PHARMA’S BIG DEFEAT: US Rebate Proposal Hits …...The rebate proposal released in Janu-ary would have revised the existing an-ti-kickback safe harbor for rebates and replace it

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GENERIC DRUGS

Generic Companies Race To Withdraw ANDAs, p. 18

R&D

UK Pilot To Generate Real World Data On Medicinal Cannabis Use, p. 13

GENERIC DRUGS

Mylan/Biocon’s Insulin Glargine Has Narrow Window For Approval In US, p. 16

10 July. In a statement, the White House said, “Based on careful analysis and thor-ough consideration, the president has decided to withdraw the rebate rule.”

“The Trump Administration is encour-aged by continuing bipartisan con-versations about legislation to reduce outrageous drug costs imposed on the American people, and President Trump will consider using any and all tools to ensure that prescription drug costs will continue to decline,” the White House press office said.

The rebate proposal released in Janu-ary would have revised the existing an-ti-kickback safe harbor for rebates and replace it with a safe harbor that pro-tects upfront discounts that are passed through to beneficiaries at the point of sale through a new system.

It was in the final phase of bureaucratic re-view, under evaluation by the White House.

While there was broad support for changing the rebate system, which shrouds the cost of drugs in a cloak of secrecy and doesn’t always benefit the patients who buy medicines, critics said the proposal would result in higher in-surance costs and that it would elimi-nate the biggest tool payers rely on to drive down the costs of drugs. Pharmacy benefit managers (PBMs) and insurers were generally critical of the proposal.

Drug companies, on the other hand, have been pushing the rebate story for close to two years, trying to convince legislators and the public that increased list prices have largely been offset by higher rebates, and eliminating rebates

PHARMA’S BIG DEFEAT: US Rebate Proposal Hits The End Of The RoadJESSICA MERRILL [email protected]

T he White House will not move forward with a proposed rule to eliminate manufacturer rebates,

delivering a defeat to the industry, which had lobbied heavily in favor of the policy change. It is the second big proposal from the Department of Health and Hu-man Services blueprint on drug pric-ing to go up in smoke this month after a federal judge struck down the Trump Administration’s rule requiring the dis-closure of drug prices in TV ads.

Unlike with the direct-to-consumer (DTC) ad policy, industry advocated in

favor of eliminating rebates, the pay-ments it makes to payers off the list price of drugs to negotiate placement on drug formularies. Those payments are made directly to payers, who say they help to lower insurance premiums, but the big drawback is that those payments do not usually make their way directly to patients paying for drugs at the point of sale. As a result, patients can end up fronting the full cost of those medicines, depending on their insurance coverage.

The Office of Management and Budget officially removed the rebate proposal on

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Now that US FDA has approved the final EU authority, mutual recognition efforts could expand and deepen. Former FDA chief counsel Rebecca Wood discusses the future of approval standards harmonization in Pink Sheet interview.

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There are rumblings a drug importation proposal is coming, but there are no signs that the HHS/FDA working group has been active in the year since it was created.

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COVER Pharma’s Big Defeat: US Rebate Proposal Hits The End Of The Road

R E I M B U R S E M E N T 5 A Win For Alnylam In England As NICE Reverses

Onpattro Rejection

6 AstraZeneca To Fight NICE Knockback For Tagrisso In England

7 UK Plans Upfront Payment Scheme To Spur Antimicrobial Development

R E G U L ATO RY U P D AT E 9 EMA’s Rasi To Head Global Coalition Of Drug Regulators

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11 Pharma’s Bedtime Horror Stories: Gene Therapy, Digital Revolution, Pricing ‘Fixes’

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15 Australia Could ‘Look Worse Than Comparable Countries’ Under Proposed GCP Inspections

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For Approval In US

18 Generic Companies Race To Withdraw ANDAs

20 US FDA, USP Cooperate On Small Molecule Drug Monograph Updates To Speed ANDAs

M A N U FAC T U R I N G Q UA L I T Y 21 Apotex Withdraws 31 ANDAs After Failing To Ensure

Data Integrity At Two Indian Manufacturing Plants

A D V I S O RY CO M M I T T E E S 23 Recent and Upcoming FDA Advisory Committee Meetings

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or giving them directly to consumers would help to alleviate the problem.

When seven big pharma leaders testi-fied before the Senate Finance Commit-tee on drug pricing in February, rebate reform was one of the policy initiatives the CEOs said would help lower drug spending. (Also see “Big Pharma Defuses Drug Pricing Landmines On Capitol Hill “ - Scrip, 26 Feb, 2019.)

PHRMA SPEAKS FOR PHARMAThe Pharmaceutical Research and Manu-facturers of America (PhRMA) said in a statement, “Of all the policies proposed in Washington right now, this was the only proposal that would provide immediate savings at the pharmacy counter, instead of only saving the government or insur-ance companies money. It is disappoint-ing that despite support from policymak-ers on both sides of the aisle and from a wide array of consumer, patient, pharma-cist and provider groups that they have decided to backtrack.”

Drug companies reached for comment widely pointed to PhRMA’s statement and avoided giving any individual reaction.

Across the health care spectrum, there were concerns about upending a system by the 1 January 2020 deadline without a careful transition.

The implementation of a sweeping re-bate change seemed almost inevitable until it suddenly seemed highly unlikely in May. That was when the Congressio-nal Budget Office estimated the proposal would increase federal spending on Medi-care Part D by about $170bn from 2020 to 2029 and would raise federal spending on Medicaid by $7bn. (Also see “One More Score: CBO Projects HHS Rebate Proposal Would Boost Part D Spending $170bn” - Pink Sheet, 2 May, 2019.)

Owning a policy that substantially increased federal spending, especially should it turn out to deliver a financial windfall to big pharma, was considered unpopular heading into the 2020 elec-tion cycle.

Pharmaco-economic specialist Peter Bach, director of the Center for Health Policy and Outcomes at the Memorial

Sloan Kettering Cancer Center, has ad-vocated in favor of reforming the rebate system but nonetheless had concerns with HHS’ proposal.

“It was not good policy in isolation as it removed a source of leverage from PBMs that helped to hold down net prices,” he said after the proposal was revoked. “I am not a fan of rebates that are not passed through at the point of sale, but dumping them and not replacing them with another mechanism to hold prices down would have led to a huge transfer from taxpayers to pharma.”

HHS Secretary Alex Azar – a former pharmaceutical executive – had strongly pushed for the pro-posal as a cornerstone of his plan to reduce drug prices. White House Domestic Policy Council director Joe Grogan was seen as an opponent, with the price tag being a key wor-ry. (Also see “For All The Palace Intrigue, Rebate Rule, IPI Go To OMB For Review” - Pink Sheet, 25 Jun, 2019.)

WHAT COMES NEXT?It’s unlikely the decision by the White House will end debate over rebate re-form altogether.

“I don’t see this as the end of the discus-sion of how to ensure that patients ben-efit from the rebates earned on the drugs they are taking,” Rock Creek Policy Prin-cipal Ian Spatz said. “The issue will now likely become intertwined with larger reforms of patient cost sharing in Part D.”

While the proposed rule would have impacted drugs reimbursed under fed-eral programs, many stakeholders said they expected changes would eventu-ally roll over to the private insurance market. Some insurers have recently implemented new programs to pass re-bates onto the point of sale.

The big question now is if not re-bates, what? Many of the policy ideas outlined in the Trump Administration’s drug pricing blueprint released in 2018 are far less desirable from the perspec-tive of drug makers.

The other key policy under review at OMB is an International Pricing Index for drugs in Medicare Part B. The proposal, which would test a new payment model for Part B drugs in which they are reim-bursed based on prices paid in Europe, Ja-pan and Canada, is vehemently opposed by industry. (Also see “Medicare’s Foreign Price Bench-marking Will Only Hurt Bad Ne-gotiators, HHS’s Azar Argues” - Pink Sheet, 25 Oct, 2018.)

Another possibility is movement on a proposal around drug importation, even more loathsome from industry’s point of view. (Also see “Drug Importa-tion Working Group Has Been Publicly In-visible As Buzz Grows On Proposal “ - Pink

Sheet, 7 Jul, 2019.)While HHS’ blueprint on drug

pricing was released a year ago with a lot of fanfare and sweep-ing ideas, little in the way of actu-al policy changes have emerged. But the Trump blueprint has certainly kept big pharma busy pushing for and against a range of ideas on Capitol Hill.

Published online 11 July 2019

CONTINUED FROM PAGE 1

The big question

now is if not

rebates, what?

Many of the policy

ideas outlined

in the Trump

Administration’s

drug pricing

blueprint released

in 2018 are far less

desirable from the

perspective of

drug makers.

P R I C I N G D E B A T E

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related stories available only online.

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Attention Turns (Again) To Congress

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R E I M B U R S E M E N T

A Win For Alnylam In England As NICE Reverses Onpattro RejectionNEENA BRIZMOHUN [email protected]

T he National Institute for Health and Care Excellence (NICE) has reversed its preliminary rejection of Alnylam

Pharmaceuticals’ Onpattro (patisiran), say-ing that the innovative gene silencing drug can now be used under England’s National Health Service as a treatment for hereditary transthyretin-related (hATTR) amyloidosis.

Final NICE guidance, published this week, shows that Alnylam helped change the in-stitute’s mind by providing evidence to ad-dress the doubts it had over the potential lifetime benefit for patients with hATTR, a progressive, life-threatening disease.

In preliminary guidance rejecting the treatment last December, NICE said that clinical trial evidence for Onpattro showed that while the product reduced disabil-ity and increased quality of life, there was a lack of evidence to support the drug’s long-term benefits.

According to the final guidance, NICE said it took into account additional factors “such as the uncaptured health-related benefits of stopping and potentially re-versing the condition, the rarity and sever-ity of the condition, the potential lifetime benefit for people with the condition and the innovative nature of the treatment.”

NICE noted that some assumptions in the economic modeling were still uncer-tain, particularly around the utility values and the modeling of mortality. “Also, the range of cost-effectiveness estimates pre-sented is somewhat higher than what NICE usually considers acceptable for highly specialised technologies.”

Nevertheless, it said that Onpattro is now recommended for use via NHS England as an option for treating hATTR in adults with stage 1 and stage 2 polyneuropathy. Wales generally follows NICE decisions.

