

S everal European countries have formal mechanisms for allowing patients early access to as-yet unap-proved medicines. These include the UK’s Early Access to Medicines Scheme and (EAMS) and France’s Temporary Use Au-thorization (ATU) program. While these are high-profile schemes, Italy has a program that is less well known, and which, impor-tantly, tends to be used mainly for off-label uses of authorized medicines.

Among the most recent products to be included in Italy’s program are Swedish Or-phan International AB’s Kineret (anakinra) for recurrent idiopathic cortico-depen-dent and colchicine-resistant pericarditis, nicotinamide for treating some forms of skin cancer, and Roche’s Avastin (bevaci-zumab) for the treatment of impaired vi-sion due to diabetic macular edema. All of these listings relate to unapproved uses of already authorized medicines.The Avastin listing is particularly interesting in light of the controversy over the Italian govern-ment’s decision to reimburse the product for another off-label indication, wet age-related macular degeneration, for financial reasons. (Also see “EU Avastin Court Ruling Deals Yet Another Blow To Novartis “ - Pink Sheet, 21 Nov, 2018.)

Massimo Scaccabarozzi, president of the Italian pharmaceutical industry associa-tion, Farmindustria, said that the program “works well” in getting important treat-ments to patients. He stressed that com-panies play no part in determining which products or indications are selected for early access. The system “is not managed by companies, but by clinicians, on the ba-sis of evidence.”

Under Law 648 of 1996, Italy’s regulato-ry agency AIFA manages a list of products or indications that can be fully funded by the national health service (SSN), even if they are not authorized for that use. There must be a strong justification for including a product on the list – for example there must be no other alternative therapeutic treatment available, and there must be

some clinical evidence of the product’s effectiveness in the particular condition.

The law says that the SSN will pay all costs for products on the list if they are innovative medicines that are approved for marketing in other countries but not in Italy; products that are not yet autho-rized but have results from Phase II clinical

trials; or as yet unapproved uses of medi-cines that are already on the market (off-label use).

It is the last category of products that tend to be included on the list most fre-quently. “It is normally used for drugs that are already marketed but not for that indi-cation,” Scaccabarozzi told the Pink Sheet. “The drug is then paid for by the state.”

As for the kinds of drugs that are cov-ered by the early access system, Scac-cabarozzi said they were mostly prod-ucts such as anticancers, hematologicals,

neurologicals, drugs for transplantation, cardiovasculars, pediatric medicines and drugs for rare diseases.

The recommendation to place a medi-cine on the 648 list is made by AIFA’s tech-nico-scientific advisory committee, the CTS, at the request of a physician, who must provide some evidence that the drug works in that particular indication, Scaccabarozzi said. Patient associations can also file re-quests for a listing, citing evidence of effi-cacy from the scientific literature.

Requests must be accompanied by a report describing the seriousness of the disease and the lack of valid therapeutic alternatives, Phase I and II clinical trial data (with details of any ongoing trials), and a description of the therapeutic plan – such as dosage, duration of therapy, and inclu-sion and exclusion criteria. The report must also estimate the number of patients who might stand to benefit from treatment, and the likely costs of treatment.

This system “allows patients to be treat-ed who otherwise might not be treated,” Scaccabarozzi observed. “In the end it is good for patients.”

Patients taking products on the list must be closely monitored. In the case of Kineret for pericarditis, for example, the treatment protocol states that a clinical evaluation should be carried out every month for the first three months, and then every three months or in the case of relapse or adverse events.

Products remain on the list unless there is a change in the conditions that led to them being placed on the list in the first place – for example the product or indica-tion is submitted for, and receives, a mar-keting authorization valid in Italy, or an-other drug is approved for that use.

Like other countries, Italy also has a compassionate-use system for providing access to unapproved medicines for indi-vidual patients, but these are not paid for by the state.


Among the most recent products to be included

in Italy’s program are previously off-

label uses of Swedish Orphan’s Kineret and

Roche’s Avastin.




Korea To Reform Reimbursement Management To Cut Expenditure JUNG WON SHIN [email protected]

S outh Korea plans to conduct a re-evaluation of reimbursed drugs with a view to cutting their prices or delisting them from the national health insurance tariff if they fail to meet certain conditions, and also to lower prices of generics through regular comparisons with overseas prices.

