Vol. / No. February , 2020 · FOR THE LATEST INSIGHT ON BIOPHARMA REGULATION AND POLICY, VISIT:...

CONTINUED ON PAGE 4

FOR THE LATEST INSIGHT ON BIOPHARMA REGULATION AND POLICY, VISIT: PINK.PHARMAINTELLIGENCE.INFORMA.COM

Vol. 82 / No. 6 February 10, 2020

DRUG APPROVAL STANDARDS

ICER Will Assess Real-World Evidence On Accelerated Approvals After Two Years, p. 11

CLINICAL TRIALS

Decentralized Clinical Trials Among Topics Slated For CDER Guidance In 2020, p. 5

DRUG REVIEWS

EU: PRIME Success For Givlaari At CHMP, p. 9

Novel Virus Brings Novel Threats To Global Pharmaceutical ManufacturingBOWMAN COX [email protected]

E fforts to contain the novel coronavi-rus outbreak that sprang from Wu-han, China, in December are placing

new challenges on the global pharmaceu-tical manufacturing infrastructure that has emerged in the 21st century.

In the immediate term, quarantines and travel restrictions are raising questions about the transport of drug products and ingredients to and from cities in China hit by the 2019-nCoV coronavirus.

There is also the disruption to activities in-volving travel to manufacturing facilities in China – the regular flow of corporate audi-tors, global quality managers, subject mat-ter experts, equipment vendor represen-tatives and government inspectors upon which the proper functioning of global manufacturing operations depends.

The US Food and Drug Administration’s drug shortages staff has been checking with drug manufacturers about the pos-sibility of drug shortages related to the coronavirus, but none have been reported, at least so far. (Also see “Coronavirus Not Impacting Rx Manufacturing Supply Chain – Yet” - Pink Sheet, 29 Jan, 2020.)

AS THE CORONAVIRUS SPREADSEventually, it is possible that plant op-erations in China could be threatened by shortages of parts, supplies and materials as transport routes are cut off.

Absenteeism could also be a concern as the outbreak spreads into eastern China’s manufacturing areas and workers try to avoid exposure or become infected.

The Chinese province with the most coro-navirus cases by far is Hubei, where the out-break began, which hosts 32 US FDA-regis-tered drug manufacturing facilities and had 11,177 cases as of 2 February, according to the Johns Hopkins University Center for Sys-tems Science and Engineering, which hosts a coronavirus tracking database.

At 724 cases, Zhejiang Province is a distant second, but it hosts more FDA-registered drug manufacturing facilities, 105, than any other province. Many other

eastern provinces also have significant concentrations both of coronavirus cases and drug manufacturing facilities, includ-ing Guangdong, Jiangsu and Shandong, as well as the city of Shanghai.

A QUESTION OF API INVENTORIESLonger term, there could be global drug shortages as manufacturers exhaust in-ventories of active pharmaceutical ingredi-ents sourced exclusively from China.

Generic drug manufacturers typically or-der APIs for two to five years out and have supplier redundancies in place, Rachel

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pink.pharmaintelligence.informa.com February 10, 2020 | Pink Sheet | 3

CJEU Confirms ‘Pay For Delay’ Settlements Can Break EU Lawhttps://pink.pharmaintelligence.informa.com/PS141515

The UK’s Competition and Markets Authority has welcomed an EU Court of Justice ruling that settling patent disputes can break EU law by restricting competition. The case involved so-called “pay for delay” settlements regarding generic competitors to GlaxoSmithKline’s antidepressant Seroxat (paroxetine).

Biosimilars: US FDA Proposes Streamlined Pathway For Indication Carve-Inshttps://pink.pharmaintelligence.informa.com/PS141642

Sponsors may submit supplemental applications for additional indications in advance so that approval will coincide with expiration of a reference product’s exclusivity or patent protection, new draft guidance states; agency targets six-month review of such supplements, rather than the 10 months provided under BsUFA II.

exclusive online contentCover Novel Virus Brings Novel Threats To Global

Pharmaceutical Manufacturing

C L I N I C A L T R I A L S 5 Decentralized Clinical Trials Among Topics Slated

For CDER Guidance In 2020

M A R K E T ACC E S S 6 Zolgensma ‘Lottery’ Attacked From All Sides

D R U G R E V I E W S 9 EU: PRIME Success For Givlaari At CHMP

10 EU Firsts Beckon For Alnylam & Novo; Wins For A Raft Of Others

D R U G A P P R O VA L S TA N D A R D S 11 ICER Will Assess Real-world Evidence

On Accelerated Approvals After Two Years

B I O S I M I L A R S 12 FDA, FTC Join Forces To Eliminate Barriers

To Biosimilar Competition

R E G U L ATO RY U P D AT E 13 Adverse Events For Generic Of GSK’s Advair Diskus

On US FDA’s Radar

16 US FDA Seeks Withdrawal Of Injectable Bacitracin Despite Extensive Off-Label Use

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

inside: 10 6 9

Get Ready For User Fee RenegotiationsPublic meetings are expected to get under way later this year to set the stage for industry/US FDA negotiations to update product review user fees, the framework that also sets review timelimes and other policy agreements. Go online for the Pink Sheet’s exclusive four-part analysis of key issues.

• Predicting The User Fee Reauthorization Schedule https://bit.ly/38bI5y8

• PDUFA VII: Will Gene Therapy’s Rise Influence Talks? https://bit.ly/2H5BNo4

• BsUFA III: Could Regulatory Science Research Emerge With Other Tweaks? https://bit.ly/2H265rw

• GDUFA III: How Much Of A Fee Increase Can Industry Stomach? https://bit.ly/2UyNHyL

P U B L I S H E R ’S S P OT L I G H T 17 EDITOR’S NOTE:

Please Help Pink Sheet Serve You Best

4 | Pink Sheet | February 10, 2020 © Informa UK Ltd 2020

Schwartz, director of communications for the Association for Accessible Medicines, told the Pink Sheet.

However, consultant Steven Lynn cau-tioned that it is important for manufactur-ers to use the outbreak as an opportunity to check supplier quality systems and sup-ply chain operations. There could be gaps and vulnerabilities of which they were unaware. Lynn, who has headed the FDA’s drug manufacturing compliance office and managed quality issues for Mylan and Novartis, put it this way: “As Churchill said, ‘don’t let a good crisis go to waste.’”

THE VULNERABILITIES OF GLOBALIZATIONMuch depends on the severity of the out-break, including factors such as transmis-sibility of the virus, efforts to contain it and development of vaccines against it.

Amid all the uncertainty, however, arise questions about the advisability of the highly interdependent system in place to-day for the manufacture of medicines.

Ultimately, the outbreak poses anew the

question of whether the efficiencies of glo-balization outweigh its vulnerabilities.

This is a question that has resurfaced in various guises in the globalization era.

THE HEPARIN CRISIS AND THE LURE OF CHINAThere was the heparin crisis of 2008, in which economically motivated adultera-tion of heparin API in China causes dozens of patients to die in the US.

