CONTINUED ON PAGE 4

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

Vol. 82 / No. 12 March 23, 2020

DRUG REVIEWS

UK: NICE Wins Argument Over Appraisal Of BioMarin Rare Disease Drug, p. 10

US FDA

Drug Office Reorg Enters Homestretch With Leadership Nods For Three Clinical Offices, p. 7

UK NICE

Leng And Nebhrajani: New Chief & Chair For England’s NICE, p. 8

Clinical Trial Sponsors Should Consider Changing Data Collection Amid COVID-19, US FDA SaysSUE SUTTER sue.sutter@informa.com

T he US Food and Drug Administra-tion is urging sponsors, clinical research organizations and inves-

tigators to consider alternative means for conducting safety assessments and collecting efficacy data to mitigate the impacts of the COVID-19 pandemic on ongoing clinical trials.

The recommendations could help drive data collection through digital means and spur greater adoption of remote clinical trial monitoring during the pandemic and

even after it concludes. Some companies have already started announcing changes to their clinical trial plans due to the coro-navirus outbreak. (Also see “Provention An-nounces First Clinical Trial Delay, Others Fol-low As COVID-19 Concerns Persist” - Scrip, 18 Mar, 2020.)

In a new guidance released on 18 March, the agency addresses the pan-demic’s potential effects on the conduct of clinical trials, recognizing there are likely to be “unavoidable protocol devia-tions” due to COVID-19 illness or control measures, such as quarantines, travel re-strictions, site closures and supply chain interruptions.

These challenges may lead to difficul-ties in meeting protocol-specified proce-dures, including administering or using the investigational product or adhering to protocol-mandated visits and labora-tory/diagnostic testing, the FDA said.

The guidance outlines general con-siderations to help sponsors ensure the safety of trial participants, maintaining compliance with good clinical practice and minimizing the risks to trial integrity.

The FDA said it is implementing the guidance immediately, without prior public comment, due to the public health emergency. However, the agency will ac-cept public comments on the document.

“With this guidance issued today, the FDA is helping industry and investigators navigate the COVID-19 pandemic and help assess how to move forward with critical clinical trials,” Anand Shah, deputy commissioner for medical and scientific affairs, said in an agency press release.

The FDA is implementing

the guidance

immediately, without

prior public comment,

due to the public health

emergency.

GENERAL ENQUIRIES:Jo KirkpatrickT: +44 (0) 20 7017 7180E: jo.kirkpatrick@informa.com

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pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 3

TV Drug Advertising Spend Rising, But Few Brands Provide Pricing Infohttps://pink.pharmaintelligence.informa.com/PS141887

DTC spending had shown an uptick in 2020 compared with 2019. Many advertisers are not, however, providing clear drug pricing information in their TV spots, despite some voluntary commitments to do so.

The BPCIA Transition: Products, Patents And Exclusivitieshttps://pink.pharmaintelligence.informa.com/PS141841

Pink Sheet infographic looks at the 95 NDAs moving from regulation as drugs to biologics on 23 March; list includes 27 insulin products, seven of which have unexpired exclusivity that will not carry over when they are delisted from the ‘Orange Book.’

EU Guides On ATMP Trials, Genetically Modified Cells To Be Finalized This Yearhttps://pink.pharmaintelligence.informa.com/PS141852

The 2020 work plan of the European Medicines Agency’s committee on advanced therapies shows that two keenly-awaited guidelines are due to be finalized this year.

US FDA Outlines Wishlist For Decentralized Clinical Trialshttps://pink.pharmaintelligence.informa.com/PS141843

As interest in conducting remote decentralized clinical trials grows, a senior US regulator explains what companies should consider when planning such trials.

exclusive online contentCO V E R Clinical Trial Sponsors Should Consider Changing

Data Collection Amid COVID-19, US FDA Says

C L I N I C A L T R I A L S 5 Global CRO Body Urges Sponsors To Focus On Key Risk

Factors As Coronavirus Threatens To Upend Clinical Trials

17 Gilead’s Robust Expanded Access For Remdesivir Signals Confidence In Study Enrollment

U S F D A 7 US FDA Drug Office Reorg Enters Homestretch With

Leadership Nods For Three Clinical Offices

U K N I C E 8 Leng And Nebhrajani: New Chief & Chair For England’s NICE

D R U G R E V I E W S 9 Keytruda Dropped From England’s Cancer Drugs

Fund For Bladder Cancer

10 UK: NICE Wins Argument Over Appraisal Of BioMarin Rare Disease Drug

R E G U L ATO RY U P D AT E 11 Sweden Urges Pharma To Engage In AMR Initiative

M A N U FAC T U R I N G 12 China’s Global Pharma Supply Chain Operations Resuming

In Wake Of Outbreak, USP Says

P O L I C Y P E R S P E C T I V E 13 Palforzia Peanut Allergy Immunotherapy:

Aimmune CEO On REMS Restrictions, Manufacturing

B I O S I M I L A R S 15 Biosimilar Competition: Still More Focus On FDA Than FTC

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

inside: 15 5 11

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4 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

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

RE-EVALUATING NEED FOR IN-PERSON ASSESSMENTSThe FDA’s guidance comes a week after the UK’s Medicines and Healthcare products Regulatory Agency said it expected to see protocol-related deviations in clinical trials as a result of COVID-19. (Also see “UK MHRA: COVID-19 To Spark Rise In Clinical Trial-Related Deviations” - Pink Sheet, 12 Mar, 2020.)

In a 12 March guideline, the MHRA said any increase in protocol deviations resulting from the novel coronavirus “will not con-stitute a serious breach” and should not be reported to the agency unless there is a risk to patients.