Both moves are being mulled in an attempt to cut rising expen-diture under the universal care system.

The latest plan is part of follow-up measures after South Korea announced in 2017 a road map to raise the country’s health insur-ance coverage ratio to 70% by 2022, from 67% in 2017. The govern-ment is also aiming to reallocate resources to increase coverage of essential medicines for serious diseases that have high social and clinical demands, while reducing unnecessary expenditure within the NHI scheme.

Under the new reimbursement management plan, an outline of which was unveiled by the Ministry of Health and Welfare, the gov-ernment will introduce a comprehensive product re-evaluation system that includes a consideration of clinical efficacy and finan-cial impact. It noted that real world data may show a difference between a drug’s effect in clinical trials and in the actual patient treatment environment.

The ministry will conduct the re-evaluation in stages in line with various reimbursement types, and based on the results the govern-ment plans follow-up steps including price adjustment, changes to reimbursement levels and whether to maintain reimbursement.

At present, only drugs which have no production records within the previous year, or no prescription records within six months, will be delisted from reimbursement.

‘REASONABLE USE’ PLAN The government said it would also come up with measures to fos-ter “reasonable use” of drugs by encouraging a reduction in pre-scribed drug cost, and seek measures to ensure predictable and reasonable costs by referring to overseas cost management mea-sures for particular products.

It plans to come up with steps this year to reform the generic drug pricing system by adjusting prices regularly through compar-ison with levels overseas for each product category.

The government also plans to set out its mid-to long-term re-imbursement strategy and to improve the expenditure structure based on an analysis of current drug spending under the NHI scheme. Insurance resources saved through the planned re-eval-uation will be used to step up coverage of serious and rare disease drugs with high public demand.

In 2017, South Korea’s government unveiled measures to raise the NHI coverage ratio to the levels seen in advanced countries, although this did raise concerns that this might lead to sharp drug price cuts.

A report by IQVIA predicted that the so-called Moon Jae-In scheme (after the current president) would be the most important factor affecting the healthcare environment in the country over the next five years, and may push the government to pursue new cost-containment policies.

The report had predicted that the government is likely to try to generate pharmaceutical savings by targeting the off-patent origi-nal product and generics sectors, where current prices remain rela-tively high by international standards. (Also see “Korea May Adopt Further Cost-Containment Steps Under ‘Moon Jae-In Care’ – IQVIA “ - Pink Sheet, 13 Aug, 2018.)

FOREIGN PHARMA GROUP RAISES CONCERNSWhile the latest proposals remain in outline form, with detailed methodology still unclear, they are already drawing a negative re-sponse from the pharma industry, particularly foreign multination-als operating in the country.

The Korea Research-based Pharmaceutical Industry Association (KRPIA), which represents such companies, said it regretted the lat-est plan did not include measures to recognize the overall value of drugs or a reform plan for the reimbursement listing system.

“The comprehensive plan is largely meaningful as the govern-ment has prepared a predictable blueprint based on mid- to long-term visions on health insurance. [However], the plan will have a significant impact on advancement of the pharma industry and medicine supply, and there wasn’t an opportunity or process to sufficiently reflect views of medicine suppliers,” the KRPIA said in a statement.




In addition, it regretted that existing regulations, such as the post-approval re-evaluation system, have become tougher, while policies to efficiently induce reimbursement and recognize the full innovative value of products were not included in the latest gov-ernment measures.

As one example, the new plan did not mention any improve-ments in the risk-sharing, economic evaluation or accelerated reimbursement systems, which had been proposed as some mea-sures to improve flexibility in NHI listing procedures.

While the government said it would introduce a comprehensive drug re-evaluation system, the plans don’t align with the overlap-ping post-approval price management system (under which prices in general and reviewed and revised), and the added measures

could hurt the value of medicines. This could become a major fac-tor blocking the advancement of the pharma industry in Korea, the KRPIA said.

The association urged the government to set up a new consul-tative group that directly includes the pharma industry to help determine details of the comprehensive health insurance reform measures.