That crisis precipitated legislative re-forms to US pharmaceutical supply chain regulation in the July 2012 FDA Safety and Innovation Act, or FDASIA, that en-abled the US Food and Drug Administra-tion to increase its oversight of foreign drug manufacturing.

There was the consolidation and global scale-up of pharmaceutical manufac-turers over the past decade or two that enabled and depended upon cost sav-ings from the shifting of manufacturing to less-regulated countries like India and China, where a 2009 World Bank study found wages were at least 10 times lower than in the US.

This was part of a trend that hollowed out the economies of industrialized na-tions’ manufacturing areas, which in turn has been linked to the rise of authori-tarianism in recent years and a reckoning for transnational economic systems that boost urban economies while deflating rural ones.

LOSS OF MANUFACTURING RESILIENCY FEAREDThe US Congress has grown increasingly worried that China has been driving down prices to corner the global market on APIs, and that it might later raise API prices and even threaten to withhold them, for ex-ample, in the event of a global pandemic.

In written testimony last October, Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, told a House subcommittee hearing on safe-guarding pharmaceutical supply chains in a global economy that the number of FDA-registered API manufacturing facili-ties in China more than doubled between 2010 and 2019.

The 230 API manufacturing facilities in

CONTINUED FROM PAGE 1

P U B L I C H E A L T H C H A L L E N G E S

Coronavirus Spreads Toward China’s Pharma Manufacturing Facilities

Source: Pink Sheet analysis of US FDA and Johns Hopkins University data (as of 30 January, 2020).

Number of Facilities

0 10 20 30 40 50 60 70 80 90 100

Cases(by province)

Facilities(by province)

>600 Cases

100-199 Cases

200-600 Cases

50-99 Cases

1-49 Cases

Visit https://bit.ly/389mCGc

for the interactive verison

of this map


China still only account for 13% of those registered with the US FDA as of August 2019. Another 28% were in the US and 59% were in the rest of the world, accord-ing to CDER’s analysis.

However, Woodcock said the FDA can-not determine how dependent the US is on China APIs or how resilient the US manufacturing base would be to any withdrawal of China from the market be-cause the agency lacks information about the volume of API output from each plant. (Also see “Real-Time Manufacturing Volume Reporting Could Help Prevent Drug Shortages, Woodcock Tells Congress” - Pink Sheet, 31 Oct, 2019.)

The coronavirus outbreak could test that resiliency.

WILL GLOBAL MANUFACTURERS PASS THIS TEST?In its efforts to contain the outbreak, Chi-na on 23 January quarantined Wuhan, the city in Hubei Province with a population of 11m where the outbreak began. By 27 January, China had quarantined 11 other cities that also are in Hubei Province, ac-

cording to press reports, bringing the to-tal quarantined population to 50m.

Although the World Health Organization 10 January advised against any travel or trade restrictions on China and 27 January reiterated its advice against restrictions on international traffic, many countries have imposed travel restrictions against for-eign visitors recently in China, including, according to press reports, the US, Singa-pore, Japan, South Korea, Australia, New Zealand, Italy and Russia.

Meanwhile, there are increasing reports of shortages in Wuhan of medical sup-plies needed to treat patients infected with the virus.

If medicines can’t get into China and active pharmaceutical ingredients can’t get out, it would degrade the global phar-maceutical supply chain’s ability to help suppress the coronavirus outbreak, and eventually its ability to treat other condi-tions even in parts of the world that are not directly threatened by the outbreak, if there be any.

Published online 3 February 2020

P U B L I C H E A L T H C H A L L E N G E S

Go DeeperGo online to keep up with our ongoing coverage of developments related to the coronavirus. Recent articles include:

• Coronavirus Supply Chain Threats Demand Coordinated Industry Response https://bit.ly/2GZGRtZ

• EU Firms Called In As Coronavirus Cases Soar https://bit.ly/3bjah4n

• Coronavirus Efforts Could Benefit From Little-Used Medical Countermeasures Incentives https://bit.ly/31v7pgh

• Coronavirus Not Impacting Rx Manufacturing Supply Chain – Yet https://bit.ly/2UvFFGB

Decentralized Clinical Trials Among Topics Slated For CDER Guidance In 2020BRENDA SANDBURG [email protected]

T he US Food and Drug Administra-tion plans to offer sponsors more guidance on clinical trial issues this

year, including in the areas of pharma-cogenomic data submission and use of digital health technologies.

The Center for Drug Evaluation and Re-search’s 2020 guidance agenda of new and revised draft guidances it plans to publish during the calendar year covers 14 catego-ries. Of the 88 guidances on the list, 40 are carried over from its 2019 agenda, which included 93 planned guidances.

Clinical trial design has been a hot topic for industry and FDA. The agency pub-lished one of the guidances related to clini-

cal trials on its to-do list last year. The docu-ment “Interacting with CBER and CDER on the Use of Novel Clinical Trials Designs” was issued in September. Other planned guid-ances, including one on “Multiple End-points in Clinical Trials,” were rolled over to this year. (Also see “Clinical Trial Reform Is A Focus For CDER’s 2019 Guidance Agenda” - Pink Sheet, 14 Mar, 2019.)

Clinical guidances new to this year’s list include those on “Decentralized Clinical Trials,” “Use of Digital Health Technologies for Remote Data Acquisition in Clinical Investigations,” and “Pharmacogenomic Data Submission.”

The biopharma industry has emphasized

its interest in these topics at public meet-ings over the past year. For example, at FDA’s meeting seeking recommendations on how the Office of New Drugs could promote ef-fective drug development programs, Re-generon Pharmaceuticals Inc. urged the agency to use genomic information more broadly in evaluating new drugs. (Also see “Genomics Data Should Get More Attention In FDA Drug Review And Labeling, Regeneron Says” - Pink Sheet, 2 Dec, 2019.)

NON-OPIOID ANALGESICS, ANTISENSE OLIGONUCLEOTIDES The guidance agenda provides some in-sight into what FDA is focusing on. How-

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


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

ever, the agency issues guidances on top-ics that don’t make the list. For example, it recently issued several guidances related to gene therapy that were not on CDER’s 2019 agenda and are not on its current agenda. (Also see “Orphan Exclusivity For Gene Therapies Hinges On Two Big Factors” - Pink Sheet, 28 Jan, 2020.)

And in December, FDA issued final guidance on adaptive designs for clinical trials of drugs and biologics which was not included in the 2019 guidance agen-da but was in the 2018 agenda. (Also see “Disease-Specific Drug Development Guid-ances Coming From US FDA In 2018” - Pink Sheet, 19 Jan, 2018.)

In 2018, the agency focused on develop-ment of drugs for specific diseases, with planned guidances targeting six diseases.

This year, the agency plans guidances on development of non-opioid analgesics for acute pain; development of anti-infective drugs for the pediatric population; and type 2 diabetes: evaluating the safety of new drugs for improving glycemic control. There is also a planned guidance on IND submissions for individualized antisense oligonucleotide therapies.