The price of Onpattro is £7,676.45 ($8,541.19) per 10mg vial (excluding VAT). The product is administered once every three weeks by intravenous infusion at a dose of 0.3mg/kg. Alnylam has a commer-

cial arrangement that makes the product available to the NHS with a discount that has not been publicly disclosed. Onpat-tro is a high-ticket product with an annual list price of $450,000 in the US (Also see “Amyloidosis Drug Competitors Can Coex-ist While Growing The Market, Alnylam CEO Says” - Scrip, 7 Jun, 2019.)

At the time of the evidence submission, there were thought to be around 150 peo-ple with hATTR amyloidosis in the UK.

The final NICE guidance document is ex-pected to be published on 14 August.

COMPETITIVE LANDSCAPEOnpattro, a small interfering RNA thera-peutic that received EU marketing autho-rization in August 2018, is one of several products targeting the hATTR market. Ak-cea Therapeutics/Ionis Pharmaceuticals’ Tegsedi (inotersen), an antisense oligonu-cleotide that was also approved in the EU last year, received a positive recommenda-tion from NICE this April, having also been initially turned down by the institute. (Also see “NICE Says Yes To Akcea’s Tegsedi After ‘Improved’ Commercial Offer” - Pink Sheet, 17 Apr, 2019.)

Pfizer received EU marketing authoriza-tion for its transthyretin stabilizer, Vyndaqel (tafamidis), in 2011, for the treatment of amyloidosis in adult patients with stage 1 symptomatic polyneuropathy. NICE is cur-rently planning to appraise the product as a treatment for transthyretin amyloid car-diomyopathy (ATTR-CM), for which it notes that current treatment options are lim-ited. This is a broader indication than the one patisiran and inotersen are indicated for in the EU. Pfizer notes that regulatory submissions for the use of Vyndaqel in pa-tients with ATTR-CM have been submitted to the European Medicines Agency and are under review.

Onpattro, Tegsedi, Vyndaqel and a differ-ent formulation of the Pfizer product, Vyn-damax, were recently approved in the US.

hATTR amyloidosis is an ultra-rare condi-tion caused by inherited mutations in the transthyretin (TTR) gene. These mutations cause abnormal amyloid proteins to ac-cumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations.


NICE’s final guidance

took into account

additional factors “such

as the uncaptured

health-related benefits

of stopping and

potentially reversing

the condition, the

rarity and severity

of the condition, the

potential lifetime

benefit for people with

the condition and the

innovative nature of

the treatment.”



0.3mg/kg



AstraZeneca To Fight NICE Knockback For Tagrisso In EnglandNEENA BRIZMOHUN [email protected]

A straZeneca has said it will appeal against last week’s decision by the National Institute for Health

and Care Excellence (NICE) to recommend that its drug, Tagrisso, should not be used on England’s National Health Service as a first line treatment for a certain type of lung cancer.

NICE issued final guidance on 5 July say-ing that Tagrisso (osimertinib) was not an acceptable use of NHS resources for adults with untreated locally-advanced or meta-static epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

By contrast, it issued final guidance on the same day that recommended Pfizer’s Vizimpro (dacomitinib) for the same indi-cation. (Also see “UK NICE Says Yes To Vizim-pro & Libtayo But Rejects Tagrisso” - Pink Sheet, 5 Jul, 2019.)

As well as appealing against the institute’s decision on Tagrisso, AstraZeneca said it was time for a comprehensive review of how NICE values innovative medicines.

CRITICAL FACTORThe company said that a critical factor in NICE’s decision was that Tagrisso was not eligible for end of life (EoL) consideration, a status that it believes would make the drug a cost-effective use of NHS resources and which it merited based on the evi-dence it provided.

For EoL medicines, NICE recognizes that it may be appropriate to exercise flexibility around what it considers a cost-effective use of NHS resources, a spokes-person for AstraZeneca told the Pink Sheet. “The standard cost-effectiveness threshold is between £20,000-30,000 per quality-adjusted life year (QALY) gained, but EoL medicines may exceed this.”

AstraZeneca provided NICE with an analysis of real-world data from Public Health England that showed that overall survival (OS) in England for NHS patients

who would be eligible for Tagrisso was less than 17 months, which is within the 24-month short life expectancy threshold for EoL consideration.

But NICE rejected this evidence. One of the reasons it gave for doing so “is that it would be inconsistent to define life ex-pectancy on real-world data, when data from a clinical trial are being used to eval-uate efficacy and cost-effectiveness,” the spokesperson said.

AstraZeneca argues that “it is impor-tant to remember that the ‘End of Life medicine’ status was established to make medicines available that could be a cost-effective use of NHS resources for pa-tients who are nearing the end of their life. Therefore, establishing what the real-world outcomes are for people in England needs to be taken into account.”

NICE has historically based its decisions about EoL consideration on how long patients survive in the “standard of care” group in the medicine’s clinical trial.

But because clinical trial results show pa-tient outcomes as an average from across multiple countries, the UK, which has the second-lowest survival rate for lung cancer

in Europe, may or may not be one of the countries included in the clinical trial, the spokesperson said. “Any outliers or differ-ences in patient outcomes between coun-tries may not always be apparent.”

In AstraZeneca’s FLAURA clinical trial of Tagrisso, patients in the standard of care arm were estimated to have a median OS of 31.54 months. This study was con-ducted across 29 countries, including six patients from the UK.

“Recognising that the UK has the sec-ond-worst lung cancer survival outcomes in Europe, likely due to differences in the patient diagnosis and treatment journey compared to other countries, AstraZene-ca provided an analysis of real-world NHS data… for the population under consid-eration for treatment with osimertinib,” the spokesperson said. This data, which included the records of 336 patients from England, “showed that median OS for Per-formance Status (PS) 0/1 patients was less than 17 months.”

The NICE committee agreed that osimer-tinib was likely to meet the efficacy crite-rion for EoL consideration because it can extend life by over three months, but it did




not agree that the target patient group has a life expectancy of less than 24 months, despite the analysis of real-world NHS data that the company provided.

“We believe we have demonstrated that osimertinib would be considered a cost-effective use of NHS resources if EoL status was granted,” the spokesperson maintained.

“It is sad that, in this instance, osimer-tinib will not be available to patients in England when it was discovered here and many other countries across Europe and the world have already decided to reimburse this medicine.” In Europe, the product is reimbursed as a first-line treat-ment for EGFR mutation-positive NSCLC in Belgium, Bulgaria, Denmark, Luxembourg, Spain and Sweden.

AstraZeneca declined to comment fur-ther on its plan for its appeal against NICE’s decision. If its application for appeal is ac-cepted, publication of the final guidance, which had been scheduled for 14 August, will be postponed.

THE NEED FOR CHANGE“NICE methods and processes need to con-tinue to evolve to keep pace with rapidly changing science to avoid delays in patient access to medicines, postcode prescribing and avoidable waste of NHS resources,” the spokesperson declared.

The company added that it was worth noting that NICE recently launched a consultation looking at how it should use different sources of data, including real-world evidence, to develop its guid-ance. (Also see “UK: NICE Seeks Views On Using RWD To Inform Guidance” - Pink Sheet, 3 Jul, 2019.)

“As a UK life sciences leader, we have been very active in discussions about the need to reform NHS medicines ac-cess, bringing to the table proactive proposals and engaging collaboratively with DH [Department of Health], NICE, NHSE [NHS England] and patient organ-isations, especially in the last three years, to help shape the Life Sciences Industrial

Strategy and the vision for the future of life sciences in the UK,” the spokesperson said. “We have ideas around simplifica-tion of the system, use of real-world evi-dence, and the introduction of modifiers for ‘severity’ and ‘rarity’.”

TAGRISSO VERSUS VIZIMPROTagrisso, like Vizimpro, is a EGFR tyrosine kinase inhibitor. According to NICE’s final guidance on Vizimpro, Pfizer’s product also did not meet EoL criteria, but NICE still rec-ommended it for use on the NHS for the same indication for which AstraZeneca is seeking reimbursement.

Asked why NICE might have said yes to Vizimpro and no to Tagrisso, AstraZen-eca’s spokesperson said: “Osimertinib and dacomitinib have different efficacy and tolerability profiles, therefore, the circum-stances around NICE’s decision are not wholly comparable.”


UK Plans Upfront Payment Scheme To Spur Antimicrobial DevelopmentIAN SCHOFIELD [email protected]

T he UK government is planning to test a new scheme aimed at foster-ing the development of new an-

timicrobials whereby companies will be paid upfront for new drugs on the basis of their expected value to the national health service, rather than on the volume of prod-ucts actually used on the NHS.

The trial, involving what the government describes as “the world’s first ‘subscription’ style” payment scheme, is intended to help tackle the growing problem of antimicro-bial resistance (AMR) and will be devel-oped and run by the health technology assessment (HTA) body NICE, NHS England and NHS Improvement.

It will initially be tested using two anti-microbial drugs and will be in two phases. The first phase – developing an evaluation

framework and identifying the two products – is expected to be completed by the end of this year. The second phase, including value assessments of the products and the imple-mentation of payments, should be finished by the end of 2020.

NICE and NHS England are calling on companies to identify products they would like to be considered for the initial phase of the project. A stakeholder advisory group will shortly be set up with representatives of industry, experts in public health and the clinical and health economic evaluations of vaccines, as well as a “wide range of national and international representatives”.

The group will be used to support a pe-riod of targeted engagement that will begin shortly in order to “secure stakeholder input into the development of key areas of the





project, including the proposed approach for topic selection, the approach to evalua-tion, and the outline commercial model,” the organizations said.

It is widely accepted that companies see investment in novel antibiotics as commer-cially unattractive because of the high cost of R&D and the low returns on investment. The Department of Health and Social Care said the new scheme would “make it more attractive for companies to invest the esti-mated £1 billion it costs to develop a new drug, as they can be reassured they will still be paid for the drug even though it may be stored for reserves.”

The project was welcomed by the Asso-ciation of the British Pharmaceutical Indus-try, which described it as a “big step forward” that could have “a big impact on the future of health and research by making it sustain-able for companies to keep investing.”