In addition, the KRPIA urged the government to more active-ly communicate with the industry in setting strategies for the planned improvement in the drug expenditure structure and the mid- to long-term reimbursement plan.


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

THE QUALITY LOWDOWN: Foreign Burden, Border Destruction, Particles, SterilityBOWMAN COX [email protected]

H ow would foreign firms react if the US FDA increased their regulatory burden? How valid are industry pharmaceuti-cal cost-effectiveness analyses? These are just two of the questions the agency is considering asking contractors it may hire.

Another question for the agency concerns how it will destroy the increasing number of adulterated, misbranded and counterfeit drugs it expects to stop at the border. The agency is looking into answering that question with a contract as well.

Customer complaints left the FDA with many questions about Aurobindo Pharma Ltd.’s efforts to find and fix the source of red and black particulates in injectables the Indian firm manufactured for the US market.

The agency challenged a Denver-based infusion firm to upgrade aseptic compounding operations at an Ohio site.

Meanwhile, FDA gave a Columbia, Missouri, compounder a run-down of all the reasons why it didn’t qualify as an outsourcing facil-ity, despite having twice registered for that status.

Also of note: one addition to the FDA’s drug GMP import alert and several drug recalls.

HOW WOULD FOREIGN FIRMS RESPOND TO INCREASED FDA REGULATION?Would foreign firms respond differently than domestic firms to a regulatory crackdown?

That’s one of the questions the US FDA’s economics staff might have for a contractor or two that they would like to hire, according to a draft pre-solicitation notice the agency published April 4.

The idea is that the contractor would model the behavior of foreign firms to predict their response to regulations that increase production costs – and validate the model for existing FDA-regulated products.

Another question on their list: How valid are the growing num-ber of cost-effectiveness analyses that pharmaceutical companies are preparing regarding their new products? And what would be an appropriate methodology for answering such a question?

As both cost and effectiveness have soared, there has been a growing focus in the US on pharmaceutical “value frameworks.” (Also see “Valuing Drugs In The US: How We’re Doing And What’s Ahead” - Pink Sheet, 22 Jan, 2018.)

The agency said it’s considering offering one or two potentially five-year contracts for economic studies of FDA regulations.

The main scope of work would be to develop new ways of as-sessing the economic impact of its regulations, conducting base-line measurements of the industries it regulates and estimating the effects of potential regulatory actions.



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

FDA NEEDS HELP DESTROYING DRUGSThe US FDA is requesting information from organizations that could destroy drugs that were refused US admission for being adulterated, misbranded or counterfeit.

The agency had less than 2,000 lines of product destroyed in fis-cal year 2018, but as Congress increases funding for border inter-diction of illicit pharmaceuticals, the information request indicates that figure could jump to 98,000 lines.

Section 708 of the July 2012 FDA Safety and Innovation Act, implemented by a rule FDA proposed in May 2014 and finalized in September 2015, only applies to drugs valued at $2,500 or less.

Prior to FDASIA, FDA had to return the drugs to the firms, giving them another chance to try to slip them into the country.

FDA explained in an April 10 request for information that most of these drugs arrive in international mail and are routed by the US Postal Service to Customs and Border Protection, which turns them over to FDA for examination and to decide on admissibility.

The drugs can pose a threat by having too much, too little or none of the active ingredient, or by having the wrong active ingre-dient or containing toxic ingredients.

Responses are due May 15.

PARTICLES PROMPT AUROBINDO 483 REPORTParticulates and sterility assurance failures dominated a Form 483 report FDA investigators delivered March 1 to Aurobindo Pharma’s plant in Bachupally, India, and later posted in redacted form on the agency’s website.

There were incomplete investigations into the complaints of particulates in injectables manufactured at the plant in the state of Telananga in southern India, the report said. There also was incom-plete visual inspection of drug product vials.

There was a failure to disqualify an active pharmaceutical in-gredient supplier after tracing red particulates to gasket materi-als the supplier used and black particulates to filling operations at the API firm.

Additionally, locations for non-viable particle counters used in environmental monitoring weren’t scientifically justified, smoke studies were deficient and media fill protocols were deficient, ac-cording to the report.