Another guidance targets cannabis, “Cannabis and Cannabis-Derived Com-pounds: Quality Considerations for Clinical Research.” FDA regulation of cannabidiol

(CBD), which is derived from cannabis, is being closely watched by some in the pharma industry. (Also see “US FDA’s De-cade In Review: From Biosimilars To Real-World Evidence” - Pink Sheet, 15 Jan, 2020.)

GENERICS, POSTMARKETING REQUIREMENTS Generic drugs get the most attention, with 20 planned guidances devoted to this cat-egory. Eleven are carried over from the pre-vious year, including those on refusal to re-ceive ANDA submissions, failure to timely respond to an ANDA complete response letter, and three-year exclusivity determi-nations for drug products.

New to the 2020 list are guidances on eval-uation of therapeutic equivalence, statistical approaches to establishing bioequivalence, pediatric exclusivity general considerations for ANDAs, and the impact of court orders on 30 month stay of approval.

In previous years, biosimilars were a prominent topic. This year, only one planned guidance references them, “Pro-motional Labeling and Advertising Con-siderations for Prescription Biological Reference and Biosimilar Products – Ques-tions and Answers.”

One of the guidances carried over from last year addresses drug shortages, “Risk Management Plans to Mitigate the Poten-

tial for Drug Shortages.”Another guidance carried over addresses

postmarketing requirements, “Civil Mon-etary Penalties for Failure to Meet Acceler-ated Post Marketing Requirements.” It is unclear what prompted this guidance. In a November 2018 report on the status of postmarketing requirements and commit-ments, FDA noted that most of these stud-ies were progressing on schedule and then-Commissioner Scott Gottlieb said he was “pleased” with their progress. (Also see “Drug Sponsors Are On Schedule With Most Post-Approval Studies” - Pink Sheet, 18 Nov, 2018.)

However, a few years ago, a pair of aca-demicians proposed imposing penalties on drug makers who don’t start confirmatory trials shortly after accelerated approval. (Also see “NEJM Takes Aim At Expensive Accelerated Approval Drugs Amid Congressional Drug Pricing Debate” - Pink Sheet, 24 May, 2017.)

Revised draft guidances on pediatric drug development under the Pediatric Research Equity Act and Best Pharmaceuticals For Children Act were also rolled over. Industry representatives cited the need for these doc-uments at a recent FDA meeting focused on this legislation. (Also see “Pediatric Studies: In-dustry Seeks Narrower, More Timely Requests From US FDA” - Pink Sheet, 6 Jan, 2020.)


M A R K E T A C C E S S

Zolgensma ‘Lottery’ Attacked From All SidesFRANCESCA BRUCE [email protected]

N ovartis/Avexis have come under fire from EU member states, pa-tients and legal experts for their

“lottery-style” managed access program (MAP) for the gene therapy for spinal mus-cular atrophy, Zolgensma. Critics have cit-ed ethical concerns and claim the program is a reputational risk for the companies and the wider pharmaceutical industry.

But Nils Hoppe from the law firm Hill Dick-inson LLP says the controversy surround-ing the program could generate dialogue about how MAPs need to be designed and

governed with greater patient input.The aim of providing a much-needed

treatment to patients in need sits un-easily alongside the clear commercial gains from the program, which include increased interest in Zolgensma, and the gathering of safety and efficacy data in markets where the company is seeking regulatory approval, said Hoppe. “The juxtaposition of these aims generates a reputational risk and establishing suf-ficient transparency in the relevant pro-cesses is not a trivial task,” he said.



Belgium, the Netherlands, Luxembourg, Austria and Ireland have levelled fierce criticism at AveXis Inc., under the banner of BeNeLuxA, the cross-country collabo-ration on improving access to medicines. They have accused the companies of leav-ing to chance the important decision on who gets access to Zolgensma.

However, a Novartis spokeswoman has defended the program and said the com-pany had worked with bioethics experts to develop the MAP. She added that the company was listening to stakeholders to “guide” the program forward.

THE PROGRAM US-based AveXis, which is a subsidiary of Novartis, announced in December that it was experiencing increasing demand for its Zolgensma (onasemnogene abeparvovec) from outside the US. It said it would be of-fering a global managed access program to make up to 100 doses of the spinal mus-cular atrophy (SMA) treatment available throughout 2020. Patients under the age of two in markets where it does not yet have regulatory approval would be eligible.

Controversially, and unusually for such programs, patients will be selected through a lottery-style draw. “A third party administers a blinded selection on a bi-weekly basis,” said AveXis in its statement announcing the MAP. “If a patient is not selected to receive the therapy during that selection round, they automatically roll over to the pool for the next selection as long as they remain medically eligible.”

The company claimed that it designed a MAP that was “anchored in principles of fairness, clinical need and global acces-sibility to best determine the equitable global distribution of a finite number of

doses that doesn’t favor one child or coun-try over another.”

ETHICS IN QUESTIONHowever, the program’s critics disagree. According to Hoppe, lottery-style man-aged access programs are virtually un-heard of for very good reason.

“There are absolutely decades of ethical and legal scholarship that say if you allocate a scarce resource in the health sector, then a lottery is not the way to go, as long as you have a better way to distinguish between your populations,” Hoppe told the Pink Sheet.

In declining to take the “hard decision” about who gets the product and instead leaving it to chance, the company failed to make an ethically sound decision, he claims.

Instead of a lottery system, a more ap-propriate program would stratify patients according to clinical parameters, said Hoppe. Some children might have a more advanced form of the condition and be in greater need, while comorbidities that might reduce the efficacy of treatment could also be considered, for example.

Other factors that are more subjective could be taken into account to narrow the patient population down further if need be, including the geographical location of the patient and proximity to disease experts. “You can come up with a much more nuanced managed access program. Especially in the context of a rare disease like this, you can very quickly whittle down the numbers to find the 100 children that genuinely need it the most. That is a solid managed access program, leaving it up to lady luck is not.”

UNDER PRESSUREHoppe also warned that the announce-ment of the program and engagement with the media had put regulators under pressure. He pointed to Germany’s Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, which on 3 February announced it had approved the drug for compassionate use. “[The com-panies] have basically created a situation where an authority in a member state in the European Union felt they needed to expedite their decision making. They are creating pressure,” Hoppe said.

He explained that if a patient wins the Zolgensma lottery, regulators will feel they need to act quickly to approve the product for compassionate use to avoid negative publicity and blame for delaying access. The situation is “forcing them to be quick, or at least talk about why they aren’t being quick,” he said. “I think it at least shifts the balance between all the stakeholders.”

This kind of approach undermines the many years the pharmaceutical industry has worked to rid itself of a reputation for being too profit-orientated and reck-less, said Hoppe. He believes that it could “drive a wedge” between pharma compa-nies, regulators and other stakeholders who have started to work in partnership much more over recent years. “The risk is that it will change the way stakehold-ers work together,” and that Novartis itself could be perceived as a company that no longer works in partnership with other stakeholders, he warned.

Meanwhile, there is a danger that other companies may start to consider similar approaches to avoid making the difficult decisions as to which patients can access their programs. These decisions are “a big emotional and marketing strain” and also constitute a PR risk, according to Hoppe.