Dr Sheuli Porkess, the ABPI’s executive di-rector of research, medical and innovation, said the announcement was “an example of how the UK can lead the world in this fight and hopefully brings us closer to fixing the problems that have hampered investment in antibiotics research for so long.” She said ABPI members were “ready to get started, and the sooner we get this pilot up and run-ning, the sooner we can apply what we find to other antimicrobials in development.”

The scheme is also seen by the govern-ment as a model for other countries to emu-late. Health Minister Nicola Blackwood said: “This project is an important step but it will only address global market failure if other countries do the same, which is why we want to involve as many countries as we can and share our learning from this work. Today we are sending a strong signal to the rest of the world that there are workable models to stimulate investment in these vital medi-cines and that together we can tackle AMR.”

THE NEW PAYMENT MODELThe announcement of the trial follows the publication in January of the government’s “20-year vision” and five-year “action plan” for containing and controlling AMR. The plans outlined in those documents included cut-ting the number of drug-resistant infections by 10% by 2025, and reducing the use of antibiotics in humans by 15%. They also said

that NICE and NHS England would explore a new payment model for antibiotics.

A key part of the new approach will be to use revamped HTA methods to assess the likely value of new drugs. NICE and NHS England said that research conducted by EEPRU (Economic Methods of Evaluation in Health & Care Interventions), which is fund-ed by the National Institute for Health Re-search, had confirmed that “capturing the full value of a new antimicrobial is complex” and that a robust evaluation of benefits “may not always be feasible or practical.”

The research did, however, conclude that “an adapted HTA framework, informed by health economic modelling and expert opinion, could be developed to capture the full value of novel antimicrobials.” NICE, NHS England and NHS Improvement have now established a jointly led project sup-ported by EEPRU to “develop and test in-novative models for the evaluation and purchase of antimicrobials.”

THE TWO PHASESThe two organizations said they were working closely with the DHSC and stake-

holders including industry, and that they had set up a central project team to lead the work and facilitate input from experts and stakeholders.

The first phase of the project, which is expected to be completed by the end of this year, will focus on possible adaptations to the current HTA framework, the devel-opment of an outline reimbursement and payment model, and the selection of two products to undergo trial assessment and commercial discussions.

“It is therefore important that compa-nies have notified the project team if they have a product which could be considered through this process,” according to the two organizations. If not, companies should get in touch with [email protected].

The reimbursement and payment mod-el would include “a strong emphasis on companies needing to ensure that optimal stewardship arrangements are maintained through the introduction of the product and that they are making efforts to keep environmental contamination of antimi-crobials to a minimum.”

The second phase, expected to last until the end of next year, will involve an assess-ment of the two selected products, includ-ing the development of NICE guidance by a special committee to be convened for the project. It will also see commercial dis-cussions on the two products, the imple-mentation of payments, and monitoring of the use of the products.

“Evaluation and communication will be ongoing throughout the project and the evaluation will be critical in shaping UK policy on the wider application of the model,” the organizations said.


The scheme will

“make it more attractive

for companies to invest

the estimated £1 billion

it costs to develop

a new drug”

– UK Department of

Health and Social Care

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

EMA’s Rasi To Head Global Coalition Of Drug RegulatorsVIBHA SHARMA [email protected]

T he European Medicines Agency’s executive director, Guido Rasi, has been elected as the new chair of the International Coalition of Medicines Regulatory Authorities and he will

take charge of the post from 1 October.While Rasi’s mandate at the ICMRA is for a three-year period, he

is due to leave the EMA in November 2020. (Also see “Search For Rasi’s Successor At EMA Extended” - Pink Sheet, 1 Jul, 2019.) The IC-MRA press release on Rasi’s appointment does not say what will happen after this date.

The ICMRA is a voluntary initiative that comprises heads of medi-cines agencies from around the world who have joined hands to address current and emerging drug regulatory and safety chal-lenges. Rasi will replace the IMCRA’s current chair, Ian Hudson, who is also stepping down from his role as chief executive of the UK’s Medicines and Healthcare products Regulatory Agency in Septem-ber. (Also see “UK Agency Boss Hudson Leaves Brexit Challenge To Successor” - Pink Sheet, 20 Nov, 2018.)

Rasi was elected to lead the ICMRA at the coalition’s latest ple-nary meeting in San Diego on 23 June. Two vice-chairs were also elected: John Skerritt, deputy secretary of health at Australia’s health department was re-elected for a second term, and Yasuhiro Fujiwara, chief executive of Japan’s Pharmaceuticals and Medical Devices Agency, was newly elected.

“When development, manufacture and distribution of medicines is global, we regulators must work together globally to prepare for new medicines and technologies and improve global oversight of the safety and quality of medicines,” Rasi said on being elected the ICMRA’s new chair. “We owe this to patients around the world.”

Among the many projects underway at the ICMRA is an initia-tive to address the challenges in the area of innovation.The ICMRA recently published a report on the initial part of its innovation proj-ect, which incorporates horizon scanning and novel approaches to licensing as key focus areas.

The next phase of the work involves plans to establish an infor-mal innovation network among ICMRA members in mid-2019. The network, when in place, will aim to build on the positive interac-tions during the initial project and will help explore further chal-lenges and harmonized solutions on a global level.

Rasi is expected to play a key role in establishing the ICMRA’s inno-vation network, considering his interest in this area. In 2015, he was instrumental in establishing the EU Innovation Network, which links up national innovation offices in the EU member states to the EMA’s Innovation Task Force to support innovation and early development of new medicines. (Also see “New Network To Boost Coordination On Innovative Drugs Across Europe” - Pink Sheet, 23 Jan, 2017.)


Oncology Dominates As China Drug, Biologic Approvals SurgeBRIAN YANG [email protected]

I n a bid to bring more cancer and rare disease treatments to the country, China has significantly increased approvals re-lated to novel therapies. Throughout 2018, a total of 25 Category 1.1 new drug approv-

al (NDA) applications were accepted by regulators, an increase of 150%. Among these, small molecule drugs accounted for 16, up by 100%, and large molecule biologics for nine, surging by 450%, notes a new annual review released by the National Med-ical Products Administration’s drug review wing, the Center for Drug Evaluation (CDE).

Investigational new drug (IND) filings also rose, among which oncology took the absolute lead. Of a total of 457 INDs filed by both domestic and international applicants, anticancers was the leading therapeutic area, followed by endocrinology and gas-trointestinal and cardiovascular medicines. It was a similar situa-tion for biologics, where 70% of the INDs were for cancer.

ONCOLOGY REMAINS FRONT AND CENTERThe CDE annual report report highlights a heavy focus on on-cology and increasing attention on rare disease treatments in China.

Oncology accounted for 70% of new biologics approvals, which included four PD-1 checkpoint inhibitors, two of which were from multinationals: Bristol-Myers Squibb Co.’s Opdivo (nivolumab) and Merck & Co. Inc.’s Keytruda (pembrolizumab). The other two were Tuoyi (toripalimab) from Junshi Pharma and Tyvyt (sintilimab) from Innovent Biologics Inc.

In fact domestic drug makers appear to be catching up fast, securing several NDAs for their novel cancer treatments. These



innovation.The




included Jiangsu Hengrui Medicine Co. Ltd. with Iruini (pyrotinib) and Hutchison MediPharma Ltd. with Elunate (fruquintinib), along with anlotinib from Chiatai Tianqing, a part of China Bio-logic Products Inc.

Meanwhile, Roche/Chugai Pharmaceutical Co. Ltd. ’s Alecensa (alectinib) also gained approval in China for ALK mutation-positive patients with non-small cell lung cancer.

GLOBAL FIRST APPROVALSAs China speeds up the introduction of novel therapies to the country, regulators are eagerly highlighting several world-first new drug approvals granted to products filed first in China.

One of these was FibroGen Inc.’s roxadustat, for anemia associ-ated with chronic kidney disease (CKD) and patients on dialysis. It was the first approval worldwide for the first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, which is marketed by AstraZeneca PLC in China.

With an estimated 120 million sufferers, the country has one of the largest CKD patient populations in the world, and the associ-ated burden of dialysis is increasing. (Also see “First Approval For AZ’s Roxadustat With China Green Light“ - Scrip, 18 Dec, 2018.)

Similarly, domestic biotech startup Nanjing Pioneer gained the first approval worldwide for albuvirtide, its peptide therapy for HIV infections. The long-acting injection is billed as China’s first domes-tically-developed drug for combination use in patients who have been on antiviral treatment.

ORPHANS GETTING MORE ATTENTIONThe annual report also highlighted the Chinese regulator’s increas-ing focus on rare disease treatments. Last May, the National Health Commission in China released the first-ever Rare Diseases Catalog, ushering in a new chapter for orphan drugs development in the country. Orphan drugs have also been selected for priority reviews and clinical trials waivers as long as they have already been ap-proved in the US, EU and Japan.

Biogen Inc.’s spinal muscular atrophy treatment Spinraza (nusin-ersen) became the first approved treatment for the devastating neuromuscular degenerative condition following a speedy review

and without local clinical trials. Alexion Pharmaceuticals Inc.’s Soliris (eculizumab) also gained nods for paroxysmal nocturnal hemoglo-binuria and atypical hemolytic uremic syndrome, both included by the commission in the list of 122 designated rare conditions.

Also approved during the year were Roche/Chugai’s Hemlibra (emicizumab) for hemophilia A and Sanofi’s Aubagio (teriflunomide) for relapsing multiple sclerosis, and other notable orphan clear-ances included Amgen Inc.’s PCSK9 inhibitorRapatha(evolumab) for rare heterozygous familial hypercholesterolemia, and Acte-lion Pharmaceuticals Ltd.’s Uptravi (selexipag) for pulmonary ar-terial hypertension. China has few available treatment options for the latter disease, a severe and life-threatening condition, noted the CDE report.

J&J SCORES DARZALEX APPROVALOther notable approvals included Johnson & Johnson’s antibody Darzalex (daratumumab) as a single therapy for relapsed and in-tractable multiple myeloma; the product was also the first CD38-targeting antibody to gain approval in China. Darzalex was origi-nally developed by Genmab AS of Denmark, and J&J has licensed exclusive rights in the US and China among other territories.

Multiple myeloma has overtaken acute leukemia/lymphoma as the second mostly common hematological malignancy in the country, especially among middle aged and older people, and mortality rates are high due to frequent recurrence and relapse.