FDA WARNS INFUSION FIRM ON ASEPTIC PRACTICESA March 20 FDA warning letter to Denver-based infusion and home care management solutions provider BioScrip Inc. focuses on aseptic processing issues at the firm’sInfusion Partners LLC, fa-cility in Canfield, Ohio.

During a January 2018 inspection, FDA investigators saw issues with the design of the facility’s cleanroom areas, the state of its high efficiency particulate air filters, the likely influx of air from an unclassified area and the operators’ aseptic practices.

The firm was producing multiple penicillin and cephalosporin drug products in the same positive press ISO 5 laminar airflow hoods where it made other injectable drugs.

The firm does not describe itself as a compounding pharmacy,

nor does the warning letter refer to it as a Section 503A com-pounder or 503B outsourcing facility.

However, the warning letter does direct the firm to the agency’s web page on human drug compounding guidance, compliance and regulatory information “for more information.”

APOLLO WARNED OVER GMP SHORTCOMINGSColumbia, Missouri, drug compounder Apollo Care LLC, which had twice registered to become a 503B outsourcing facility, neverthe-less failed to meet numerous drug GMP requirements that apply to such facilities, according to a March 20 FDA warning letter.

The firm also failed to meet certain 503B conditions, such as labeling all products with the dosage form, date compounded and instructions for storage and handling.

FDA also found a lack of sterility assurance during an inspec-tion that ran from Feb. 12 to March 13, 2018, noting, for example, that multiple HEPA filters were leaking, dirt and debris was on top of ISO 5 laminar airflow hoods, and laminate work surfaces in the hoods were cracked and chipped. Smoke studies were in-adequate and none of the firm’s media fills were successful even though they didn’t present the most challenging or stressful conditions, as required.

Apollo said it had taken numerous corrective actions, but FDA said it couldn’t evaluate any of them for lack of adequate sup-porting documentation.

IMPORT ALERT UPDATEFDA added Xi’an Livingbond Nonwoven Products Corp. Ltd., in Xi’an, a city in central China’s Shaanxi Province, to the “red list” for its drug GMP import alert No. 66-40 on April 12.

DRUG RECALLSSome notable drug recalls listed in the US FDA’s April 10 enforce-ment report:

• Pfizer Inc. on March 15, 2019, recalled three lots of 8.4% sodium bicarbonate injection USP 50ml in single-dose fliptop vials manufactured by its Hospira Inc. unit due to the presence of glass particulates (Class I).

• Johnson Matthey Inc., West Deptford, New Jersey, on March 5, 2018, recalled one lot of morphine sulfate USP active pharmaceutical ingredient due to bioburden out-of-specifi-cation results (Class II).

• Pacific Compounding Pharmacy & Consultations Inc., Stock-ton, California, on Aug. 23, 2018, recalled a lot of cefuroxime after a physician reported particulate matter that FDA later identified as coring of the rubber stopper (Class II).

• Pfizer Inc. March 15, 2019, recalled 18 lots of Cleocin Phosphate (clindamycin injection) USP due to high out-of-specification results for several impurities at the 24-month time point (Class III).



Pharma Told To Maintain Drug Stockpiles Despite Six-Month Brexit DelayVIBHA SHARMA [email protected]

W hile the UK government received a six-month exten-sion from the EU to find a solution to the Brexit impasse, there is no such reprieve for the pharmaceutical indus-try which has been told that the stockpiling of medicines and other drug contingency plans should “remain in place but on hold until further guidance is available.”

This message was emailed to drug companies by the UK’s De-partment of Health and Social Care on April 12, two days after the European Council decided that the UK should have an extension beyond the original Brexit date of 29 March. The DHSC message comes at the heels of the government’s decision to stand down Operation YellowHammer, its contingency operation plan for a no-deal scenario as the Brexit deadline is now set for October 31.

However, as a no-deal scenario is still a possibility, the DHSC said that the medicines supply contingency planning program should continue. But maintaining a heightened state of readiness over a long period of time is not sustainable for drug companies, especially biotech companies, according to the UK BioIndustry Association (BIA). Industry wants clarification from the govern-ment on the practical implications of the latest missive from the DHSC. “We want to know… what’s their thinking,” said the BIA’s CEO, Steve Bates.