SILVER LININGAlthough the importance of MAPs is ac-knowledged, there is little discussion about them. Nevertheless, the controversy over the program also presents an oppor-tunity to change this and to debate better ways of approaching managed access pro-grams, said Hoppe.

“The risk is that it

will change the

way stakeholders

work together.”

- Hoppe

“The approach adopted

by Avexis raises a number

of ethical questions.”

– SMA Europe


PATIENT RESPONSEIt is very hard to believe that patients were adequately involved in designing the Zol-gensma program, according to Hoppe, who feels these kinds of programs need more patient input.

The patient group SMA Europe said in a statement that it had mixed feelings about the program. “Every life saved is a gift,” it said. However, it added that it struggles to support the program because of the way it selects patients. “We believe that a health lottery is an inappropriate way of address-ing the unmet medical need in this severe disease in a fair and equitable way. The ap-proach adopted by AveXis raises a number of ethical questions.”

The organization also has concerns about the lack of involvement of neuro-muscular experts and SMA patient organi-zations in the design and implementation of the program.

Furthermore, there is limited safety and efficacy data on the treatment, said SMA Europe, which is calling for long-term follow-up for all patients receiving the ex-perimental gene therapy. The organization has approached AveXis to work with the company on improving the managed ac-cess program.

Meanwhile, the BeNeLuxA initiative points out that the drug is estimated to cost €2m per patient and is urging No-vartis and AveXis to “enter into a genuine dialogue with the Beneluxa initiative to explore sustainable, clinically and ethically appropriate ways to provide this medica-tion to all young patients who need it after obtaining marketing authorization.”

“The high level of uncertainty and the

non-transparent approach is unaccept-able. It proves no sincere commitment to patients and only increases the distress of the families concerned. They are given false hope. If one equals the fate of a pa-tient to a lottery ballot, human dignity and moral values get out of sight. Lotter-ies are by their nature a form of gambling and this is absolutely the wrong model to bring to healthcare,” said the initiative in a statement.

Through the BeNeLuxA initiative, Bel-gium and the Netherlands negotiated a pricing and reimbursement deal for Bio-gen’s own SMA treatment, Spinraza.

COMPANY RESPONSEThe Novartis spokeswoman said the com-pany recognized that the “program will not be a solution for all families in all countries.” She added that “AveXis is listening carefully to the SMA community and engaging with healthcare professionals, patient advocacy groups and others to capture learnings to

help guide the company as the program moves forward.”

The company had worked with an inde-pendent bioethics advisory committee to develop the program. “The program’s pa-rameters, including blinded selection ad-ministered by a third-party group, are a re-sult of this work,” the spokeswoman said.

She also highlighted the fact that AveXis has just one manufacturing facil-ity licensed to produce the gene therapy. Although it is expanding capacity, the company’s main obligation is to supply markets where Zolgensma has been ap-proved, where regulatory approval is pending, where early access agreements are in place and where clinical trials are under way. “Therefore, until now, we haven’t been able to supply a broad glob-al managed access program,” she said.

“Given these constraints, we chal-lenged ourselves and engaged in dia-logue internally and externally to explore ways in which this could be achieved while meeting all of our obligations. At the heart of this challenge was launching a global program that is necessarily lim-ited due to supply constraints, and still fair and equitable.”

In addition, the spokesperson said the company had been in talks with various stakeholders and interest groups, includ-ing regulators and reimbursement bod-ies, since the announcement was made in December. “Whenever possible, we are engaged in dialogue to look at the vari-ous options for accelerated access in each country,” said the spokesperson.



“It proves no sincere

commitment to patients

and only increases

the distress of the

families concerned.”

– BeNeLuxA

Intelligence with a Global PerspectiveTo find out more, visit: www.pharmaintelligence.informa.com


EU: PRIME Success For Givlaari At CHMPNEENA BRIZMOHUN [email protected]

A lnylam Pharmaceuticals has wel-comed the European Medicines Agency’s decision to recommend

pan-EU approval for Givlaari (givosiran), the company’s RNAi therapeutic that the EMA fast-tracked and is now set to be-come Europe’s first treatment for acute hepatic porphyria (AHP).

The EMA’s recommendation recognizes the potential of Givlaari to address the urgent unmet need of those living with AHP, said the company. AHP is a rare life-threatening genetic condition that causes attacks of severe abdominal pain, vomit-ing and nervous system disorders, such as seizures, depression and anxiety. Givlaari was approved in the US last November, nearly three months ahead of the user fee action date. (Also see “Alnylam Wins FDA Approval For Givlaari, Its Second RNAi Drug“ - Scrip, 20 Nov, 2019.)

Orphan drug Givlaari benefited from PRIME, the EMA’s priority medicines scheme that provides participating com-panies with the opportunity for early and enhanced dialogue with the EMA. “This in-teraction led to a more robust application package to demonstrate the medicine’s benefits and risks, which allowed the accel-erated assessment of Givlaari in 150 days,” the agency said in statement. The standard review timeline is 210 days.

Alnylam said it was committed to bring-ing Givlaari to patients in Europe “as rapidly as possible.” Formal approval from the Euro-pean Commission is likely within the next two months or so, after which the company will have to convince health technology assessment bodies across the EU that the drug provides value for money. In the US, the drug will launch with an ultra-high price tag: $575,000-per-patient-per-year before discounts. The company told investors to expect a net price more in the range of $425,000 after discounts and rebates. (Also see “For An Ultra-High-Priced Drug, Alnylam Brings A New Idea” - Scrip, 20 Nov, 2019.)

Givlaari is Alnylam’s second commercial product and only the second RNAi-based

therapy to reach the market. The company’s Onpattro (patisiran) – for hereditary trans-thyretin-mediated amyloidosis (hATTR), another rare genetic disease – was the first RNAi therapeutic approved in the EU.

The positive recommendation from the EMA for Givlaari is based on efficacy and safety findings from Alnylam’s pivotal ENVI-SION Phase III study, including data on the re-duction in the annualized rate of composite porphyria attacks compared with placebo.

Givosiran is a subcutaneously adminis-tered RNAi therapeutic targeting aminolev-ulinic acid synthase 1 (ALAS1). Monthly sub-cutaneous administration of the product has the potential to significantly lower in-duced liver ALAS1 levels in a sustained man-ner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid (ALA), and porphobilinogen (PBG), toward normal levels, said Alnylam. “By reducing accumu-lation of these intermediates, givosiran has the potential to prevent or reduce the occur-rence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease.”

The EMA noted that there are no approved treatments that directly ameliorate or pre-vent chronic symptoms experienced by many AHP patients and no approved treat-ments to reduce the risk of attacks. Intrave-nous hemin, a human blood-derived haem formulation, is the only therapy currently approved for the treatment of acute attacks. However, it is not approved as a chronic treatment to prevent attacks. Additional treatments include painkillers and antiemet-ics (to treat nausea and vomiting), chemical-ly-induced menopause with hormonal sup-pression therapy, and liver transplantation.