The FDA guidance does not go so far as to say that such protocol deviations should not be reported. However, the agency appears to give sponsors wide latitude to make pro-tocol changes to address the practical im-pacts of COVID-19.

As with the MHRA guideline, the FDA guidance states the reason for protocol de-viations and changes should be thoroughly documented, and the safety of study partici-pants must remain paramount.

“Sponsors should consider each circum-stance, focusing on the potential impact on the safety of trial participants, and modify study conduct accordingly,” the guidance states. “Study decisions may include those regarding continuing trial recruitment, con-tinuing use of the investigational product for patients already participating in the trial, and the need to change patient monitor-ing during the trial. In all cases, it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them.”

Since trial participants may not be able to come to the study site for protocol-specific visits, sponsors should evaluate whether alternative methods for safety assessment could be implemented and would be suf-ficient to assure participant safety. These alternative methods could include phone contact, virtual visits or conducting the eval-uations in alternative locations, such as local labs or imaging centers.

Sponsors also should determine if in-person visits are necessary to fully assure the safety of participants.

“The need to put new processes in place

or to modify existing processes will vary by the protocol and local situation,” the guid-ance states. “For example, this assessment could include consideration of whether it is appropriate to delay some assessments for ongoing trials or, if the study cannot be properly conducted under the existing pro-tocol, whether to stop ongoing recruitment, or even withdraw trial participants.”

The guidance envisions the potential

use of alternative secure delivery meth-ods for investigational drugs that are self-administered if access to clinical sites is significantly impacted. For investigational products that normally are administered in a health care setting, sponsors should con-tact the FDA review division about plans for administration at alternative locations, such as at nursing homes or other sites by trained, non-study personnel.

Sponsors should consult with the ap-propriate FDA review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delayed assessments and alternative collection of research-specific specimens if feasible.

“For individual instances where efficacy

endpoints are not collected, the reasons for failing to obtain the efficacy assess-ment should be documented (e.g., iden-tifying the specific limitation imposed by COVID-19 leading to the inability to per-form the protocol-specified assessment),” the guidance states.

DOCUMENT, DOCUMENT, DOCUMENTWhile the FDA recognizes that changes in study visit schedules, missed visits or pa-tient discontinuations may lead to miss-ing data for protocol-specified procedures, it stresses the needed to document why these data are missing.

“It will be important to capture specific information in the case report form that ex-plains the basis of the missing data, includ-ing the relationship to COVID-19 for missing protocol-specified information (e.g., from missed study visits or study discontinuations due to COVID-19). This information, summa-rized in the clinical study report, will be help-ful to the sponsor and FDA.”

The guidance notes that protocol chang-es typically are not implemented before re-view and approval by an institutional review board or independent ethics committee and, in some cases, the FDA.

Sponsors and clinical investigators should engage with IRBs/IECs as early as possible when urgent or emergent changes to the protocol or informed consent are anticipat-ed as a result of COVID-19. Protocol changes intended to minimize or eliminate immedi-ate hazards or to protect the life and well-be-ing of research participants, such as limiting exposure to COVID-19, may be implement-ed without IRB approval or before filing an IND amendment, but they must be reported afterwards, the guidance states.

The implementation of alternative pro-cesses should be consistent with the pro-tocol to the extent possible, and sponsors and clinical investigators should document the reason for any contingency measures implemented. “Sponsors and clinical inves-tigators should document how restrictions related to COVID-19 led to the changes in study conduct and duration of those chang-es and indicate which trial participants were impacted and how those trial participants were impacted,” the agency said.

CONTINUED FROM PAGE 1

“It will be important

to capture specific

information in the case

report form that explains

the basis of the missing

data, including the

relationship to COVID-19

for missing protocol-

specified information

(e.g., from missed

study visits or study

discontinuations due

to COVID-19).” – FDA

pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 5

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

COVID-19 screening procedures required by a health care system in which a clinical trial is being conducted do not need to be reported as a protocol amendment even if done during study visits unless a sponsor is going to use the data collected as part of a new research objective.

A sponsor should consult the relevant FDA review division when protocol changes necessitate amending the data manage-ment or statistical analysis plans. “Prior to locking the database, sponsors should ad-dress in the statistical analysis plan how pro-tocol deviations related to COVID-19 will be handed for the prespecified analysis.”

REMOTE MONITORINGSponsors also should consider optimiz-ing use of central and remote monitoring programs to maintain oversight of clinical sites if planned on-site monitoring visits are not possible.

The FDA has been trying to encourage greater use of centralized and remote monitoring methods to improve the effi-ciency and quality of clinical trials. (Also see “Clinical Trials: US FDA Should Frame Risk-Based Monitoring As Best Practice, ACRO Says” - Pink Sheet, 19 Mar, 2019.)

However, the CRO industry asserts that numerous factors have slowed the move to digital in the clinical trials space, includ-ing resistance to change, unanticipated burdens, study complexity and regulatory uncertainty. (Also see “Digital Transforma-tion Of Clinical Trials Is Shared Responsibility, CRO Industry Says” - Pink Sheet, 5 Dec, 2018.)

The Association of Clinical Research Or-ganizations is recommending that spon-sors, CROs and investigators implement emergency interim measures – including remote reviews of subject data – to ensure that trial monitoring is maintained during the COVID-19 pandemic.