The BIA, for example, wants to know what the govern-ment’s revised no-deal planning assumptions are and what has changed because of the new Brexit deadline, Bates said during the BIA’s Brexit webinar on April 12. Companies also want to know how many weeks of stock they should now maintain, and what will happen to the ferries that were to be used as alterna-tive transport route.

The BIA will raise these issues at its next meeting with the Eu-ropean Union Relationship Group that is scheduled for April 25. “I hope, this will give the government enough time to share new guidance with industry on what they expect us to do,” Bates said.

The BIA CEO explained that industry is keen to get clarity on what’s being asked of them because although the six-month delay means that the no-deal scenario is less likely and no longer immi-nent, “ it doesn’t mean we can stand down entirely… We know all too well that supply chains are not eminently flexible. It’s taken a lot of work to get to this stage and it will take some careful thinking [to manage the situation further].”

The six-month Brexit extension can be terminated earlier than October 31 if a withdrawal agreement is ratified. If no agreement is ratified by 22 May, the UK will have to hold elections to the Eu-ropean Parliament that month and, if it fails to do so in accordance with law, it will be forced to leave the EU on 1 June. Bates said that industry would seek assurance from the government that the pos-sibility of a 1 June no-deal Brexit “is legally ruled out.”

However, getting this assurance may not be as easy as the UK government has already made it clear that it is not keen to hold the EU elections. Foreign secretary Jeremy Hunt told the BBC on April 15 that it was an “absolute priority” for the government to leave the EU by 23 May to avoid having to take part in European elections.

While industry waits for clarity from the government, Bates said that companies should go through the guidance documents is-sued by the UK medicines regulator MHRA in anticipation of a no-deal scenario and to report any “bugs” that they notice to their trade bodies so that these can be dealt with if the guidelines are implemented in case of a no-deal.

The MHRA’s no-deal guidelines “will be in the cupboard for now and may end-up going in the bin – we don’t know,” he said. “We may have to bring them out again in May for the 1 June Brexit deadline or in September for the 31 October deadline. All this just highlights the challenges for us as a sector to deal with hugely dif-ferent outcomes at a short notice.”


B R E X I T

The BIA wants to know what

the government’s revised

no-deal planning

assumptions are and what

has changed because of the

new Brexit deadline.



WHO Consults On Remaining Shelf-Life Policy For Medical ProductsVIBHA SHARMA [email protected]

T he World Health Organization is inviting stakeholder feedback on a draft policy that explains how drugs and other medical products in the supply chain should be handled so that there is a balance between enforcing their remain-ing shelf-life and ensuring their availability to the end-user.

The WHO explained that the policy would for the first time provide procurers and donors with a harmonized approach regarding shelf-life. “This will assist sup-pliers, donors, procurers and distribution points in managing medical products throughout the supply chain, ensuring the availability of quality products within the remaining shelf life, in reaching the end user,” the organization said.

The policy, which is expected to be finalized later this year, applies to all medical products in the supply chain, including pharmaceuticals, medical de-vices, diagnostics, reagents and kits. It can be implemented by all stakeholders in the medical products supply chain, such as suppliers, donors, procurers and distributors, and can also be integrated by WHO member nations within their na-tional policies.

The policy aims to address a number of issues, such as ensuring that there is sufficient stock of medical products with acceptable remaining shelf-life in a country, addressing barriers to access and supply of medical products, preventing dump-ing and stock-outs, preventing donations of medical products that are not appropriate and preventing the build-up of ex-pired stock. It also aims to facili-tate the national authorization

of importation of stock, where applicable. The WHO recommends taking a “realis-

tic” approach and states that the details may vary for different categories of prod-ucts, depending on their type, storage condition, resources in the country and other factors. The policy makes a clear distinction between manufacturing and expiry/install by dates and states that for all products with an expiry date, the purchaser or the recipient should never undertake re-testing for the purpose of extending shelf-life.

The manufacturer or supplier can, how-ever, obtain approval from the concerned national regulatory authority for a new

or extended shelf-life and this should be applied to batches of the product to be delivered. Products with a re-test date al-located by a manufacturer or supplier should have at least one year of shelf-life remaining on the date of delivery.