Givlaari is among the 15 new medicines that were recommended for approval at the latest monthly meeting of the EMA’s drug evaluation committee, the CHMP, which took place on 27-30 January. (Also see “EU Firsts Beckon For Alnylam & Novo; Wins For A Raft Of Others” - Pink Sheet, 31 Jan, 2020.)

Published online 31 January 2020

D R U G R E V I E W S

“This [PRIME]

interaction

led to a more

robust application

package to

demonstrate the

medicine’s

benefits and risks,

which allowed the

accelerated

assessment of

Givlaari in 150 days.”


EU Firsts Beckon For Alnylam & Novo; Wins For A Raft Of OthersNEENA BRIZMOHUN [email protected]

T he European Medicines Agency this week recommended pan-EU marketing authorization for a raft of new medi-cines including the first treatment for acute hepatic por-

phyria – Alnylam Pharmaceuticals’ Givlaari (givosiran) – and a first of its kind oral drug for type 2 diabetes – Novo Nordisk’s Rybel-sus (semaglutide). Givlaari benefited from accelerated assess-ment at the EMA.

Two applications have been withdrawn – Celgene has pulled its marketing authorization application for its acute myeloid leuke-mia treatment, Idhifa (enasidenib), and Merck Sharp & Dohme has withdrawn its request to extend the use of Keytruda (pembroli-zumab) in the treatment of cancer of the oesophagus.

A total of 15 new medicines were recommended for approval at the latest monthly meeting of the EMA’s drug evaluation com-mittee, the CHMP, which took place on 27-30 January. (Also see “Novo Awaits EMA’s Verdict On Oral Form Of Antidiabetic Blockbust-er Semaglutide“ - Pink Sheet, 28 Jan, 2020.) They also included:

• Bayer/Orion’s Nubeqa (darolutamide), for treating men with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease.

• Emergent BioSolutions’ cholera vaccine, Vaxchora ((cholera vac-cine (recombinant, live, oral)), for use in adults and children.

• Eli Lilly’s fast active formulation of insulin lispro, Liumjev, for treating diabetes mellitus in adults.

• Two treatments that Esperion Therapeutics has developed to treat primary hypercholesterolemia and mixed dyslipidaemia – Nilemdo (bempedoic acid) and Nustendi (bempedoic acid/ezetimibe).

• Pfizer’s Staquis (crisaborole) for atopic dermatitis.

Two of the other drugs that received a positive recommendation are hybrid products (hybrid applications rely in part on the results of pre-clinical tests and clinical trials of an already authorized refer-ence product and in part on new data):

• Teva Pharmaceutical’s budesonide/formoterol Teva Pharma (budesonide/formoterol fumarate dihydrate), for the treat-ment of asthma and chronic obstructive pulmonary disease.

• SciPharm’s orphan drug Trepulmix (treprostinil sodium), for treating chronic thromboembolic pulmonary hypertension.

A further four of the products are generic medicines:

• Two azacytidine products made by betapharm Arzneimittel (Azacitidine betapharm) and Mylan (Azacitidine Mylan) respec-tively, both for treating myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia.

• Mylan’s Arsenic trioxide Mylan (arsenic trioxide), for acute promyelocytic leukemia.

• Accord Healthcare’s Cinacalcet Accordpharma (cinacalcet), for secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism.

One product is a biosimilar:

• Pfizer’s Ruxience (rituximab), for treating non-Hodgkin’s lym-phoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, and pemphigus vulgaris.

INDICATION EXTENSIONSThe CHMP also recommended extensions of indications for sev-eral already authorized products: Biofrontera Bioscience’s Ameluz (5-aminolevulinic acid); Roche’s MabThera (rituximab); Janssen-Cilag’s Rezolsta (darunavir /cobicistat); Sanofi’s Suliqua (insulin glargine/lixisenatide); Gilead Sciences’ Tybost (cobicistat); and Ab-bVie’s Venclyxto (venetoclax).

The CHMP’s recommendations are forwarded to the European Commission for the final say on marketing authorization; these legally binding decisions should be made by the commission within 67 days.


D R U G R E V I E W S

LET’S GET SOCIAL@PharmaPinksheet


D R U G A P P R O V A L S T A N D A R D S

ICER Will Assess Real-World Evidence On Accelerated Approvals After Two YearsCATHY KELLY [email protected]

T he Institute for Clinical and Economic Review will begin a pi-lot program this year to generate new real-world evidence on prescription drugs approved by the US Food and Drug

Administration under accelerated approval pathways.The pilot will “explore how best to develop and assess new RWE

as a cornerstone” of the group’s process for updating its cost ef-fectiveness assessments after a period of time, ICER said in a 31 January release on its revised value framework for 2020-2023. The project is among the more notable additions to the framework.

“The goal of the pilot will be to supplement the comparatively limited evidence base that often accompanies accelerated approv-als with real-world evidence to provide stakeholders with a more comprehensive understanding of the early impacts of these thera-pies,” the framework says.

The process will begin two years after ICER’s original cost effec-tiveness report is issued and “will span several months, depending on the nature of the evidence to be generated.” To begin the pi-lot, ICER will identify a drug it has already reviewed and that has been on the market at least 24 months. The drug chosen will be announced in the next few months, a spokesman said. It will likely be one assessed by ICER during 2017-2018. Stakeholders have been pushing ICER to incorporate RWE more fully in its assessments and the pilot program is meant as a response to those requests. (Also see “ICER Value Framework Update Reaffirms Support For Real-World Evi-dence “ - Pink Sheet, 22 Aug, 2019.)

Genentech applauded the change. “We commend ICER for con-tinually refining their value assessment framework and increas-ing its use of real-world evidence,” Jan Elias Hansen, VP evidence for access, US medical affairs, said in a statement.

“Clinicians, payers, and health authorities recognize the need for evidence that goes beyond clinical trial data and they use real-world evidence not just to assess treatment safety but to better understand the effectiveness of interventions when making treat-ment, coverage, and regulatory decisions,” Hansen added.

The framework reaffirms ICER’s commitment to using RWE “when-ever it can provide additional perspective on comparative clinical effectiveness or cost-effectiveness” with caveats. RWE “often has

greater vulnerability to known and unknown biases that create limi-tations in our ability to rely on it when making judgments about rela-tive effectiveness of different care options,” it cautions.

Nevertheless, RWE can be “particularly helpful under certain circumstances such as when long-term safety or a treatment or durability of a medication’s effect is unclear,” ICER pointed out, add-ing RWE can also help support consideration of a drug’s “potential other benefits” not addressed in clinical trials.

REAL-WORLD CONCERNS FOR SICKLE CELL DISEASEICER incorporates a substantial consideration of real-world evi-dence in it recently-released draft report on treatments for sickle cell disease, the organization’s spokesman pointed out. The report discusses at some length the ways the disease impacts patients that go beyond clinical effects. The analysis covers Novartis AG’s Adakveo (crizanlizumab), Global Blood Therapeutics Inc.’s Oxbryta (voxelotor), and Emmaus Life Sciences Inc.’s Endari (L-glutamine)

“Patients, family members, clinicians, and other members of the sickle cell community conveyed that it is hard to imagine a condition that ravages people’s lives more than SCD. It is a danger to minimize the impact of the condition by reducing it to pain crises, or even to the better known acute and chronic organ effects,” the report says.