Several companies have been active in China with new ther-apies, including Takeda Pharmaceutical Co. Ltd. and Celgene Corp.. Takeda’s Ninlaro (ixazomib) gained the green light in China last April as the first approved oral-only treatment for multiple myeloma, while Celgene’sRevlimid(lenalidomide) was cleared last February in combination with dexamethasone for previously untreated, transplant-ineligible multiple myeloma patients.

Marketed in China by BeiGene Ltd. under a previously-agreed deal, Revlimid has however seen only a slow uptake in China de-spite its strong showing in the US.

Last May, the US FDA approved Darzalex in combination with Velcade (bortezomib), a proteasome inhibitor, for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. “As the first CD38-targeting antibody approved in China, the novel treatment is ex-pected to redefine the multiple myeloma treatment in China,” J&J said in a statement.

The next step the product will face is market access, given that there is no immediate reimbursement coverage for newly ap-proved drugs in China.


As China speeds up the

introduction of novel therapies to

the country, regulators are eagerly

highlighting several world-first new

drug approvals granted to products

filed first in China.

LET’S GET SOCIAL@PharmaPinksheet



THE CELL AND GENE THERAPY LANDSCAPE

Peter Marks, director, US Food and Drug Administration’s Cen-ter for Biologics Evaluation and Research

“From our perspective as an agency, the two places I see us put-ting a lot of effort in over the next few years are, first of all, helping to do what we can to advance the manufacturing of these prod-ucts. And that also includes what we can do to help offer up guid-ance for how one might be able to get from a small process to a larger process in this area and in terms of process scale.”

“And another area is how we will try to address dealing with a landscape where there are going to be some very challenging products that are not traditional drug products. Normally, we have one product and one drug, one approval. And here we’re going to have essentially gene therapies where there might be very slight tweaks, where the product changes slightly in order to address a different mutation, and we’ll have to have a regulatory framework that can address that without having to go back to square one. Do we have it all worked out yet? No, but you’ll see us working dili-gently to do so in the next short while.”

“Those are, I think, the two things that keep me up at night.”

Bob Smith, senior VP, global gene therapy business, Pfizer Inc.“I wake up every morning excited about gene therapy and I go

to bed every night worrying about gene therapy.”

Mo Heidaran, VP-technical, Parexel International Corp.“My worries are that we go too fast and do not deal with the issues

appropriately, and that we will actually hit a pothole that derailed the whole business like it did maybe 15 years ago in gene therapy.”

“The issues related to safety of these products – short term they are very safe. Long-term safety has to be established. The efficacy of the product, reliability and reproducibility … has to be another consideration. Cost would also be a factor. You have to be able to take these products and … pharmaceuticalize, I call it.”

“It requires attention, it requires work, it requires government agencies working with private industry, incentivizing platform technologies to be developed, automation to be introduced, scale-up to be considered early on, or a scale-out. There’s a number of different things. … It’s about sustainability of this business.”

Debra Miller, CEO and founder, Cure Duchenne“What keeps me awake at night is the access, and by that I mean a

lot of different factors. I know when my son was diagnosed 16 years ago we wouldn’t have dreamt to have the options we have now. And to see the fact that we have patients that are enrolled in clinical trials for Duchenne and seem to be doing well, and it’s a dream come true for those families whose sons qualify for these trials.”

“So when I talk about access, I’m not just talking about the manu-facturing limitations that we have, which they’re real. And I’m not just talking about the price of the product, which is going to be a concern of insurance companies. I’m also talking about the fact that many of these kids have pre-existing antibodies, and will not be eligible for an AAV delivery treatment. If it isn’t durable and it doesn’t last a long time, they then will have antibodies and will not be able, with today’s technology, to be re-dosed. And where does that leave us?”

PHARMA’S BEDTIME HORROR STORIES:

Gene Therapy, Digital Revolution, Pricing ‘Fixes’SUE SUTTER [email protected]

It seems there’s a lot to worry about in and around the pharmaceutical industry these days. Regulators, industry execu-tives and patient advocates are having trouble sleeping thanks to a host of challenges and anxieties, including the need for evolving regulatory paradigms, the threat of federal drug pricing “fixes” that could undermine innovation,

and patients’ ability to access life-changing medicines.At the recent Biotechnology Innovation Association annual meeting in Philadelphia, stakeholders shared some

of the professional challenges and concerns that are keeping them awake at nights. The comments are drawn from panel sessions at BIO, as well as one-on-one interviews with the Pink Sheet.





“So I think there’s a lot of issues that we have to deal with as a disease community. … All of us that are interested in gene thera-py need to be taking a really, really deep look at how we can treat all the patients.”

AFFORDABILITY AND DRUG PRICING ‘FIXES’

John Maraganore, CEO, Alnylam Pharmaceuticals Inc.“I think the number one thing that keeps me up at night is some

crazy piece of policy, like IPI [International Pricing Index], gets put into place from people in Washington or at the state level who don’t understand, who might be mad about the drug price issue, emotional, and don’t understand how wonderful it is, important it is, that we have an innovation environment in this country that al-lows us to bring these types of medicines to patients.”

Susan Cantrell, CEO, Academy of Managed Care Pharmacy“We’re in this amazing period of innovation but also this really

challenging period of innovation where you have, potentially, rules being proposed, like the rebate safe harbor rule, that would totally change the way we do things, totally change the model that has been in place for more than two decades for contract-ing. And what does that mean to health care costs? What does that mean to patients being able to get and afford their medica-tions? Because the best drug in the world doesn’t help if you can’t get access to it. So that’s probably, of everything, what keeps me awake at night. How do we make these medications more afford-able and how do we avoid doing anything that would undermine

our ability to achieve that?”

THE DIGITAL REVOLUTION

Ameet Nathwani, chief medical officer and chief digital officer, Sanofi

“I have to say I don’t sleep much and I’m very excited about what I do. Actually I have nothing that really keeps me up in terms of get-ting scared. I’m just incredibly excited. I think this is the best time for people of my generation to be in our industry. So what keeps me awake, I suppose, would be my impatience to get things done, because I feel it’s moving so fast.”

“We still are an industry that is rather sluggish compared to the tech industry or to other companies or industries that have ad-opted technologies much earlier than we have and have used it to transform their business. And the pace that we have to change

makes me scared because this is an exponential change that’s hap-pening outside of us.”

“If we don’t jump on that bandwagon soon and adopt it, I don’t think we can go back through our normal cycles of decision-mak-ing. … But it’s the excitement. It’s not that I’m scared of it, I just think people just have to embrace it.”

THE SCIENCE BEHIND THE DEALS

Michael Crowley, head of business development for pharma research and early development, Roche

“I think seeing the breadth of deals and especially in areas that are critical for us, like oncology, to see the comprehensive ap-proach that we’re taking, it actually makes me in fact more relaxed that we’re doing what needs to be done, versus pursuing only ap-proaches that we’re more comfortable with. These are all getting out of our comfort zone. The scientists probably are losing more sleep maybe than the partnering people are.”

THE GOOD, THE BAD AND THE UGLY DRUGS

Amy McKee, VP of regulatory consulting services, Parexel“I worry that good drugs will stumble and that bad drugs may

find a way to squeak through.”

“Good drugs can stumble based on the trial design. … You may have companies that don’t have as significant resources and can’t rescue a program based on a minor trial detail that perhaps could have been improved upon, or maybe they didn’t know about at the time, or maybe the standard of care changed. … I think a drug de-velopment program can be destabilized by just one wrong decision here, or one mistake there, or one intervening therapy that gets ap-proved while the trial is running – things that may be out of their control. And I would hope that all the good drugs get through.”

“It can happen” that bad drugs get through. “Dose is one of the biggest things. There are drugs that get approved with a dose that is clearly not the right dose. And we may not understand what the true clinical benefit is at the dose that the patient will actually get in the real world. That’s what keeps me up at night.”


@PharmaPinksheet


R & D

UK Pilot To Generate Real World Data On Medicinal Cannabis UseIAN SCHOFIELD [email protected]

A pilot program is to be launched in the UK to generate a solid body of evidence for the use of medicinal

cannabis in patients with a range of medi-cal conditions such as chronic pain, mul-tiple sclerosis and Tourette’s syndrome, in the expectation that eventually a new kind of licensing status might be available for such products.

Project TWENTY21 will be run by the independent charity Drug Science, whose stated aim is to provide “objective informa-tion on drug effects, harms and potential medical uses to the public, professionals and decision makers.”

The pilot will be launched on 18 July by the charity’s medical cannabis working group, which includes representatives of the United Patients Alliance, several aca-demic researchers, and a number of me-dicinal cannabis companies that will be providing the substances at their own cost. The charity, which aims to enrol 20,000 pa-tients in the pilot by the end of next year, will use a real world data patient registry to assess efficacy, safety, cost-effectiveness and patient reported outcomes.

Drug Science was founded in 2010 by David Nutt, who was famously sacked in 2009 as chair of the UK government’s Ad-visory Council on the Misuse of Drugs after claiming that ecstasy and LSD were less dangerous than alcohol.

Outlining the rationale for the medici-nal cannabis pilot, Nutt said that despite last year’s rescheduling of cannabis from Schedule 1 of the Misuse of Drugs Regu-lations to Schedule 2 – which means that unlicensed medical cannabis products can now be legally supplied as a prescription medicinal product – there have as yet been “only a handful of prescriptions” on the Na-tional Health Service.

“The big problem with medical cannabis is that patients know more than the doctors, and the doctors resist the idea that patients are telling them what to do,” Nutt said. “We

have a very paternalistic health service. That’s not a bad thing, I am a great supporter of the NHS in most of what it does, but in this area it hasn’t moved with the times,” he told the Pink Sheet in an interview.

He said the new pilot would “allow pa-tients to get vital therapy without breaking the law” and would also provide “a solid clini-cal database from which experience of, and confidence in, medical cannabis prescribing will develop, providing a foundation for oth-er medical prescribers to build on.”

Such a project was necessary because pharmaceutical companies tended to shy away from medicinal cannabis, Nutt said. One exception of course is GW Pharma-ceuticals, which developed and holds a marketing authorization for Sativex (delta-9-tetrahydrocannabinol plus cannabidiol) oral spray for use in multiple sclerosis spas-ticity. Sativex is the only cannabis-based medicine to have a UK marketing autho-rization, although it has not been recom-mended by the health technology assess-ment body NICE because it is not cost effective in MS. The company has a second product, Epidyolex (cannabidiol), in the fi-nal stages of regulatory review under the EU centralized procedure. (Also see “Romo-sozumab Among Latest Drugs Up For CHMP Opinion” - Pink Sheet, 25 Jun, 2019.)