Among other things, the policy clarifies when and how

suppliers, recipients and national authori-ties may negotiate deviations from the remaining shelf-life policy.

Comments on the draft policy will be accepted until 5 May.

The final policy is to be presented at the 54th meeting of the WHO Expert Commit-tee on Specifications for Pharmaceutical Preparations, which is scheduled to take place in Geneva, Switzerland, in October.

The WHO clarified that the policy should not be regarded as a standalone document and should be read in con-junction with other documents and guidelines, including but not limited to, the WHO’s guidelines on stability testing, good storage and distribution practices, donations and the Model Quality Assur-ance System for Procurement Agencies. In addition, stakeholders should refer to the pharmacopeia, guidelines issued by the International Council for Harmonisa-tion as well as other related guides and recommendations.


D I S T R I B U T I O N

The potential new WHO policy would for the first time provide procurers and donors with a harmonized approach regarding shelf-life.

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N E W P R O D U C T S

NICE Says Yes To Akcea’s Tegsedi After ‘Improved’ Commercial OfferFRANCESCA BRUCE [email protected]

A kcea Therapeutics has managed to convince NICE, the health tech-nology appraisal (HTA) institute for England and Wales, to recommend its ultra-rare disease treatment, Tegsedi (inot-ersen), for hereditary transthyretin-related amyloidosis (hATTR) for use on the Nation-al Health Service. Following initial negative recommendations from NICE, the com-pany submitted new evidence, economic modeling, and crucially, an “improved commercial arrangement.”

Akcea hopes other HTA and reimburse-ment agencies across Europe will follow “NICE’s lead in making inotersen available as a treatment option for patients with this disease,” said Richard Jones, the company’s senior vice president and head of Europe.

Meanwhile, the UK ATTR Amyloidosis Patients Association said: “This is a land-mark day for people with hATTR amyloi-dosis who have had very limited options available to them to date. There is a criti-cal need for innovative new therapies for people across the UK living with this de-bilitating disease.”

The new decision was made through an evaluation via NICE’s highly specialized technologies (HST) program and was pub-lished in a final evaluation document on 16 April. NICE now recommends Tegsedi for treating Stage 1 and Stage 2 polyneu-ropathy in adults with hATTR. This is an ul-tra-rare condition that is thought to affect around 150 people in the UK.

The positive recommendation comes af-ter the institute previously published draft guidance rejecting the drug in December 2018. In that earlier guidance, NICE ac-knowledged that Tegsedi is an innovative treatment and that it offers some benefit to patients as it slows disease progression and improves quality of life. However, the institute had concerns about whether the benefits were maintained in the long term. NICE also expressed doubt about the com-pany’s economic modeling. The institute

said it did not think that a managed access arrangement proposed by the company that would involve further data collection would resolve the uncertainties.

The company came back with new evi-dence that was not available at the time of the initial committee meeting in support of the long-term benefits of Tegsedi and changes to its economic modeling. It also put forward an “improved commercial ar-rangement,” which offers a confidential discount on the list price.

According to NICE, there remain un-certainties surrounding the long-term benefits of the product and in relation to assumptions in the company’s eco-nomic modeling, such as utility values and health care costs. Nevertheless, NICE concluded that “despite the uncertain-ties, inotersen is likely to provide impor-tant clinical benefits for people with he-reditary transthyretin-related amyloidosis and value for money within the context of a highly specialised service.”

Tegsedi is an antisense oligonucleotide inhibitor of human transthyretin produc-tion. According to Akcea, it “is the first and only subcutaneous RNA-targeting drug designed to reduce the production of hu-man transthyretin protein.” It is self-admin-istered once a week and a weekly dose of 284mg has a list price of £5,925, excluding VAT and any discounts.

Tegsedi should become available on the NHS within 90 days of publication of final guidance, which is expected on May 22.

Meanwhile, NICE is still to make a de-cision on whether to recommend Al-nylam’s Onpattro (patisiran) for treating hATTR in adults. In December, the insti-tute declined to recommend Onpattro, claiming that there were doubts about the product’s long-term benefits and the company’s economic modeling. “Patisir-an reduces disability and increases qual-ity of life and is innovative. But it does not appear to provide value for money

in the context of a highly specialised ser-vice,” it said.