FDA CHECKLISTThe FDA said that for all trials impacted by the pandemic, sponsors should describe the following in the clinical study report or in a separate study-specific document:

• Contingency measures implemented to manage study conduct during dis-ruption resulting from COVID-19;

• A listing of all participants (by unique subject number identifier and site lo-cation) affected by the disruption and a description of how their participa-tion was affected; and

• Analysis and discussion of the impact of the implemented contingency mea-sures, including alternative procedures used to collect critical efficacy or safety data, on the efficacy and safety results reported for the study.

Published online 18 March 2020

Global CRO Body Urges Sponsors To Focus On Key Risk Factors As Coronavirus Threatens To Upend Clinical TrialsVIBHA SHARMA vibha.sharma@informa.com

C ontract research organizations, clinical trial sites and sponsors are being urged to introduce emer-gency interim measures to deal with the increas-

ing impact of the coronavirus outbreak on clinical trial oversight, particularly onsite monitoring.

The interim measures are outlined in a guidance docu-ment issued by the global Association of Contract Re-search Organizations (ACRO), which lists “Considerations to Support Clinical Trial Monitoring Oversight During COVID-19.” ACRO hopes that the guideline’s adoption will ensure that data quality is unaffected, clinical trial sites are supported and patients enrolled in clinical trials are kept safe.

The guideline addresses a range of trial monitoring is-sues, including remote reviewing of subject data, carry-ing out source document review and source data verifi-cation, and using a risk-based approach to identify any trends that may require temporary interventions.

ACRO explained that its guideline is relevant in situa-tions where trial sites have suspended or restricted all vis-itors, including clinical research associates (CRAs), from

6 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

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

accessing medical facilities, but where patient visits are still occurring. It is also relevant in cases where local health officials have implemented regional quarantines and where local CRAs are unable to travel to the sites for personal health reasons or because of travel restrictions.

REMOTE REVIEWING OF DATAThe ACRO guideline states that in cases where on-site monitoring visits cannot be completed, one should consider implementing re-mote review of subject visit data via electronic data capture while focusing on data most important to subject safety and data quality.

While this will not cover the review of source documentation, ACRO said this could still alert the CRAs to:

• Eligibility violations visible in medical history, scales, electronic patient reported outcomes (ePROs), eDiaries, physical exam findings and concomitant medications.

• Protocol non-compliance with visit windows, gaps in in-vestigational product administration, dose taper and dose titrations, reporting of serious adverse events, adherence to withdrawal criteria, etc.

• Safety concerns through the assessment of labs, adverse events and other assessments reported in the electronic data capture system (or lack thereof).

ACRO expects sponsors/CROs to document the results of such remote reviews and suggests that subsequent site follow-up can be managed through remote interim monitoring visit reports. However, it cautions against data review approaches that could compromise patient privacy, such as accessing electronic health records remotely (unless the process was already established with appropriate privacy and access controls) or the trial site fax-ing source documents for remote review.

The guideline recommends that clear strategies should be agreed with the sponsor on how data would be monitored during the in-terim period and then documented. ACRO believes that during the interim period, it would not be necessary to perform 100% source document review and source data verification of all subjects, visits and data. Strategies should also be agreed with the sponsor, and documented, if a database lock is scheduled to occur during the in-terim period. A risk-based approach should be taken when assessing whether the database lock can occur or if it could be delayed.

To support oversight, the guideline recommends using ex-isting key risk indicators (KRIs) and key performance indicators (KPIs) to assess the impact on early termination, electronic data capture data entry backlog, deviations, the volume of missed subject visits, adverse event reporting cadence, etc.

In addition, it recommends the use of KRIs and KPIs to identify any trends that may require temporary interventions. “Identi-fied trends should be assessed for scale of impacts across sites which may require discussions across the project team/spon-sor to mitigate risks to accommodate investigational product shortages, missed endpoints, alternative methods of monitor-ing subject safety, etc.”

GUIDELINES BY REGULATORSACRO’s guideline builds on recent advice issued by the UK’s Medicines and Healthcare products Regulatory Agency on the management of clinical trials in relation to coronavirus. (Also see “UK MHRA: COVID-19 To Spark Rise In Clinical Trial-Related Deviations” - Pink Sheet, 12 Mar, 2020.) On 18 March, the US Food and Drug Administration also issued guidance for industry, investigators and institutional review boards conducting clinical trials during the coronavirus pandemic.

The FDA recommends, among other things, that sponsors should evaluate alternative methods for assessments, like phone contacts or virtual visits. They should also consider offering additional safety monitoring for those trial participants who might no longer have ac-cess to the investigational product or the investigational site.

In addition, the Danish Medicines Agency has also updated its guidance on “Extraordinary measures for clinical trials due to COV-ID-19.” The updated guideline deals with, among other things, a tem-porary possibility for sponsors to distribute trial medicines directly to the subjects without involving the investigator or hospital pharma-cies in cases where may be an acute shortage of the investigational medicinal product due to COVID-19.

COVID-19 IS AFFECTING ONGOING TRIALSThe guidelines by ACRO and regulators comes as the impact of CO-VID-19 is being felt by the clinical research industry. For example, clinical stage biopharmaceutical company Provention Bio has an-nounced a temporary pause in the randomization of patients with newly diagnosed type 1 diabetes into its global Phase III PROTECT study of teplizumab (PRV-031).

The company explained that its decision was not based on any study-related COVID-19 infections or other safety events, “but rath-er a preponderance of caution relating to the ongoing pandemic, and our concern for the well-being of recently diagnosed T1D pediatric patients and their caregivers.” The demands on medical institutions and their clinicians during this unprecedented global crisis were also a main consideration in this decision, it added.