But Nutt said that such licensed prod-ucts were “extraordinarily expensive” be-cause of the costs of running clinical trials, meeting good manufacturing practice standards, and so on.

“Those tight criteria are not necessarily of any use, they are just rules, and cannabis probably won’t comply with those rules. That is one of the reasons why companies won’t pursue the study of cannabis. We have rules that actually make it impos-sible for companies to really work in this space, and if they do and they spend that much money, they won’t get reimbursed. We have created barriers that will never be overcome.” (Also see “UK Committee At-

tacks Pharma Over Lack Of Medicinal Can-nabis Research” - Pink Sheet, 4 Jul, 2019.)

A NEW ROUTEProject TWENTY21 is intended to take a different approach to gathering data on the prescribing of unlicensed medicinal cannabis products. It will initially target a number of conditions and clinical situa-tions, focusing in particular on instances where other treatments have not been successful, including chronic pain, post-traumatic stress disorder, multiple scle-rosis, Tourette’s syndrome, and cannabis use disorder.

Three medicinal cannabis companies so far are involved with the pilot project. Althea is an Australian producer and ex-porter of pharmaceutical grade cannabis that operates in highly regulated markets including Australia and the UK. Alta-Flora produces a range of botanical products, while Cannuba Holdings specializes in the cultivation of the cannabis plant as well as the production, licensing and sale of high-quality medicinal cannabis products.

Drug Science is currently raising mon-ey to fund the project. “It is expensive to do this,” Nutt said. “We reckon it will cost £400,000 per year for two years. We have several companies involved already, and we are talking to other companies. We had the first working group meeting yesterday [2 July] and we are putting our team to-gether. If we get five companies on board then we can really make a difference.”

Its strategy is to assemble expert groups for each of the targeted condi-tions. “For example, we have the UK’s leading experts in Tourette’s working with us,” Nutt said, noting that a project on this condition will be led by Eileen Joyce, professor of neuropsychiatry at the Institute of Neurology, University College London.

All patients who choose to be involved in the Tourette’s project will be prescribed




R & D

“a form of cannabis – we haven’t decided what this will be yet – and 100 patients will be treated for a year. They will be moni-tored using standardized diagnostics, rat-ings, collection of adverse effects, and at the end of a year we will know whether it works in Tourette’s,” Nutt added. “We have experts, six professors of various aspects of neuropsychiatry involved, and my be-lief is that if you get the top experts com-fortable with this, the rest of the medical profession will follow suit.”

REGULATORY CHANGE?He also believes that the charity’s efforts could lead to some sort of new licensing system for medicinal cannabis, which he said “doesn’t really fit into the conventional form of medicine. Doctors have to go back to a different kind of medicine, and the reg-ulatory system, I believe, will have to adapt.”

He said he planned to meet the UK regu-lator, the MHRA, shortly to discuss the mat-ter and to ask it to “work with us. It’s not as if this is the first medicine that has come along where people have had to think differently. In gene therapy, for example, people are thinking differently. You have to have a more mature and sophisticated approach.”

Drug Science is currently collating data from around the world on which countries are doing the most creative research on facilitating models of regulation. But Nutt questioned why a charity had to be doing this kind of work. “Why are we doing this,

why is a charity having to pull together evi-dence from overseas? Why can’t the gov-ernment do it, why can’t NICE [the health technology assessment body] do it? They are defensive, they don’t want to do it. There is an institutional resistance to can-nabis that goes very deep.”

NICE WORKNICE is currently looking at the clinical and cost effectiveness of medicinal cannabis, and a consultation on draft guidance is expected to start on 23 July and run to 20 August.

It is also preparing separate appraisals of Epidyolex in Lennox-Gastaut syndrome, a severely debilitating form of pediatric epilepsy that usually begins between two

and seven years of age, and in Dravet syn-drome, a severe form of epilepsy that af-fects both children and adults. Draft guid-ances are expected at the end of this year.

UK RESCHEDULINGThe use of cannabis for medical purpos-es is a controversial subject, given that in most countries it is a controlled sub-stance. Until 2018, it was listed in Sched-ule 1 of the UK Misuse of Drugs Regula-tions 2001, meaning it was deemed to be “of no therapeutic value.”

But last year, the government’s drug ad-visers and the chief medical officer for Eng-land said there was evidence of therapeutic benefit in some conditions, and in Novem-ber it was moved to Schedule 2.

The government also agreed a definition of a cannabis-based product for medicinal use: it contains cannabis, cannabis resin, cannabinol or a cannabinol derivative, is produced for medicinal use, and is a me-dicinal product, or a substance for use as an ingredient of, or for the preparation of, a medicinal product.

Prescribing of such products can only be done by doctors on the Specialist Register. For patients to access a product, it must either be a special (an unlicensed medica-tion), an investigational medicinal product in a clinical trial, or a medicinal product with a marketing authorization.


Project TWENTY21 will

initially target a number

of conditions where

other treatments have

not been successful,

including chronic pain,

posttraumatic stress

disorder, multiple sclerosis,

and Tourette’s syndrome.

The most trusted source of health care deal intelligence

www.Pharmamedtechbi.com/STLP Available via annual subscription. For more information and to request a complimentary demonstration, visit:

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R & D

Australia Could ‘Look Worse Than Comparable Countries’ Under Proposed GCP InspectionsNEENA BRIZMOHUN [email protected]

D rug companies have warned that proposals to introduce a domestic good clinical practice inspections

program in Australia could be counter-productive to the regulator’s stated aim of improving global competitiveness and could even make Australia’s GCP quality look worse than comparable countries.

They argue that Australia already has a strong regulatory and ethical/governance framework for clinical trials and suggest that the TGA’s resources may be more efficiently and effectively used for other activities.

The comments are among industry’s re-sponses to the Therapeutic Goods Admin-istration’s consultation earlier this year on proposals to introduce a 12-month pilot program of domestic GCP inspections, fol-lowed by a permanent inspections program.

AusBiotech, for example, contends that the TGA’s rationale and evidence in the consultation document “do not support that an inspections program would further enhance the safety and quality of the over-all clinical trials system in Australia.”

The industry group takes issue with the regulatory authority’s statement that there is “a gap in the current regulatory oversight of the conduct of Australian clinical trials” and says “it is AusBiotech’s position that no gap is articulated” in the document. It says Australia has a “reputation as a safe and de-sirable place to conduct trials.”

According to Medicines Australia: “It

would be more appropriate for the stated purpose of implementing this program to be to protect the rights, safety and wellbe-ing of subjects enrolled in clinical trials and to verify the integrity of the data collected.”

AusBiotech says that the evidence cited by the TGA in support of the proposed pilot appears to be based on the UK pro-gram of auditing investigator-initiated trials (IITs), which was found to raise the standard of conduct and quality of clinical trials, particularly those sponsored by non-commercial organizations.

“There is no discussion as to how this experience may relate to commercially sponsored clinical trials, or how a domes-tic audit program may enhance Australia’s clinical trial infrastructure, quality or repu-tation in this sector,” AusBiotech declares.

WORRIES OVER A RISK-BASED APPROACHThe TGA’s proposal to use a risk-based ap-proach to select trials for inspections has also raised concerns.

Medicines Australia says that if the TGA uses an approach based on risk (eg, more complex studies, more high-risk therapies, higher risk sites or sponsors, especially non-commercial sponsors), the results from the program “are likely to be worse than” pro-grams by the US Food and Drug Adminis-tration or the European Medicines Agency.

The TGA data set will be biased towards

studies and sites with a different risk pro-file to the EMA and FDA programs, the industry group says, explaining that these programs largely focus on confirming the dependability and acceptability of data generated in study sites that support mar-keting applications.

Similarly, Ausbiotech says “there is a risk of generating poorer performance metrics than the FDA or EMA due to selection of high-risk clinical trials and IITs which are not generally subject to as stringent spon-sor audits as industry-funded clinical trials.”

Ausbiotech also notes that the FDA, the EMA and other regulatory bodies “can and do already audit commercially sponsored clinical trials” in Australia.

“We suggest that the current audit pro-gram of commercially-sponsored clinical trials from other regulatory agencies and clinical trial sponsors adequately address-es this sector of the market. The TGA audit of same would not serve the purpose of improving Australia’s commercially-spon-sored clinical trial capability or quality, nor would it improve Australia’s desirability as a destination for clinical trials.”

“Given a resource-constrained environ-ment, the TGA’s resources may be more effi-ciently and effectively used for other activi-ties, for example greater early consultation in the licensure process,” AusBiotech says.

The TGA proposed in the consultation document that if an inspection identified serious issues with the conduct of the trial or data integrity then information of the observed issues would be released to the approving Human Research Ethics Com-mittee and/or authorizing institution. Sev-eral submissions to the consultation cau-tioned against overburdening the HREC with non-critical findings, the authority said, adding that this would be further clar-ified in guidance documents, .

AusBiotch wants to know what would constitute a “serious issue, and which “compliance powers” would be used.




R & D

Industry also wants more information on how the findings of the audits are to be published or who they will be sent to. Roche, for instance says “we would like to know how that information will be shared with the public and other agencies, for example, could the industry source an ag-gregate of the results. If the trial selection strategy is comparable to other jurisdic-tions, aggregated results may help dem-onstrate the quality standards in Australian clinical trials.”

WHO SHOULD BEAR THE COSTS?Drug companies have concerns about the TGA’s proposal for industry to bear the cost of conducting clinical trial audits. For example, AusBiotech asks: “How will the system ensure that local, Australian com-panies are not compensating and taking the brunt of the cost when the majority of inspections are for internationally-spon-sored clinical trials?”

In addition, it argues that if clinical trial sites or sponsors were to be obliged to bear the costs, “the cost of Australian clini-cal trials would increase, having a detri-

mental effect on Australia’s attractiveness as a destination for clinical trials.”

VOLUNTEERS FOR THE PILOTThe TGA received a total of 43 submissions to its consultation, of which 10 were from the pharmaceutical, biotechnology and medical technology sectors, four were from industry associations or similar, and the remainder were other stakeholders including universities, CROs and medical research institutes.