“There is fatigue, there is anxiety and depression, there is a hopelessness that has haunted patients with SCD. The condition presents challenges at home, school, work, and social relation-ships. People with SCD often end up on formal disability programs, which unfortunately carries its own stigma.”

The report also notes ICER is collaborating with the patient ad-vocacy group Sick Cells and the Sickle Cell Disease Association of America to conduct an online survey to help assess the compara-tive effectiveness of the interventions and allow ICER to “better quantify important information on quality of life and productivity.” Data points from the survey results will be incorporated into the cost effectiveness model “where appropriate.” In the meantime, the draft report concludes that none of the three agents could be considered cost effective within generally accepted willingness-to-pay thresholds. “Treatment costs were the main driver of the cost-effectiveness results, with average annual costs of $88,000 for crizanlizumab, $84,000 for voxelotor and $24,000 for L-glutamine, considering many will discontinue each treatment,” the report said.

“Combined with relatively small improvements in [quality-ad-justed life years] gained (0.85 for crizanlizumab, 0.96 for voxelotor, and 0.10 for L-glutamine), all [incremental cost effectiveness ratios] were estimated to be over $1m per QALY,” well above the common-ly used threshold of $150,000 per QALY, it concluded.


To begin the pilot, ICER will identify

a drug it has already reviewed and

that has been on the market at least

24 months. It will be announced in

the next few months.


B I O S I M I L A R S

FDA, FTC Join Forces To Eliminate Barriers To Biosimilar CompetitionBRENDA SANDBURG [email protected]

B iologic manufacturers could face a wave of enforcement actions against behavior that impedes the marketing of biosimilars as the US Food and Drug Administration and

Federal Trade Commission are teaming up to promote competi-tion in biologics markets.

The two agencies issued a 3 February joint statement in which they committed to strengthening efforts to curtail and discour-age anticompetitive behavior.

The FTC and FDA will coordinate to: promote greater compe-tition in markets for biologics and biosimilars; deter behavior that impedes access to samples needed to develop these prod-ucts; take appropriate action against false or misleading com-munications about these products; and review patent settle-ment agreements for antitrust violations, the statement says.

“Strengthening efforts to curtail and discourage anticom-petitive behavior is key for facilitating robust competition for patients in the biologics marketplace, including through bio-similars, bringing down the costs of these crucial products for patients,” FDA Commissioner Stephen Hahn said in a release an-nouncing the statement.

In a Federal Register notice slated for publication on 4 Febru-ary, FDA also announced that it would hold a public workshop with the FTC on 9 March to discuss their collaborative efforts to support appropriate adoption of biosimilars and deter an-ticompetitive behaviors in the biologic product marketplace. FDA also released a Q&A guidance on promotional labeling and advertising considerations for prescription biological reference and biosimilar products.

FDA said the “FDA/FTC Workshop on a Competitive Market-place for Biosimilars” is intended for the agencies to engage with stakeholders about US biosimilar markets and the FDA ap-proval process, enforcement activities by FDA and FTC, the ben-efits of competition, and improving stakeholder engagement in education and access.

FDA asked for comments on steps the two agencies can take to facilitate a competitive market for biological products. The docket (FDA-2019-N-6050) is open until 9 April.

ACTION PLAN AND CITIZEN PETITIONOver the past two years, FDA has taken steps to bolster bio-similar competition but the renewed collaboration with the FTC indicates a heightened effort to go after behavior that blocks access to biosimilars.

FDA issued a Biosimilars Action Plan in July 2018, in which it said it would seek to reduce “gaming” of FDA requirements and other attempts to unfairly delay competition and develop effec-tive communications to improve understanding of biosimilars.

Biosimilar makers have objected to promotions by innovator biologic manufacturers that suggest biosimilars are inferior to the reference product. Pfizer Inc. submitted a citizen petition to FDA in August 2018 asking the agency to issue guidance to deter such communications. (Also see “Pfizer Wants FDA To Stop Sponsor Promos From Implying Biosimilars Are Inferior” - Pink Sheet, 28 Aug, 2018.)

FDA has not yet issued a response to the petition, but an FDA official noted at the FDA/CMS Summit in December that the agency was considering policies to ensure communications about biosimilars and interchangeable biosimilars do not scare patients away from using the products. (Also see “Biosimilars: US FDA Considering ‘Guardrails’ To Prevent Misinformation” - Pink Sheet, 5 Dec, 2019.)

The Biosimilars Forum praised FDA and FTC for issuing the joint statement. “We applaud the FDA and FTC for joining to-gether to dispel misinformation and address anticompetitive behavior to promote competition and drive innovation and health care savings for taxpayers,” Juliana Reed, president of the Biosimilars Forum, said in a statement.

FDA and FTC noted that they have a long history of working collaboratively to support their missions. But it is rare for them to issue a joint statement and an FTC spokesperson could not recall any joint workshop.

FTC held a solo workshop on follow-on biologics in 2008 that resulted in a report on follow-on biologic drug competition. It also held a workshop on the impact of legislation and regula-tory naming proposals on competition among follow-on bio-logics in 2014. And in 2017, it held a workshop on barriers to generic competition.



R E G U L A T O R Y U P D A T E

Adverse Events For Generic Of GSK’s Advair Disku On US FDA’s RadarDERRICK GINGERY [email protected]

T he US Food and Drug Administration sees proactive surveillance of com-plex generics as a chance to avoid

patient rejection of first generics in addition to monitor for any potential safety problems.

Among the first test cases is the launch of Mylan NV’s Wixela Inhub (fluticasone propionate/salmeterol), the first generic of GlaxoSmithKline PLC’s Advair Diskus. How-ard Chazin, director of the clinical safety surveillance staff at the FDA Office of Ge-neric Drugs, said if device-related confusion emerges, the agency could take action, such as by releasing a statement reminding pa-tients to read the label or take other steps to try and ensure the issues do not perma-nently hamper generic uptake.

“We can’t solve the problem, but I don’t want people rejecting the generic because it’s different,” Chazin told the Pink Sheet after a 29 January presentation at the Drug Infor-mation Association Pharmacovigilance and Risk Management Strategies Conference. “The idea is to get us ahead of the curve.”

Surveillance staff in OGD are review-ing FDA Adverse Event Reporting System (FAERS) complaints about Wixela Inhub for trends monthly. Chazin said significant reports were expected when the product launched because many patients who had been using Advair Diskus had their medi-cine substituted by pharmacists. He said

the agency will watch whether device and other complaints remain elevated as more patients use the product.

“We expect complaints to go up when a generic drug first comes out on to the mar-ket and we expect it to go down,” Chazin said during the conference presentation.