In addition, Addex Therapeutics has postponed a registrational efficacy and safety study of dipraglurant to treat levodopa induced dyskinesia (PD-LID) in patients with Parkinson’s disease due to CO-VID-19. Also, Iveric bio has delayed the initiation of enrolment of patients in the second pivotal clinical trial for Zimura (avacincaptad pegol) for patients with geographic atrophy secondary to dry age-related macular degeneration due to the pandemic.

Separately, the Society of Clinical Research Sites has launched a survey to better understand the challenges that clinical trial sites are facing due to the COVID-19 outbreak. The society said it would use the survey results to address and meet the needs of sites re-garding disaster and crisis preparedness.

Published online 18 March 2020

@PharmaPinksheet

pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 7

U S F D A

US FDA Drug Office Reorg Enters Homestretch With Leadership Nods For Three Clinical OfficesSUE SUTTER sue.sutter@informa.com

T he US Food and Drug Administration announced three new office leaders under the last phase of the massive Office of New Drugs reorganization, one of whom will be

doing double duty as OND acting deputy director.Hylton Joffe, who had been director of the Division of Bone,

Reproductive and Urologic Products (DBRUP) under the old OND structure, has been named acting director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM).

The announcement came from OND Director Peter Stein in a 16 March email discussing the beginning of the fourth, and last, implementation phase of the OND reorganization.

Stein also announced the leadership for two other new clinical offices. Ellis Unger will head the Office of Cardiol-ogy, Hematology, Endocrinology and Nephrology (OCHEN), and Julie Beitz will lead the Office of Immunology and Inflammation (OII). (See box.)

JOFFE RETAINS OND ACTING DEPUTY ROLEIn addition to serving as acting director of ORPURM, Joffe will continue in the role of OND acting deputy director for clinical, the agency told the Pink Sheet.

Joffe has served as OND acting deputy director since early December. (Also see “US FDA Office Of New Drugs Reorg: Phase 3 Pushed To January” - Pink Sheet, 3 Dec, 2019.) Khushboo Sharma is the OND deputy director for operations.

The acting title on the ORPURM role could suggest Joffe is destined for the OND clinical deputy director’s slot on a full-time basis pending appointment of a permanent leader for the new review office.

ORPURM was formed from divisions in the old Office of Drug Evaluations III and IV, and the deputy director’s position currently is listed as “pending selection.”

Joffe is a 14-year agency veteran who has served in various posi-tions, including almost eight years as director of DBRUP and more than four years as lead medical officer in the diabetes drug group of the Division of Metabolism and Endocrinology Products.

UNGER, BEITZ FILL OUT OFFICE DIRECTOR POSITIONSUnger, who was tapped to lead OCHEN, has been director of the ODE I since July 2012. He formerly served as deputy director of ODE I and deputy director of the Division of Cardiovascular and

Renal Products.Mary Thanh Hai was named deputy director of OCHEN. She

had been deputy director of ODE II before stepping in as acting director. She is a former director of the Division of Metabolism and Endocrinology Products.

Julie Beitz, who has served as director of ODE III since 2006, is the new director of OII; the deputy director position has not yet been filled.

LEADERSHIP IN PLACEThe OND reorg is intended to bring a more disease-focused structure to CDER’s new drug review activities while also flattening the operation.

Under the reorg, the number of of-fices that oversee review divisions has in-creased from six to eight, while the num-ber of clinical divisions has grown from 19 to 27. The new structure also includes six non-clinical review divisions.

The reorganization received congressional approval in Sep-tember 2019 and has been implemented in four phases. The first phase saw the establishment of the Office of New Drug Policy, Office of Program Operations, Office of Drug Evaluation Sciences, and the immediate offices of Office of Regulatory Operations and Office of Administrative Operations. (Also see “US FDA’s Office Of New Drugs Reorganization Approved, But Not Happening Over-night” - Pink Sheet, 26 Sep, 2019.)

Phase II brought the establishment of the new oncology, neu-roscience and infectious disease review offices. (Also see “Drug Review Reorganization At US FDA Coming Into Focus” - Pink Sheet, 6 Nov, 2019.)

The offices of nonprescription drugs, specialty medicine and regulatory operations were established in the third phase.

The last phase of the reorg implementation will occur over the next several weeks, Stein said. “Divisions operating in ‘transition’ from earlier phases will now operate as part of their new offices. Leadership is now in place for all offices and divisions established during our restructuring, with a few exceptions.”

One OND leadership vacancy still remaining is that of associate director for the rare diseases program. Stein is filling the slot in an acting capacity. Filling the position on a permanent basis remains a top priority for OND, although there is no specific timetable for doing so, the agency said.

Published online 17 March 2020

OND Reorg’s Last Phase Brings Three More New OfficesAgency veterans have been tapped to lead the three new review offices established under the fourth stage of the Office of New Drugs reorganization.

Office of Cardiology, Hematology, Endocrinology,

and Nephrology (OCHEN) (formed from Divisions in the Office of Drug Evaluation I, II, III and the Office of

Hematology and Oncology Products)

Office Director: Ellis UngerOffice Deputy Director: Mary Thanh Hai

Division of Cardiology and Nephrology (DCN) (formed from the Division of Cardiovascular and Renal Products)

Division Director: Norman Stockbridge

Deputy Director: Aliza Thompson

Division of Non-Malignant Hematology (DNH) (formed as a new division with personnel from the Division of Hematology Products)

Division Director: Ann Farrell

Deputy Director: Albert Deisseroth (Acting)

Division of Diabetes, Lipid Disorders, and Obesity (DDLO) (formed from select staff of the Division of Metabolism and Endocrinology Products)

Division Director: Lisa Yanoff (Acting)