The regulatory authority said that that 33 of the 37 stakeholders who commented on the introduction of a pilot program of GCP inspections and a subsequent perma-nent program supported these elements of the proposals. These stakeholders want more information regarding: the inspec-tion process (duration, selection, scope); categorization/grading of findings; mech-anisms for managing responses to find-ings, and involvement of the trial sponsor; international collaboration (to avoid dupli-cation); and inspection fees.

The TGA said it agreed that the primary objective of the program was safeguard-

ing public health, but added that “there may be additional benefits. Guidance doc-uments produced in support of the pilot and/or ongoing GCP Inspections Program will better articulate the rationale for a GCP Inspections Program.”

The regulator also said that 13 submis-sions included a response volunteering for the pilot inspections program – subject to further information. “Those organisations have been contacted directly to provide further information regarding the identifi-cation of trials and sites for the pilot GCP inspections program.”

It added that several responses included comments regarding the involvement of the study sponsor in the pilot GCP inspec-tions program. “It is noted that although the pilot program will involve inspections of investigator sites, the clinical trial spon-sor should be notified by the institution (for example, as set out in clause 4.12 of the Medicines Australia standard clinical trial research agreement), and as a matter of courtesy,” the TGA said.


Mylan/Biocon’s Insulin Glargine Has Narrow Window For Approval In USSUE SUTTER [email protected]

A bsent legislative intervention, it appears that Mylan NV will have only a few days to secure US Food and Drug Adminis-tration approval of its follow-on to Sanofi’s Lantus (insulin

glargine) once a 30-month legal stay expires.Mylan’s insulin glargine application, which is partnered with Bio-

con Ltd., is the most prominent example of a product that could get caught in the transition provisions of the Biologics Price Com-petition and Innovation Act.

The product’s tentative approval has been delayed by a June 2018 complete response letter and the need to qualify a new manufacturing site in Malaysia, which recently underwent a pre-approval inspection by the FDA.

However, the application also is the subject of a 30-month stay

of approval resulting from a patent lawsuit filed by Sanofi. That stay expires on 18 March 2020, a mere two days before the application must receive final new drug approval or face another CRL and re-submission as a biologics license application.

FINAL APPROVAL NEEDED BY TRANSITION DATEUnder the BPCIA, insulins and certain other protein products tradition-ally regulated as drugs will be “deemed” biologics on 23 March 2020.

G E N E R I C D R U G S




In a final guidance and draft Q&A guidance issued in December, the FDA explained how the transition process will work for ap-proved products, as well as the impact on pending or tentatively approved applications. (Also see “A Guide To US FDA’s Drug-To-Bio-logic Transition Process” - Pink Sheet, 8 May, 2019.)

Among the more concerning aspects for sponsors is that affect-ed applications that are pending or only tentatively approved at the time of the transition will receive a complete response letter and have to be resubmitted as BLAs.

For pending 505(b)(2) NDAs that rely to any extent on the agen-cy’s safety and effectiveness findings for a transition product, as is the case for Mylan’s insulin glargine, sponsors face an approval deadline of 11:59 pm on Friday, 20 March.

This provides a narrow window during which Mylan must se-cure final approval; Sanofi confirmed that the 30-month litigation stay of approval expires on 18 March.

Although the FDA can grant tentative approval during a 30-month stay, final approval cannot be granted until the stay either runs out or is terminated through a settlement or Mylan court victory.

That stay was triggered on 18 September 2017 when Sanofi re-ceived Mylan’s notification of its NDA submission with a paragraph IV certification against Lantus patents, according to Sanofi’s law-suit. Sanofi sued Mylan in New Jersey federal court on 24 October 2017 alleging infringement of 18 patents covering Lantus and Lan-tus SoloSTAR products.

The legal timeline, and the artificial deadline created by the March 2020 BPCIA transition, suggests Mylan may have been hard pressed to get the insulin glargine NDA to the agency and notify Sanofi of the submission before the 30-month stay overlapped with the transition date.

PRE-APPROVAL INSPECTION RESULTS IN 483The Lantus patent litigation in New Jersey federal court is ongoing.

However, Mylan scored an administrative victory in December when the US Patent and Trademark Office’s Patent Trial and Appeal Board (PTAB) ruled in favor of the company on its inter partes re-view proceedings and found all claims of two Lantus formulation patents unpatentable. (Also see “Mylan Scores IPR Victory, Paving The Way For Follow-On Lantus” - Pink Sheet, 13 Dec, 2018.)

In announcing the PTAB victory, Mylan said its NDA was under “ac-tive review” by the FDA. However, it is unclear when the NDA was resubmitted following a complete response letter in June 2018.

At the time the CRL was issued, Biocon said it had agreed with the FDA to provide additional clinical data to support a manufac-turing site change from a facility in Bangalore, India, to one in Ma-laysia. (Also see “Keeping Track: Mylan Wins First US FDA Approval

For Neulasta Biosimilar, But Lands A CRL For Insulin Glargine; Ge-nentech Nabs Broad Full Approval For Venclexta, PV Indication For Rituxan” - Pink Sheet, 8 Jun, 2018.)

The Bangalore facility has been cited by US and European regula-tors for compliance issues. (Also see “GMP Lapses At Biocon’s Indian Site – Jitters for Neulasta Biosimilar Plans?” - Pink Sheet, 3 May, 2018.)

In an 8 July announcement, Biocon said the insulin glargine drug substance, drug product, and device assembly facilities in Malaysia underwent an FDA pre-approval inspection between 24 June and 5 July.

“The inspection across these three units concluded with 12 obser-vations issued on the Form 483,” Biocon said.

Christiane Hamacher, CEO of Biocon Biologics India Ltd., told the Pink Sheet the observations “are largely procedural aimed at continuous improvement and strengthening our quality man-agement system.”

Another Biocon executive described the observations as result-ing from “silly human errors” and said the company is in the process of implementing a paperless, software-based digital quality man-agement system that will address many of the issues.

“We will respond to the FDA with a Corrective and Preventive Action Plan and are confident of addressing these observations expeditiously,” Biocon said. “We do not expect any change to our commercialization plans for insulin glargine in the US.”

The company believes that final approval of Mylan’s applica-tion is linked to the end of the 30-month stay in March 2020, Hamacher said.

For its part, Mylan has said little in recent months about the sta-tus of its US application for insulin glargine, which is marketed in the EU as Semglee.

“We continue progressing the review of our application with the agency and remain on track to bring this important product to patients at the earliest opportunity,” the company said.

While Mylan is focused on getting its insulin glargine to mar-ket before the NDA pathway closes, Eli Lilly & Co. is seeking FDA assurance that Basaglar, its Lantus follow-on, can still be marketed under a “deemed” BLA even if the company pursues a separate application for a biosimilar or interchangeable des-ignation after the March 2020 transition. (Also see “Insulin Maker Lilly Seeks US FDA Assurances On ‘Authorized Biologics’” - Pink Sheet, 20 Feb, 2019.)

Basaglar launched in late 2016 after Lilly and Sanofi settled their patent litigation. (Also see “Sanofi Settlement With Lilly Paves The Way For Biosimilar Lantus” - Pink Sheet, 28 Sep, 2015.)

“ We continue progressing the review

of our application with the agency

and remain on track to bring this

important product to patients at the

earliest opportunity.” – Mylan

An FDA pre-approval inspection of

Biocon’s Malaysia facility resulted in

12 observations issued in a Form 483.




Generic Companies Race To Withdraw ANDAs DERRICK GINGERY [email protected]

F irms continue to withdraw ANDAs at high rates in fiscal year 2019, offering another look at the changing land-

scape of the generic industry.Sponsors had pulled 252 original ANDAs

through May, according to the most recent data from the US Food and Drug Administra-tion’s generic drug program activity report. Combined with the record 606 withdrawn in FY 2018, there already have been nearly as many applications removed during less than two years of GDUFA II (858) than seen throughout the first five-year generic drug user fee program cycle (914) (see chart, p. 19).

Beginning at the start of GDUFA II in Oc-tober 2017, the agency began reporting withdrawals of approved and unapproved ANDAs, in addition to the total withdraw-als each month. Since the start of FY 2018, the number of approved ANDAs with-drawn has far outnumbered unapproved

ANDAs, 569 versus 289.While individual sponsors’ reasons for

withdrawing an ANDA vary, stakeholders partly attribute the trend to consolidation throughout the generic industry.

As mergers are completed, companies may realize that some ANDAs are not needed by the combined company or no longer fit in the long-term corporate strat-egy, said David Gaugh, senior VP for sci-ences and regulatory affairs at the Associa-tion for Accessible Medicines.

Gaugh said that many generic com-panies also are “right-sizing” or trimming their product portfolios and withdrawing ANDAs that are not needed.

Robert Pollock, senior advisor and out-side director to the board of Lachman Con-sultants, speculated that firms also are not finding reasons to keep approved appli-cations for products they are not market-

ing. He said with the pricing pressure on firms, less profitable products have been dropped, and “the sponsor may not see the same value in holding onto the asset these days as they did in the past.”

“Early in the generic program everyone saw their no-longer-marketed ANDAs as a potential asset to sell to smaller or start-up companies,” Pollock said.

Indeed, AAM has sounded alarms about consolidation in the generic industry and the potential dangers it presents. Whole-saler consolidation has limited potential buyers and created more pricing pressure on generic firms, which could force manu-facturers out of the business. (Also see “Ge-neric Industry Market Forces May Impact GDUFA III Talks” - Pink Sheet, 21 Mar, 2019.)

Reduced numbers of approved generics also may not be a positive sign for federal government efforts to lower drug costs. One of the pillars of White House and con-gressional plans is to create more com-petition through increased generic drug approvals. (Also see “Senate Drug Pricing Legislation Clears Committee With Generic Exclusivity “Parking” Provision Unchanged” - Pink Sheet, 26 Jun, 2019.)

PROGRAM FEE ALSO MOTIVATES WITHDRAWALS In May, there were 63 ANDAs withdrawn, the highest monthly total of FY 2019, includ-ing 31 approved applications and 32 unap-

LEGISLATIVE MOVESThere has been movement in Congress to try to limit the transition deadline’s impact on Mylan and any other sponsors of pending ap-plications subject to transition.