“But then if it starts rising up again, we start to think, if the market share didn’t increase but the number of complaints increases, should we pay attention to that? We’ll follow that for a number of months and if the trend goes away, fine. If the trend starts increasing or market share increases not proportional to the number of complaints, we start in OGD to think maybe a particular product is

the reason and we’ll do more investigating.”Complex generics present a different

set of issues than pills and capsules. There are concerns that the instructions for use of the generic, which regulations say must be largely the same as the reference prod-uct and require no additional training of providers or patients, still may confuse pa-tients who have switched.

And as the White House and Health and Human Services Department continue campaigns to bring down drug prices, FDA action reminding patients of differ-ences could be another step at ensuring generic uptake and, eventually, price re-ductions. (Also see “Complex Generic Ap-proval Delays Getting Congressional Atten-tion” - Pink Sheet, 21 Jan, 2020.)

Wixela Inhub was approved at the be-ginning of last year and reached the mar-ket a short time later, but the product had needed several years to gain approval, a prime example of the problems complex generics have had in navigating the FDA. (Also see “Generic Advair’s Labeling Variation Stems From Permissible Design Differences, US FDA Says” - Pink Sheet, 11 Feb, 2019.)

Delivery devices, which often have many patents protecting them, present obstacles for generic sponsors attempting to show bioequivalence. (Also see “Mylan’s Generic Advair Approval Showcases US FDA Efforts To Boost Complex Products” - Pink Sheet, 30 Jan, 2019.)

Indeed, Novartis AG announced on 29 January that it would no longer pursue development of its Advair Diskus generic after seeing no path to launch for more than a year.

“We can’t solve the

problem, but I don’t

want people rejecting

the generic because

it’s different ... The idea

is to get us ahead of

the curve.”



WIXELA DEVICE COMPLAINTS AMONG MOST POPULAR SO FAR Device complaints comprised a significant proportion of the adverse event reports re-ceived for Wixela Inhub during its first few months on the market.

The most recent FAERS data available, which is as of 30 September 2019, listed 225 case reports for Wixela Inhub. “Device Issue” was the fourth most listed com-plaint, appearing 37 times and in more than 16% of the reports. There also were

five mentions of “Wrong Technique In Product Usage Process” and three men-tions of “Device Difficult to Use,” which comprised about 2% and 1% of the total, respectively. More than one complaint may appear in individual case reports, the agency noted. (See chart.)

The vast majority of all the reports, 190, came from patients, as opposed to health care professionals, 34. One reporter was not specified. All the “Wrong Technique in Product Usage Process” reports and nearly all of the “Device Issue” reports came from patients, according to the FAERS data.

Chazin said during the conference pre-sentation that Wixela Inhub may be sus-ceptible to device complaints because the patient must hold it differently than Advair Diskus.

The Advair Diskus device is held hori-zontally to deliver the drug, while Wix-ela Inhub is held vertically. Chazin said that prior to approving Wixela Inhub, the agency determined that the device still would deliver the drug properly if held like Advair Diskus.

Patients also have reported device-specific problems with Advair Diskus. The most common was “Device Use Er-ror,” which was reported in 1,296 cases or about 4% of the total, according to the FAERS data. While the product first ap-peared in the data in 2000, “Device Use Error” reports did not appear until 2015, when 460 complaints were logged. After peaking in 2016 with 576 complaints, volume has dropped substantially. There were 243 reports in 2017, 13 in 2018 and four through 30 September 2019.

Interestingly, the second most com-mon device-related complaint for Advair Diskus was “Wrong Technique in Device Usage Process,” which appeared in 915 cases, or about 2.9% of all reports. How-ever, the complaint increased substantial-ly in recent years. There were 52 cases in 2016, then 220 cases in 2017, 422 in 2018 and then 220 in 2019, the same year Wix-ela Inhub launched.

As part of increased efforts to help more complex generics reach the mar-ket, the FDA has tried to increase its flex-ibility with requirements that instruc-tions for use be identical to the reference

Mylan’s Wixela Inhub Generating More Device-Related Adverse Event Reports Than GSK’s Advair DiskusFDA is tracking the complaints for Wixela Inhub, Mylan’s generic of GSK’s Advair Diskus, to determine whether further action is needed to ensure uptake is not hindered. Among the most common for the ANDA is “Device Issue.” Advair Diskus also generates device-related adverse event reports, although far less frequently. Below are selected adverse event reports for both products.

Multiple complaints may appear in a report. Wixela Inhub data is only from 2019, while Advair Diskus data is from 2000 through 2019.

Source: FDA FAERS Public Dashboard, data as of 30 September 2019

Wixela Inhub

Advair Diskus

Device Issue

Device Use Issue

Device Issue

Device Use Issue

Incorrect Dose AdministeredBy Device

Complication AssociatedWith Device

Device Difficult To Use

Wrong Technique InProduct Usage Process

Wrong Technique In DeviceUsage Process

Wrong Technique In ProductUsage Process

Product Dispensing Error

Device Use Error

Device Use Error

Wrong Technique In Device Usage Process



Product Use Issue

Device Malfunction

Product Design Issue

2 4 6 8 10 12 14 16 18

16.44%

3.11%

2.22%

1.33%

0.89%

0.44%

0.44%

0.44%

0.44%

Type

of A

dver

se E

vent

Rep

ort

Type

of A

dver

se E

vent

Rep

ort

Percentage of Avderse Event Reports

Percentage of Avderse Event Reports

2 4 6 8 10 12 14 16 18

4.10%

2.89%

1.74%

0.91%

0.71%

0.16%

0.11%

0.09%

0.07%

0.05%



product. Agency officials have said that they may accept variations, so long as they do not impact patient safety. (Also see “Generic Combination Products May Be Permitted Delivery Device Variations” - Pink Sheet, 4 Jun, 2017.)

Reference product sponsors usually op-pose too much variation, in part because their often patent-protected devices pre-vent generic competition from entering the market. The agency said in a citizen petition response issued to GSK upon Wixela Inhub’s approval that changes to the instructions for use may be accept-able when concerning the device. (Also see “Generic Advair’s Labeling Variation Stems From Permissible Design Differences, US FDA Says” - Pink Sheet, 11 Feb, 2019.)

Mylan has also been on the opposite side of that argument, maintaining that a proposed generic of its EpiPen (epineph-rine) could not be approved because its delivery device did not function exactly the same as the reference product and may create problems in an emergency situation. (Also see “EpiPen Familiarity May Prove Tough Hurdle For Generics” - Pink Sheet, 12 Sep, 2016.)

A TEST OF PATIENT SAVVY WITH COMPLEX GENERIC DIFFERENCES The FDA’s proactive surveillance ap-proach may help staff test, at least in some cases, the amount of flexibility patients can tolerate in device differ-

ences and instructions for use, as well as whether the agency can deal with them post-approval.

“We’re trying to cherry-pick a couple products to see if we can do something with it,” Chazin said. “Maybe with this one the public will reassure us and com-plaints will go back down.”