Deputy Director: Pending Selection

Division of General Endocrinology (DGE) (formed from select staff of the Division of Bone, Reproductive and Urologic Products and Division of Metabolism and Endocrinology Products)

Division Director: Theresa Kehoe (Acting)

Deputy Director: Pending Selection

Division of Pharm/Tox for Cardiology, Hematology, Endocrinology, and Nephrology (DPT-CHEN) (formed from Pharm/ Tox personnel currently in divisions forming OCHEN)

Division Director: Todd Bourcier (Acting)

Office of Immunology and Inflammation (OII)

(formed from divisions in the Office of Drug Evaluation II, III and the Office

of Antimicrobial Products)

Office Director: Julie BeitzOffice Deputy Director: Pending Selection

Division of Rheumatology and Transplant Medicine (DRTM) (formed from select staff of the Division of Transplant and Ophthalmology Products and the Division of Pulmonary, Allergy and Rheumatology Products)

Division Director: Nikolay Nikolov (Acting)

Deputy Director: Pending Selection

Division of Pulmonology, Allergy, and Critical Care (DPACC) (formed from select staff of the Division of Pul-monary, Allergy and Rheumatology Products)

Division Director: Sally Seymour

Deputy Director: Pending Selection

Division of Gastroenterology (DG) (formed from select staff of the Division of Gastroenterology and Inborn Errors Products)

Division Director: Jessica Lee (Acting)

Deputy Director: Pending Selection

Division of Hepatology and Nutri-tion (DHN) (formed from select staff of the Division of Gastroenterology and Inborn Errors Products)

Division Director: Joseph Toerner (Acting)

Deputy Director: Pending Selection

Division of Dermatology and Dentistry (DDD) (formed from the Division of Dermatology and Dental Products)

Division Director: Kendall Marcus

Deputy Director: Shari Targum (Acting)

Division of Pharm/Tox for Immunology and Inflammation (DPT-OII) (formed from Pharm/Tox personnel currently in divisions forming OII)

Division Director: Andrew Goodwin (Acting)

Office of Rare Diseases, Pediatrics, Urologic and

Reproductive Medicine (ORPURM) (formed from divisions in the Office of

Drug Evaluation III and IV)

Office Director: Hylton Joffe (Acting)Office Deputy Director: Pending Selection

Division of Pediatrics and Maternal Health (DPMH)

Division Director: Lynne Yao

Deputy Director: John Alexander

Division of Rare Diseases and Medical Genetics (DRDMG) (formed from select staff from the Division of Gastroenterology and Inborn Error Products and from the rare disease staff in the OND Immediate Office)

Division Director: Kathleen (Katie) Donohue (Acting)

Deputy Director: Pending Selection

Associate Director for Rare Diseases: Pending Selection

Division of Urology, Obstetrics, and Gynecology (DUOG) (formed from select staff from the Division of Bone, Reproductive and Urologic Products focused on Urologic, Obstetrics, and Gynecologic Products)

Division Director: Christine Nguyen (Acting)

Deputy Director: Audrey Gassman

Division of Pharm/Tox for Rare Diseases, Pediatrics, Urologic and Reproductive medicine (DPT-ORPURM/SM) (a newly formed division with shared P/T support to the Office of Specialty Medicine (OSM))

Division Director: Pending Selection

To view the full chart showing the Office of New Drugs reorganization, go to:https://bit.ly/2IYupM5

8 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

LENG AND NEBHRAJANI: New Chief & Chair For England’s NICENEENA BRIZMOHUN neena.brizmohun@informa.com

E ngland’s health technology assessment body NICE has ap-pointed Gillian Leng as its new chief executive. In addition, Sharmila Nebhrajani has been confirmed as the body’s new

chair, following a pre-appointment hearing by the UK parliament’s health and social care committee.

Leng, whose appointment was announced on 18 March, is cur-rently NICE’s deputy chief executive. She will take up her new role on 1 April when Sir Andrew Dillon, who has led the organization since it was established in 1999, steps down.

Nebhrajani’s appointment was made public on 13 March. She is replacing Sir David Haslam, who stepped down as chair in 2019 after more than six years in the role.

Leng has been the deputy chief executive at NICE since 2007 and is also currently its director of health and social care. In addition, she is a visiting professor at King’s College London.

According to NICE, Leng “was responsible for the initial set up and running of the clinical guidelines program, for establishing the NICE implementation function, and for setting up NHS [National Health Service] Evidence.”

“She was also responsible for a range of other functions, includ-ing the NICE accreditation program, guideline development in social care, and the NICE programs of indicators and quality standards.”

Leng trained in medicine at Leeds University, and has worked on clinical trials and epidemiological research in Edinburgh, and in London as a consultant in public health medicine. She has been

awarded a CBE (Commander of the Order of the British Empire).Commenting on her appointment, Leng said: “Under Andrew’s

leadership NICE has gained a formidable reputation both national-ly and internationally as a world leader in guidance development. I am honored and privileged to have been appointed as its second Chief Executive.”

THE NEW CHAIRAs for NICE’s new chair, Nebhrajani will take over from interim chair Tim Irish. Nebhrajani in 2017 became the chief executive of Wilton Park, an international forum for strategic discussion. Formerly, she was chair of the UK’s Human Tissue Authority, director of external affairs of the Medical Research Council and chief executive of the Association of Medical Research Charities. Nebhrajani has been awarded an OBE (Officer of the Order of the British Empire)

While NICE guidance is officially England-only, the institute has formed agreements to provide certain NICE products and services to Wales, Scotland and Northern Ireland.