Draft legislation in the Senate would require that any affected ap-plications submitted under the Food, Drug and Cosmetic Act by 23 September could continue to be reviewed under that pathway even after the transition date. (Also see “Biologics Transition ‘Dead Zone’ Could Be Eliminated Under US Senate Bill” - Pink Sheet, 28 May, 2019.)

Language in a report accompanying the US House’s FDA fund-ing bill for fiscal year 2020 urged the agency to ensure that any pending insulin product application with a goal date prior to 23

March is reviewed in accordance with the new drug review “pro-gram” model that allows for increased communication between the agency and sponsor.

The House report also urges the agency to work to identify and promote efficiencies in the review of any application submitted under the Public Health Service Act for an insulin product that was pending, but not approved, under the FD&C Act prior to the transi-tion date. (Also see “House Appropriators Tip-Toe Into Biologics Tran-sition Controversy” - Pink Sheet, 4 Jun, 2019.)

Published online 10 July 2019Anju Ghangurde contributed to this story.

As the industry

consolidates, extra ANDAs

are being seen more as

a fee-generating burden

than as potentially

salable assets.




proved applications. Another 55 ANDAs, including 36 approved and 19 unapproved applications, were withdrawn in March.

The spate of recent withdrawals is sig-nificant because the FDA is in the process of setting user fee rates for FY 2020, includ-ing the program fee, which is based on the number of ANDAs a firm owns.

FDA officials have said that ANDA with-drawal requests submitted by 1 April will be considered “deemed to have been with-drawn” for fee-setting purposes.

Program fees are split into three tiers, with the firms owning the most ANDAs pay-ing the most. Since the fee accounts for the largest portion of GDUFA revenue, firms are motivated to off-load unused or unwanted ANDAs if it will lower their user fee charges.

Pollock said the number of approved ANDAs that have been withdrawn sug-gests firms are looking to reduce their pro-gram fee exposure, although consolida-tion may be a determining factor.

Gaugh also said that with the program fee in place, firms no longer hold ANDAs for products not marketed “just in case the future brings new opportunities.”

“If the company is supporting a level of program fee and/or facility fee for prod-ucts that are not being marketed, this can lead to withdrawals,” he said.

Portfolio consolidation for user fee pur-poses began before the first program fee was announced (Also see “How US FDA’s As-sumptions Impacted Generic Program Fees” - Pink Sheet, 29 Jul, 2018.), and spawned the development of a venue to store inac-tive ANDAs and avoid the charge. (Also see “Inside The ANDA Parking Lot” - Pink Sheet, 14 Jun, 2018.)

MORE WORKLOAD HELP? The FDA may not be able to find positives from the spike in withdrawals, even in workload management.

Removing unapproved ANDAs from the queue of applications pending an action should allow the agency to focus more closely on the applications remaining, which is important as new work continues to arrive. At the end of the second quarter of FY 2019, there were 1,944 ANDAs await-ing FDA action, an increase from 1,865 at the end of the first quarter. At the end of FY

2018, the total was 2,001.But the FDA told the Pink Sheet that

many sponsors withdraw an unapproved application after receiving a complete re-sponse letter, meaning the agency had al-ready completed its work.

Agency officials have said the generics program is in a steady state, meaning there is enough work to keep assessors busy, but not overwhelm them. (Also see “US FDA’s Generics Program Reaches ‘Steady State’

Milestone” - Pink Sheet, 7 Sep, 2018.)Approvals have increased throughout

GDUFA II, which also is helping reduce the pending workload, although industry and others have called for FDA to improve its first-cycle approval rate. (Also see “US FDA First-Cycle ANDA Approvals Not Rising Along With Full Clearances” - Pink Sheet, 24 Jun, 2019.)


ANDA Withdrawals Accelerate In GDUFA IIFY 2018 and FY 2019 have seen much larger numbers of withdrawn approved and unapproved generic drug applications, compared to the first five years of the generic drug user fee program.

Withdrawals of approved and unapproved ANDAs have increased significantly since the start of GDUFA II (October 2017), in part because firms now are charged a user fee based on the number of approved applications they own. Industry consolidation also may be contributing to the withdrawal trend.

* FY 2019 data is through May.

Source: US FDA generic drugs program activity report

ANDA Withdrawals Accelerate In GDUFA IIFY 2018 and FY 2019 have seen much larger numbers of withdrawn approved and unapproved genericdrug applications, compared to the rst ve years of the generic drug user fee program.

600

500

400

300

200

100

0FY 2013 FY 2014 FY 2015 FY 2016 FY 2017 FY 2018 FY 2019*

107

179 166

248214

606

252With

draw

als

0

20

40

60

80

100

120

140

160

Ma. 2019

Feb. 2019

Nov. 2018

Aug. 2018

Ma. 2018

Feb. 2018

Nov. 2017

Aug. 2017

Ma. 2017

Feb. 2017

Nov. 2016

Aug. 2016

Ma. 2016

Feb. 2016

Nov. 2015

Aug. 2015

Ma. 2015

Feb. 2015

Nov. 2014

Aug. 2014

Ma. 2014

Feb. 2014

Nov. 2013

Aug. 2013

Ma. 2013

Feb. 2013

Nov. 2012

Withdrawals of approved and unapproved ANDAs have increased signicantly since the start of GDUFA II (October 2017), in partbecause rms now are charged a user fee based on the number of approved applications they own. Industry consolidation alsomay be contributing to the withdrawal trend. * FY 2019 data is through May.


ANDA Withdrawals Accelerate In GDUFA IIFY 2018 and FY 2019 have seen much larger numbers of withdrawn approved and unapproved genericdrug applications, compared to the rst ve years of the generic drug user fee program.

600

500

400

300

200

100

0FY 2013 FY 2014 FY 2015 FY 2016 FY 2017 FY 2018 FY 2019*

107

179 166

248214

606

252With

draw

als

0

20

40

60

80

100

120

140

160

Ma. 2019

Feb. 2019

Nov. 2018

Aug. 2018

Ma. 2018

Feb. 2018

Nov. 2017

Aug. 2017

Ma. 2017

Feb. 2017

Nov. 2016

Aug. 2016

Ma. 2016

Feb. 2016

Nov. 2015

Aug. 2015

Ma. 2015

Feb. 2015

Nov. 2014

Aug. 2014

Ma. 2014

Feb. 2014

Nov. 2013

Aug. 2013

Ma. 2013

Feb. 2013

Nov. 2012

Withdrawals of approved and unapproved ANDAs have increased signicantly since the start of GDUFA II (October 2017), in partbecause rms now are charged a user fee based on the number of approved applications they own. Industry consolidation alsomay be contributing to the withdrawal trend. * FY 2019 data is through May.





US FDA, USP Cooperate On Small Molecule Drug Monograph Updates To Speed ANDAsDERRICK GINGERY [email protected]

G eneric drug sponsors deviating from US Pharmacopeia stan-dards can now petition for a monograph change before receiving application approval, a practice the US Food and

Drug Administration endorses as part of its effort to lower drug costs.New FDA draft guidance released 10 July encourages ANDA

sponsors that will need to request changes to the official USP monograph to use USP’s Pending Monograph Process (USP PMP).

The FDA compares the quality standards in the official USP monographs to those in ANDAs during the assessment.

Historically, if an ANDA sponsor or drug master file holder is not in compliance with the monograph, it will justify the changes and may request a change to the official monograph. But sponsors of products that have not been approved by FDA could not propose USP standards changes. Often, this problem delayed an ANDA’s ap-proval and the sponsor was forced to make changes to conform with the existing monograph. Revised monographs usually were not official for six months or more, the FDA said in a Federal Regis-ter notice announcing the guidance.

The USP-PMP process was designed to eliminate the delay and allows a monograph to be revised while the ANDA assessment is ongoing, by permitting publication and comment on proposed changes. After publication, the proposals would remain unofficial until the FDA approves the application.

The USP PMP process is available in situations where no mono-graph is available for a drug or an application under review by FDA that does not meet the existing monograph requirements.

USP continues to review the guidance. Senior VP of Global Exter-nal Affairs Anthony Lakavage told the Pink Sheet that “this is one of many examples of USP’s collaboration with the FDA to advance ge-neric competition” and that the organization hopes FDA will help boost the program’s visibility.

USP said that it has received 71 requests for monograph revi-sions through the PMP process since its inception.

“We are pleased that FDA is now releasing its guidance that complements our efforts to encourage participation in the USP Pending Monograph Process,” Lakavage said. “We are confident that FDA’s voice will generate significant additional participation and is the ‘shot in the arm’ we’ve been waiting for to more fully optimize this program.”

The pathway launched in 2015 and the FDA said it has been en-couraging affected firms to use it. The agency told the Pink Sheet that using the USP-PMP process “increases efficiencies for both FDA and USP.”

However, participation does not “confer FDA acceptability of the compendial standards proposed for the product,” or “preclude full application evaluation,” according to the guidance.

“All applications will be subject to complete evaluation using

current established practices,” the FDA wrote.Acting FDA Commissioner Norman Sharpless framed the new

guidance, along with another on the inactive ingredient database, as potentially allowing generics to come to market faster.

MONOGRAPH UPDATES BETWEEN SPONSOR, USP The FDA makes clear in the guidance that while it supports the monograph revision process, the agency will not facilitate be-tween USP and sponsors.

Sponsors should begin the USP-PMP process “very early in the application evaluation process,” such as “concurrent with an appli-cation’s submission to FDA,” the agency said in the guidance.

The FDA wrote that sponsors expecting to propose products that differ from the monograph are encouraged to “contact USP di-rectly to initiate” the USP PMP process or make clear that the prod-uct will be labeled as not conforming to USP standards.

“Applicants who do not initiate the USP-PMP may risk delay in the approval of any application that is not in alignment with the official USP-[National Formulary] monograph,” the agency said in the guidance. “In either situation – initiating the USP-PMP or label-ing the product with the difference(s) – FDA will conduct thorough application evaluations using current established practices to de-termine the acceptability of the quality standards proposed in the application.”

After initiating the process, sponsors should keep USP updated of their application’s status and work with staff to make changes to the monograph revision proposal.