The agency has been working for several years to help complex generics reach the market and has allocated mil-lions of dollars toward bioequivalence research (Also see “US FDA’s Generic Re-search Projects Appear To Be Opening Way For ANDAs“ - Pink Sheet, 6 Jun, 2018.), as well as user interface questions. (Also see “US FDA’s Generic Research May In-clude EpiPen And Competitors” - Pink Sheet, 10 Apr, 2018.)

The FDA also will meet with sponsors during the development process to of-fer scientific advice and help streamline the path to approval. (Also see “Complex Generics May Need New Communica-tions Options In GDUFA III” - Pink Sheet, 25 Nov, 2019.)


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As part of increased

efforts to help more

complex generics

reach the market,

the FDA has tried to

increase its flexibility

with requirements

that instructions for

use be identical to the

reference product.



US FDA Seeks Withdrawal Of Injectable Bacitracin Despite Extensive Off-Label UseSUE SUTTER [email protected]

E xtensive off-label use of injectable bacitracin as a surgical irrigant was not enough to prevent a US Food

and Drug Administration request for mar-ket withdrawal because the drug is no lon-ger considered safe for its lone approved, but unused, indication.

On 31 January, the agency announced it has requested that all current manufac-turers of bacitracin for injection voluntarily withdraw their product from the market. “Based on FDA’s review of currently avail-able data, FDA believes that the potential problems associated with bacitracin for injection are sufficiently serious to remove the drug from the market,” the agency said.

Bacitracin for injection is approved for only one indication: treatment of infants with pneumonia and empyema caused by staphylococci shown to be susceptible to the drug. Labeling includes a boxed warn-ing on the risk of renal failure due to tubu-lar and glomerular necrosis.

“Health care professionals no longer use bacitracin for injection to treat this condition because other effective FDA-approved treatments are available that do not have the same serious risks, including nephrotoxicity … anaphylactic reactions and the need for repeated intramuscular injections,” the agency said.

REGULATORY ACTION DECADES IN THE MAKINGThe announcement of the withdrawal re-quest could reasonably be viewed as long overdue given the drug’s regulatory history.

First marketed in 1948, injectable baci-tracin has remained available despite an advisory committee recommendation in 1984 that it be withdrawn because its nephrotoxicity risk outweighed any ben-efit given the availability of numerous al-ternative treatments.

However, the drug has found a place in

clinical practice as a surgical irrigant.From 2015 through 2018, an estimated

2.3m patients received bacitracin injection annually in the hospital setting, with 97%-98% of these patients ages 17 years and older – in contrast to the pediatric indication for which is its labeled, according to an FDA analysis. A literature review and analysis of current use indicate the drug is mainly used in solutions for intraoperative irrigation of surgical wounds. (Also see “Widespread Off-Label Use Could Ensure Injectable Bacitracin’s Future” - Pink Sheet, 24 Apr, 2019.)

A review of the FDA’s Adverse Events Reporting System database through 2018 found 35 adverse events associated with use of bacitracin injection in irrigation and intravenous solutions, with the reported events primarily allergic reactions and nephrotoxicity.

At an April 2019 meeting of the Antimi-crobial Drugs Advisory Committee, all but one committee member said the drug’s benefits do not outweigh its risks in the approved indication. Panelists cited the absence of high-quality evidence of clinical efficacy, safety concerns and the availability of numerous other approved antimicrobi-als. In addition, injectable bacitracin is not included in professional society and clini-cal guidelines for treating pediatric pneu-monia. (Also see “Injectable Bacitracin’s Lone Indication Should Be Revoked, US FDA Panel Says” - Pink Sheet, 28 Apr, 2019.)

Although panelists said the drug’s off-label use in surgical procedures should be further investigated, they acknowledged that such data may be difficult to get giv-en the lack of incentives for conducting new studies of a generic drug and other practical challenges.

Bacitracin for injection is marketed un-der abbreviated new drug applications held by five companies: Pharmacia & Up-john Inc.; X-Gen Pharmaceuticals Inc.; Fre-

“Health care

professionals no

longer use bacitracin

for injection to treat

this condition because

other effective FDA-

approved treatments

are available that do

not have the same

serious risks, including

nephrotoxicity

… anaphylactic

reactions and the

need for repeated

intramuscular

injections.” – FDA



EDITOR’S NOTE: Please Help Pink Sheet Serve You BestDENISE PETERSON [email protected]

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senius Kabi USA LLC; Xellia Pharmaceuti-cals AS; and Akorn Inc.

When asked by the Pink Sheet whether the FDA had approached product sponsors about conducting studies for surgical irriga-tion, the agency said: “If a drug sponsor is interested in submitting a new application for a new indication for bacitracin for intra-muscular injection, they should contact the relevant review division within the Office of New Drugs. FDA cannot disclose discus-sions with individual drug sponsors.”

The agency’s request for voluntary with-drawal does not impact approved topical or ophthalmic drugs that contain bacitracin.

NO READ-THRU FOR MAKENABacitracin injection was the first of two products for which advisory committee ma-jorities recommended market withdrawal in 2019, with AMAG Pharmaceuticals Inc.’s preterm birth prevention drug Makena (hy-droxyprogesterone caproate injection, also known as 17P) being the other.

However, the circumstances of the two drugs are so vastly different it would be dif-ficult to infer from the agency’s willingness to withdraw bacitracin injection that it will necessarily follow suit with Makena.

In October, nine of 16 members of the

Bone, Reproductive and Urologic Drugs Ad-visory Committee voted for withdrawal of Makena’s accelerated approval in light of the failure of the PROLONG trial to confirm clini-cal benefit. Seven panelists voted to leave the drug on the market under accelerated

approval and require a new confirmatory trial. (Also see “Makena Withdrawal Dilemma: Advisory Cmte. Split Offers No Clear Direction For US FDA” - Pink Sheet, 29 Oct, 2019.)

The FDA’s decision on Makena’s future is complicated by several factors that were re-flected in panel’s divided vote.

First, it is the only FDA-approved pharma-cotherapy for reducing the risk of recurrent preterm labor. Professional society clinical guidelines have long recommended the use of 17P for preventing preterm birth, and practitioners have lobbied the FDA to keep the drug on the market.

There also are concerns that if Makena were pulled off the market, physicians and patients would turn to compounded for-mulations that lack the same level of qual-ity assurance and safety oversight as an approved product. (Also see “US FDA Tried, But Failed, To Take Compounding Issue Off The Table At Makena AdComm” - Pink Sheet, 5 Nov, 2019.)

In addition, efficacy has been the pri-mary focus of regulatory concern with Makena, in contrast to the safety concerns the agency has highlighted with inject-able bacitracin.


The circumstances of

injectable bacitracin

and Makena are so

vastly different it

would be difficult

to infer from the

agency’s willingness

to withdraw one

that it will necessarily

follow suit with

the other.

P U B L I S H E R ’ S S P O T L I G H T

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Nonprescription Drugs March 11

Are you looking to reach and do business with senior decision makers in pharma and medtech?

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Vol. / No. February , 2020 · FOR THE LATEST INSIGHT ON BIOPHARMA REGULATION AND POLICY, VISIT:...

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