Published online 18 March 2020

U K N I C E

Intelligence with a Global PerspectiveThe Premier Resource in the Life Sciences Industry

www.pharmaintelligence.informa.com

pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 9

Keytruda Dropped From England’s Cancer Drugs Fund For Bladder CancerNEENA BRIZMOHUN neena.brizmohun@informa.com

H ealth technology assessment (HTA) body NICE is with-drawing MSD’s Keytruda (pembrolizumab) from England’s Cancer Drugs Fund (CDF) as a treatment for urothelial car-

cinoma after new evidence showed that the drug was not cost-effective in this indication at its current price.

In final draft guidance published on 12 March, NICE recom-mended against the routine use of Keytruda on the National Health Service for treating locally advanced or metastatic urothelial carci-noma in adults who have had platinum-containing chemotherapy.

MSD said it was disappointed by the decision and that it was “considering what further actions are available to ensure eligible patients with advanced bladder cancer continue to have access to this medicine.”

NICE had previously made Keytruda available via the CDF for uro-thelial carcinoma in April 2018. The CDF provides interim funding for promising new treatments, via managed access arrangements, while further evidence is collected to address clinical uncertainty around a product.

Having reviewed the new evidence collected while Keytruda was available via the CDF, NICE said: “Uncertainty remains regard-ing the long-term benefit of this second-line immunotherapy treatment in comparison with other options, meaning it is not a cost-effective use of NHS resources at its current price.”

It noted that clinical trial evidence showed that Keytruda signifi-cantly improved overall survival compared with docetaxel or pacli-taxel, which are also used to treat locally advanced or metastatic urothelial carcinoma. MSD’s product also met NICE’s criteria to be considered a life-extending treatment at the end of life.

But even when the product is offered with its agreed discount, “the most plausible cost-effectiveness estimate remains above what NICE normally considers acceptable, even for end-of-life treatments,” the HTA body said. The list price for Keytruda is £2,630 per 100mg vial, which would be given as 200mg intravenously ev-ery three weeks.

The final guidance has now been sent to consultees, who have until 26 March to consider whether they wish to appeal against it. Once it has been published, Keytruda will be withdrawn from the CDF; the expected publication date is 15 April. This means that no new patients will be offered the drug, although this will not affect those whose treatment was started before the final guid-ance was published.

The managing director of MSD UK and Ireland, David Peacock, said: “It is very disappointing that a treatment which is considered a standard of care for this patient population may no longer be available for future patients with advanced bladder cancer.”

Peacock added: “In its appraisal, NICE noted the positive impact on overall survival of pembrolizumab for patients living with ad-

vanced bladder cancer. Throughout this appraisal, medical profes-sionals and patients have strongly expressed the value they are experiencing through extensive use of the medicine in the Cancer Drug Fund.”

The final draft guidance also noted that Roche’s Tecentriq (at-ezolizumab) was a possible treatment for previously treated lo-cally advanced or metastatic urothelial carcinoma. But it said that because the product had not been established clinical practice in the NHS at the time of the original Keytruda appraisal, it was not included in the scope of the review for MSD’s product. Tecentriq received a positive NICE recommendation for the urothelial carci-noma indication in June 2018.

Published online 16 March 2020

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“It is very disappointing that a

treatment which is considered a

standard of care for this patient

population may no longer be

available for future patients with

advanced bladder cancer.”

– David Peacock, MSD

10 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

UK: NICE Wins Argument Over Appraisal Of BioMarin Rare Disease DrugFRANCESCA BRUCE francesca.bruce@informa.com

A high court judge in England has rejected an application for a ju-dicial review of the way that the

health technology appraisal body NICE approached its evaluation of BioMarin’s Kuvan (sapropterin) for the rare metabolic disease phenylketonuria (PKU).

The decision has disappointed critics of NICE’s approach to rare disease treatments, including BioMarin, but the institute said the decision was an “endorsement” of its processes and methods.

The case centered around the claim that NICE acted unlawfully by using the stan-dard technology appraisal (STA) process for reviewing Kuvan instead of the highly spe-cialized technologies (HST) program. (Also see “UK: NICE’s Rare Disease Gatekeeping Comes Under The Microscope“ - Pink Sheet, 30 Jan, 2020.) It was argued that, as an ex-pensive rare disease drug, Kuvan would not have passed the cost-effectiveness test under the STA process.

However, the judge presiding over the case rejected claims that NICE had applied “the wrong test” because it had misunder-stoodw and misapplied criteria from 2017 guidance on the HST program, leading it to assess Kuvan under the STA process. The judge also rejected a claim that NICE was “irrational” in the conclusion it reached.

CONSEQUENCESPeter Todd of law firm Hodge Jones & Allen Solicitors, which is representing the 11 year-old claimant, told the Pink Sheet that permis-sion to appeal was being sought from the Court of Appeal.

Unless an appeal is successful, the judge-ment means that there is likely to be little change to the way NICE decides to evalu-ate rare disease treatments, said Todd. He added that “subject to the pending appeal it is likely that HST appraisals will be few and far between.”

The evaluation route that a rare disease treatment takes through NICE is impor-

tant because it can have a big impact on its chances of winning a recommendation from NICE. For example, under the HST program NICE can consider an incremental cost-effectiveness ratio (ICER) of £100,000 per quality adjusted life year (QALY). Under the standard process, cost-effectiveness thresholds of only £20,000-£30,000 per QALY are deemed acceptable..

“It follows that the test for drugs and treatments under HST is, in this key respect, easier to satisfy, and some drugs or treat-ments may obtain a recommendation from NICE if the HST assessment process were used, but would not obtain such a recom-mendation if the [STA] process is used,” says the high court judgement.