“For example, if during FDA’s evaluation the applicant is notified that the application’s specifications must be modified before it can be approved (and therefore the application’s final specifications will differ from what was proposed in the USP-PMP proposal), the ap-plicant (or the referenced [master file] holder, as applicable) should contact USP to update the proposal,” the FDA said in the guidance. “This ensures that the compendial standards in the proposal reflect the standards in the application at the time of approval.”

Monograph updates initiated through the process will not be-come official until after final FDA approval and its conformation of the compendial specifications in the proposal. Sponsors also should inform USP when their application is approved by FDA, which will allow USP to begin the confirmation process with FDA. The agency will not confirm specifications for tentatively approved applications, according to the guidance.

FDA-USP SPAT OVER BIOLOGICS CONTINUES FDA’s cooperation with USP on the small molecule drug mono-graph issue is a stark contrast to the ongoing soap opera between the two related to biologics monographs.




Both groups have fought for years over how USP mono-graph standards apply to biologics and biosimilars. The FDA argues that monographs can restrict biosimilar development and threaten the growing industry in the US. Draft legislation removing the requirement sparked a letter from USP and other stakeholders stating the change would have a negative impact on public health. (Also see “USP Rivalry With US FDA Over Com-pendial Standards Provision Busts Into Open Legislative Fight” - Pink Sheet, 11 Jun, 2019.)

USP and FDA also sparred over biosimilar naming, and even a USP attempt to align with FDA biologic naming standards was met

by objections from the FDA. USP eventually pulled the proposal. (Also see “USP Backs Down From Biologic Monograph Naming Plan Amid US FDA Objections” - Pink Sheet, 30 Apr, 2018.)

The naming issue stretches back to the FDA’s first approved bio-similar, when USP said that Sandoz Inc.’s Zarxio (filgrastim-sndz) should carry the same nonproprietary name as its reference prod-uct, Amgen Inc.’s Neupogen (filgrastim), and notably not carry a suffix, if the product met the USP monograph requirements. At that time, the FDA said Zarxio did not meet the monograph.


Apotex Withdraws 31 ANDAs After Failing To Ensure Data Integrity At Two Indian Manufacturing PlantsBOWMAN COX [email protected]

I t appears that the US Food and Drug Administration’s growing frustration with a Canadian drug maker’s continuing failure to establish an effective quality system and ensure data integrity

at two facilities in India has led to the firm’s withdrawal of 31 ge-neric drug approvals listed in a Federal Register notice slated for publication on 10 July.

Apotex Inc.’s decision to withdraw the abbreviated new drug ap-plications is an unprecedented outcome of the data integrity crisis of recent years.

The FDA has identified data integrity lapses at many pharmaceu-tical manufacturers, particularly in India and China, and it is pos-sible that Apotex won’t be the last to withdraw FDA approvals due to such lapses. (Also see “FDA Advises Starting With the Lab When Sniffing Out Data Integrity” - Pink Sheet, 19 Dec, 2014.)

DATA LAPSES EVENTUALLY SANK APPROVALSAs US FDA inspections documented continued lapses in data reli-ability at the two facilities in recent years, the agency conducted “an in-depth assessment of data generated at these facilities and related to pending and approved applications, including multiple data reliability assessments provided by a third party contracted by Apotex,” the agency told the Pink Sheet in a prepared statement.

The agency stressed that it is “requiring Apotex to ensure the data submitted to support its applications are complete and reli-able. The FDA is also advising Apotex to ensure that all their medi-cines meet the agency’s standards for safety and effectiveness.”

In the end, it appears the company could not find a way to pro-vide those assurances.

The agency went on to make a lesson of it, saying that “when data integrity issues do occur, the FDA is uncovering them both during inspections and application review and taking action to en-sure companies fix these issues.”

THE APOTEX ANDA WITHDRAWALSThe FDA had granted the abbreviated new drug approvals that Apotex withdrew between October 2007 and April 2014.

A pre-publication copy of the withdrawal notice says that “after these drugs were approved, FDA became aware of concerns involv-ing material manufactured at two Apotex facilities” named in the ap-plications: the Apotex Private Research Ltd. and Apotex Pharmachem India Private Ltd. facilities located in plots 1, 2 and 1a of the Bomma-sandra Industrial Area on Jigani Link Road in Bangalore, India.

Apotex requested withdrawal of the ANDAs in January 2018 and waived its opportunity for a hearing, which the FDA interpreted as a request made under Title 21, Section 314.150(d) of the Code of Federal Regulations.

Asked if the FDA requested the ANDA withdrawal or the firm volunteered it, an FDA spokesperson would say only that the firm “requested these applications be withdrawn and waived its oppor-tunity for a hearing.”

The spokesperson added that “these are the first approved ap-plications Apotex is withdrawing,” which would suggest that there will be more.

Asked to comment, Apotex Global Corporate Communications VP Jordan Berman told the Pink Sheet, “This is a Federal Register notice which is part of the formal FDA process documenting our voluntary withdrawal of some ANDAs back in October 2017.”

The privately held firm did not disclose any possible material im-pact to shareholders as a publicly held firm might have.

THE WITHDRAWAL REGULATIONThe referenced CFR paragraph says the FDA “may notify an applicant that it believes a potential problem associated with a drug is suffi-ciently serious that the drug should be removed from the market.”

If the applicant agrees to remove the product from the US mar-

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




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

ket, permits the FDA to withdraw approval and waives its right to a hearing, the FDA will refrain from making a finding under para-graph b of section 314.150.

That paragraph sets forth 10 types of findings the FDA can use as a basis for withdrawing approval but requires the agency to notify applicants of their right to a hearing to contest any pro-posed withdrawal.

One type of finding is that the applicant lacks a system for maintaining required records or fails to maintain them.

Another is that the FDA obtains new information post-approv-al that the firm did not adequately improve manufacturing prac-tices “within a reasonable time after receipt of written notice from the agency.”

Both are potentially relevant to the situation at the two Apotex facilities.

THE NOVEMBER 2017 INSPECTIONThe pattern of uncorrected failures that can serve as a basis for withdrawal of FDA approval came to light during a 6-17 Novem-ber 2017, inspection of the Apotex Research Private Ltd. facility in Bangalore.

Observations the FDA made during that inspection led the agency on 12 April 2018 to place the facility back on the agency’s drug GMP import alert (Also see “Manufacturing Compliance Up-dates In Brief From US FDA And EU” - Pink Sheet, 10 May, 2018.) and on 9 August 2018 to issue a new warning letter.

The FDA told the Pink Sheet that the April 2018 import alert was meant “to protect patients while the agency completed its review of Apotex’s applications involving medicines made at the facility.” The agency also noted that “so far,” the review “has not identified any serious safety concerns.”

Additionally, the review has found “no information that the data reliability issues that occurred pose a risk to patients.”

THE AUGUST 2018 WARNING LETTERThe August 2018 warning letter cited repeat violations and devia-tions at multiple sites in a way that appears to illuminate the ANDA withdrawal request Apotex made seven months earlier and that now is coming to fruition.

That warning letter connected the dots of a persistent pattern of quality failures at Apotex, setting the stage for the ANDA withdraw-als that eventually followed. (Also see “FDA Warns Apotex Manage-ment To Demand Quality, Meet Specs” - Pink Sheet, 17 Aug, 2018.)

The warning letter noted the FDA had on 22 September 2014 placed the Apotex Research facility on import alert and had on 30 January 2015 issued a previous warning letter.

Additionally, the August 2018 warning letter noted the FDA had issued a 1 April 2014 import alert and a 16 June 2014 warning letter for the nearby Apotex Pharmachem India Private Ltd. active phar-maceutical ingredient manufacturing facility and laboratory.

Further, the FDA noted in the August 2018 warning letter that it had “previously communicated about the need for appropriate and global quality oversight to Apotex senior management during several regulatory meetings.”

The agency went on to conclude that “these repeated failures at multiple sites demonstrate that management oversight and con-trol over the manufacture of drugs is inadequate.”

The warning letter alerted the firm that because of the failure of Apotex’s quality unit to correct its data integrity failures, “there will be additional communication from CDER’s Office of Pharmaceutical Quality.” CDER is the FDA’s Center for Drug Evaluation and Research.

Further, the warning letter said the FDA’s Office of Generic Drugs, which is responsible for ANDA approvals, “may subsequently pro-vide comment regarding the effect of these findings … if needed.”

PRIOR WARNINGSThe Apotex Research facility’s January 2015 warning letter, based on inspection findings from 23 June through 1 July 2014, focused on laboratory records compromised by the firm’s trial sample test-ing, which enabled it to report only passing results, and on a failure to prevent unauthorized use of its computer systems, for example to hide failing trial test results.

There also were findings about the quality unit’s failure to inves-tigate deviations as required.

That warning letter referenced a previous warning letter con-cerning Apotex’s nearby Pharmachem drug product manufactur-ing facility that also documented trial injections.

It also referenced quality unit shortfalls the FDA discussed in a March 2010 warning letter and in regulatory meetings with Apotex senior management in September 2009, March 2010 and April 2014.

THE APOTEX PHARMACHEM FACILITYThe FDA on 1 April 2014 put Apotex’s Pharmachem facility on im-port alert (Also see “In Brief: Seven drug import alerts, seven EU GMP findings, several particulates recalls” - Pink Sheet, 30 Apr, 2014.)

And on 16 June 2014 the agency issued a warning letter due to observations made during a 27-31 January 2014 inspection of the Plot 1a Pharmachem active pharmaceutical ingredient manufac-turing facility that raised data integrity concerns.

The analytical laboratory at the Pharmachem plant was rou-tinely re-testing samples until obtaining passing results. The laboratory also failed to investigate unknown chromatography peaks, backdated laboratory worksheets, lost raw data, and failed to document complaint investigations, that warning letter said. (Also see “News In Brief: Cheap American Drugs Replaced; EMA, FDA Differ on Toansa; Apotex Warned; Cheaper Drug Recalls” - Pink Sheet, 26 Jun, 2014.)

The FDA has since taken the Pharmachem facility off the drug GMP import alert.

The FDA said in a 20 December 2016 warning letter closeout letter that it appeared Apotex had addressed the violations raised in the Pharmachem warning letter but warned that future inspec-tions and regulatory activities would “further assess the adequacy and sustainability of these corrections.”

The August 2018 warning letter and subsequent ANDA with-drawals suggest that the corrections were not sustained.



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