According to NICE, Alnylam is to submit further information to NICE for the HST evaluation committee to consider and a further committee discussion has been scheduled for 21 May.

Onpattro is administered once every three weeks by intravenous infusion and costs £7,676.45 per 10mg vial. Alynlam has already offered the NHS a confiden-tial discount and could well come back with a better offer to try to match that of its rival Akcea.


The new decision was made through an

evaluation via NICE’s highly specialized

technologies program, and issued 16 April.




US FDA Guidance Production May Be Slowed By New OMB Review RequirementDERRICK GINGERY [email protected]

T he US FDA’s work over the years to speed production of industry and stakeholder guidance may be cur-tailed by a White House directive requiring the Office of Management and Budget re-view all of them before they are released.

Agency guidance, in addition to pro-posed and final rules, will undergo OMB review to receive an economic impact determination, which could allow con-gressional review of the document. OMB reaffirmed the practice and set out the review system in an April 11 memo to federal agencies.

The new process will go into effect May 11.

While OMB clearance is required for many regulations already, forcing all guidances to undergo a similar clearance may significantly delay their availabil-ity to industry, which already believes the documents take too long for FDA to write and release. However, OMB justi-fied the move in the memo as an attempt to further ensure consistent compliance with current law.

The memo cites the 1996 Congressio-nal Review Act, which requires federal agencies to submit “rules” to Congress. If

unwanted, Congress may pass a resolu-tion of disapproval that if signed by the President, would invalidate it.

OMB said “rule” as stated in the law is “defined expansively,” and includes a wide range of regulatory actions, includ-ing “guidance documents, general state-ments of policy and interpretive rules.”

Rules relating to agency management or personnel and agency organization, procedure or practice not substantially affecting the rights of non-agency par-ties are exempt.

OMB must decide whether each fi-nal, interim final and direct final rule is a major regulation, such as whether it would have at least a $100m impact on the economy, result in a major increase in costs or prices for consumers, or have significant adverse effects on competi-tion, employment, investment, produc-tivity, innovation or on the ability of US businesses to compete with foreign companies.

FDA said referred questions on the memo to OMB, which did not respond to requests for comment. Faster guidance de-velopment has been a focus of the Center for Drug Evaluation and Research’s opera-

tions in recent years. (Also see “’Just Say It!’ – New Streamlined Guidance Format Com-ing, FDA’s Woodcock Says” - Pink Sheet, 14 Nov, 2017.)

Some categories of regulations may be considered “presumptively not major in order to prioritize evaluation of rules more likely to be major,” and not subject to the additional review. The White House will work with each agency to make those de-terminations, according to the memo.

OMB’s decision seems related to a simi-lar move early in the Trump Administration that required federal agencies to eliminate two old regulations for every new reg is-sued. The policy was limited to regulations deemed significant, i.e. having an an-nual effect on the economy of more than $100m and not though to pose a substan-tial effect on FDA. (Also see “US FDA Likely Not ‘Significant’, Could Be Mostly Spared From Trump’s Regulation-Slashing Order” - Pink Sheet, 10 Feb, 2017.)

The agency is quite fond if the guidance process. Anna Abram, deputy commission-er for policy, planning, legislation and anal-ysis, said April 10 that in 2018 the agency issued more guidances than ever before.

Guidances are not considered binding,

Agency guidance, in addition to proposedand final rules, will

undergo OMBreview to receive an

economic impactdetermination.




but in providing current agency thinking, they sometimes are considered so. Con-gress has complained that FDA too often issues guidance when rulemaking is more appropriate. (Also see “Senate’s Medical Innovation Bill Takes Cures’ Shape” - Pink Sheet, 6 Apr, 2016.)

NEW OMB REVIEW PROCESS OUTLINED OMB in the memo laid out a new process for determining whether guidances would be considered major.

Each agency must notify OMB’s Office of Information and Regulatory Affairs (OIRA) “regularly” of upcoming or planned rules and recommend which should be deemed major.

The Center for Drug Evaluation and Research’s 2019 guidance agenda, which includes 93 documents, could be among the lists FDA may send, although the pub-licly-released document does not include summaries that could determine whether any of them would be major or minor. (Also see “Clinical Trial Reform Is A Focus For CDER’s 2019 Guidance Agenda” - Pink Sheet, 14 Mar, 2019.)