Nevertheless, lawyers defending NICE had said it would be wrong to argue there was “no hope” of a favorable recommenda-tion through the standard process and that it was possible to pass the “cost per QALY test”. For example, they said, the company could lower its price. Evidence provided on behalf of NICE shows that “in practice manu-facturers are often willing to offer very sub-stantial discounts to the NHS, sometimes as much as 80% off list price, because the NHS is such a big customer and because if a drug is recommended for use in the NHS this may well open it up for markets in other coun-tries,” according to the judgement.

NOT FIT FOR PURPOSE?BioMarin, which pulled Kuvan out of the standard NICE appraisal process, said it

would re-engage with the STA process “in the hope of achieving a long-term fund-ing solution.” However, it added that it was concerned that the process would lead to a negative decision because of “the ex-tremely restrictive evidence criteria and thresholds applied within the process.”

The company said the judicial review ap-plication and “other recent negotiations for access to rare disease medicines highlight the need for reform of the system for ap-praising rare disease treatments in the UK, which is not currently fit for purpose.” Treat-ments for rare diseases approved in the EU are now “reimbursed more often and much faster in other European countries, leaving the UK lagging behind,” said a spokesperson.

The company said the treatment is avail-able in 26 other countries across the EU, including “less affluent” countries with less developed health systems like Romania and Bulgaria. “The UK needs a system for reim-bursing treatments that is inclusive and fair for all patients, with the capability to assess new innovations that are shifting the goal posts in rare diseases, so that patients in England can benefit from advances that are already changing lives,” said BioMarin.

But Meindert Boysen, director of NICE’s Centre For Health Technology Evaluation, described the judgement as “a welcome en-dorsement of the process and methods we use to select and route topics through our various guidance development programs.”

He added that NICE would now con-tinue with its evaluation through the stan-dard process and would be working with BioMarin to reschedule the appraisal. “We look forward to working with them so that we can establish whether the drug should be made routinely available. We understand that this is a stressful time for patients and their families, and we are keen to minimize any further delay in our decision-making process.”

Published online 13 March 2020

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Sweden Urges Pharma To Engage In AMR InitiativeSTEN STOVALL sten.stovall@informa.com

S weden’s experimental reimburse-ment program – which aims to en-sure enough antibiotics are available

to the country’s 10 million population – has advanced to the point of engagement with pharmaceutical companies and they have been asked for their feedback on the proposed procurement process, the pilot AMR program’s manager told Pink Sheet.

The Swedish project, which has been in the works for six years, is assessing full or partial de-linkage of payments from sales volume – ie, companies will be given a ne-gotiated payment for an antibiotic regard-less of its sales, in order to ensure national access to important anti-infectives.

The assumption is that any negotiated payments must be high enough to cover the production and distribution costs, as well as offer some profit margin for the company providing the antibiotic.

Another assumption is that other coun-tries will also procure enough of the same medicine to ensure the viability of the drug’s producer.

“One important aspect is that the model which we are piloting does NOT focus on incentives for research and de-velopment of new antibiotics. Rather, it is focusing on ensuring the availability of already approved and existing antibiotics in the Swedish health system,” explained Jenny Hellman, who is project managing the Swedish exercise at the Public Health Agency of Sweden (PHAS).

That contrasts with an experimental reimbursement program currently under-way in the UK which does have, as a key ambition, the goal of incentivizing innova-tion of novel anti-infectives. (Also see “UK Experimental AMR Payment Program “On Track”” - Scrip, 12 Mar, 2020.)

Unlike the UK, Sweden has a relatively small population, a very good record of stewardship around antibiotics, and low levels of antimicrobial resistance. There is thus little incentive for a company to launch a new antibiotic in Sweden, experts said.

The key AMR issue for Sweden is there-

fore access to antibiotics, levels of which are dwindling dangerously. (Also see “New AMR Report Is ‘A Wake-Up Call’, Says Indus-try Body“ - Pink Sheet, 16 Jan, 2020.)

“The overall goal of this current program in Sweden is to formulate a concrete rec-ommendation by the end of 2022. This model would ideally be something we should extend and implement throughout Sweden,” Hellman said in an interview.

If it proves viable, the model could act as a blueprint for other countries, she added.

A draft model for the procurement of antibiotics has been compiled in accor-dance with Swedish law and is now being issued to pharmaceutical companies by PHAS with a view to starting dialogue and getting sector feedback on the draft pro-curement documents.

“Our goal is to have contracts of avail-ability in place in the end of June this year involving the guaranteed supply of a de-fined amount of a number of certain anti-biotics that will be exclusively earmarked for Sweden,” Hellman said.

The pilot study involves the testing of contracting processes and legal aspects. The procurement pilot’s impact on the availability of antibiotics also will be closely monitored and assessed.

PHAS is using a bespoke algorithm try-ing to identify antibiotics that need spe-cial mechanisms in order to secure their availability.

“First, we identify antibiotics with low sales turnover and antibiotics that have few marketing authorization holders, with a view to identifying products that might have availability problems,” Hellman said.

“Secondly, we assess antibiotics with re-gards to their special medical value. To do that, we have created an algorithm that in-cludes evaluation for activity against bac-teria with identified high-risk resistance, the drug’s ecologic profile, and its role in Swedish treatment guidelines.”

“For the pilot study we needed to start with one area, and that is for antibiotics with effect against WHO´s list of critical patho-gens area number 1,” Hellman added.

On 18 February, PHAS sent a letter out to pharmaceutical companies who had voiced interest in having a dialogue on the procurement process in the pilot.