For those considered major, the agency must submit the rule for a determination at least 30 days before publication, along with an to help OIRA make its decision.

If designated major, the agency must sub-mit the guidance to Congress and then may publish it. The effective date also should be delayed until 60 days after submission to Congress or the regulation’s publication in the Federal Register, whichever is later.

A spokesperson for the Biotechnology In-

novation Organization told the Pink Sheet, “While we are still reviewing the memoran-dum, we hope that in implementing this system for centralized review ... that FDA’s guidances and regulations are not unduly delayed, and that OIRA is provided suffi-cient resources to undertake these added responsibilities in a timely manner.”

MORE OMB APPEALS TO STOP FDA POLICY ON THE HORIZON? The new process creates another entry point for stakeholders to express concerns about FDA guidances beyond the formal com-ment system, as well as potentially opens them to additional political influence.

A few highly controversial issues have prompted stakeholders to seek OMB help in stopping or slowing FDA actions in re-cent years.

In 2017, several industry groups peti-tioned OMB to stop FDA’s implementation of draft guidance on its manufacturing quality metrics program, released in draft guidance, arguing it could cost industry $1bn per year to comply or potentially cre-ate drug shortages. (Also see “US FDA And OMB Should ‘Pause’ Billion-Dollar Quality Metrics Program, Industry Groups Say” - Pink Sheet, 29 Mar, 2017.) The program then seemingly went silent, but FDA said it had not been shelved. (Also see “US FDA Qual-ity Metrics Initiative Continues Moving For-ward … Quietly” - Pink Sheet, 23 Apr, 2018.)

AbbVie Inc. also in 2017 asked OMB to nix a proposed information collection re-lated to FDA’s biologic naming convention guidance requiring a suffix be added to all biologic and biosimilar non-proprietary names. The company said retrospectively adding a suffix to the names of currently marketed biologics is an unnecessary eco-nomic and regulatory burden for those sponsors. (Also see “AbbVie Looks To White House For Relief From US FDA Naming Guid-ance” - Pink Sheet, 16 Feb, 2017.)

FDA seems to have been convinced, and recently announced that biologics approved without a suffix in their non-proprietary name would not receive a suf-fix, despite concerns from stakeholders that the policy would stoke mispercep-tions that biosimilars were inferior to their reference products. (Also see “Woodcock: Concerns About US FDA’s Biosimilars Suffix Policy Detached From Reality” - Pink Sheet, 20 Mar, 2019.)


The new process creates another entry pointfor stakeholders to

express concerns aboutFDA guidances beyond the formal comment system,

as well as potentially opens them to additional

political influence.

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

Recent And Upcoming FDA Advisory Committee Meetings TOPICS ADVISORY COMMITTEE DATE

Drug development for testosterone replacement therapy in male adolescents for nditions associated with a deficiency or absence of endogenous testosterone resulting from structural or genetic etiologies (“classic hypogonadism”)

Pediatric April 8

Pathways for approval of rabies virus monoclonal antibodies for use as the passive- immunization component of post-exposure prophylaxis Antimicrobial Drugs April 25

Safety and effectiveness of bacitracin for intramuscular injection for the treatment of infants with pneumonia and empyema caused by staphylococci shown to be susceptible to the drug

Antimicrobial Drugs April 26

Approaches to evaluate the effect of renal impairment on drug exposure; best practice consid-erations for translating pharmacokinetic information into dose individualization instructions

Pharmaceutical Science and Clinical Pharmacology May 7

Chiesi USA’s mannitol inhalation powder for management of cystic fibrosis to improve pulmo-nary function in patients ages 18 years and older in conjunction with standard therapies Pulmonary-Allergy Drugs May 8

Daiichi Sankyo’s pexidartinib for adults with symptomatic tenosynovial giant cell tumor Oncologic Drugs May 14

Daiichi Sankyo’s quizartinib for adults with relapsed/refractory acute myeloid leukemia, which is FLT3-ITD positive as detected by an FDA-approved test Oncologic Drugs May 14

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