The letter said that it was an opportunity to submit comments in writing on PHAS’s draft procurement document and some additional information including how to submit comments on the draft document concerning the pilot study on availability of certain antibiotics.

“We also said that we would like to have comments back no later than 9 March and that we are planning to open the procure-ment process in end of the first quarter of 2020,” Hellman said.

Published online 17 March 2020

12 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

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China’s Global Pharma Supply Chain Operations Resuming In Wake Of Outbreak, USP SaysBOWMAN COX bowman.cox@informa.com

C hina’s pharmaceutical manufacturing areas began recov-ering from coronavirus-related travel restrictions in mid-February, with production back up to half the normal rate,

says US Pharmacopeia CEO Ron Piervincenzi.The USP could detect that by reviewing Chinese sales of its

physical reference standards.As expected, orders for USP standards stopped in China during

the Lunar New Year holiday in the last week of January.But orders did not resume the following week as they normally

would because workplaces remained shut down as authorities sought to slow the coronavirus outbreak.

When orders finally began trickling in the following week, the USP could not fulfill them until global courier services resumed service to China.

Activity finally picked up over the last two weeks of February, according to Piervincenzi. “I’d say we’re probably operating some-where in the order of about half what we would normally be.”

The USP also saw that use of its standards in India was “a little less than we would have expected.”

Piervincenzi gave one possible explanation: if some drug prod-uct manufacturers in India were hoarding active pharmaceutical ingredients from China, their use of USP physical reference stan-dards would continue at the normal rate while that of others would decline as they ran out of API.

“I have no evidence that’s the case,” he said. “It would be some-thing we’d want to watch for.”

Pharmaceutical companies use USP standards for a wide variety

of functions to support research and development of APIs and ex-cipients, as well as to ensure quality in the drug product manufac-turing process.

FINDING THE PAIN POINTSAs the coronavirus goes global in a series of regional epidemics, now considered a global pandemic, it is important to anticipate the next pain points in the supply chain.

Even though the entirety of the pharmaceutical supply chain is global, the chain for each individual drug is not. “You’re not really robust if all your antibiotics are from China, but all your cardiovas-cular drugs are from India and all of your sterile injectables are from Puerto Rico,” Piervincenzi explained.

Although dependence on China is a concern today, the US pharmaceutical sector was once highly dependent on facilities in New Jersey. Luckily by the time Hurricane Sandy pounded that state in October 2012, much of the medicine consumed in the US was instead coming from India, he said. “You just don’t want all your medicine coming from one place, including if it’s your own place.”

Furthermore, it’s important to risk-assess every stage of the supply chain. It is great if, for example, 12 companies make a medicine in five countries, he said. But the shortage risk could still be high if they all require an API or an excipient that is only made by one company in one location.

A USEFUL PREDICTOR?The USP is not there yet, but it hopes to use its sales data routinely as a risk analysis tool for prediction and prevention of drug short-ages. Already, the pharmacopoeia can see the potential utility of the data with the coronavirus.

“We don’t quite know the effect of the slowdown of manufac-turing in China,” he said. “We’re just not sure yet because it hasn’t made its way through the supply chain.”

But the USP data gives a signal of the extent and timing of the disruption months before it hits consumers, while manufacturers and regulatory authorities still have time to act. The USP plans to complete an analysis of aggregated China supply chain data soon.

For future supply chain crises, the organization hopes to more deeply integrate its tool with pharmaceutical sales data to link medicines and manufacturing facilities globally.

“It’s complicated,” Piervincenzi said, “but you just have to peel the onion a little bit.”

HELPING THE FDA AVERT SHORTAGESThe USP has been sharing its findings with the US Food and Drug Administration, which has been handicapped in its efforts

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to anticipate drug shortages by a lack of information about manufacturing activity.

The agency knows how many companies have received its approval to manufacture drugs, but it has no information about their production levels. Typically, once a few competi-tors lock up market share for a generic drug, the others stop making it.

The FDA’s drug shortage team has been canvassing Chinese manufacturers and their customers for any signs of pending coronavirus-related shortages. So far, the agency has attrib-uted only one drug shortage to the outbreak.

FDA officials have begun to ask Congress for authority to re-quire pharmaceutical companies to tell the agency how much of each drug product they have been manufacturing. (Also see “Re-al-Time Manufacturing Volume Reporting Could Help Prevent Drug Shortages, Woodcock Tells Congress” - Pink Sheet, 31 Oct, 2019.)

Legislation is in play to impose such requirements. (Also see “Drug Shortage Legislation Gains Support As Coronavirus Threat-ens US Supplies” - Pink Sheet, 8 Mar, 2020.) However, even if it is enacted, such legislation would only give the agency an annual snapshot of manufacturing activity.

The USP data is more real-time than that, though somewhat approximate.

USP STANDARDS USED WIDELYChina is the second-highest volume user of USP standards, ac-cording to Piervincenzi.

Last year, USP’s written documentary standards, which in-clude compendial recipes for generic drugs, were accessed from 180 countries, in some cases just for procuring, but in many for manufacturing, he said.

Meanwhile, the USP last year sent physical standards to 22,000 manufacturing locations and analytical laboratories around the world. USP surveys indicate that about half of the organization’s reference standards customers use its reference standards at least several times a month, and about a third use them at least once a week.

Manufacturers use USP standards – or secondary standards qualified against USP standards – each time they test a batch of drug product for compliance with USP requirements, USP told the Pink Sheet. Sometimes they may be able to standard solu-tions, once prepared, for testing of multiple batches. They are likely to buy several months of standards at a time, UPS noted.

Published online 13 March 2020

The USP last year sent physical

standards to 22,000 manufacturing

locations and analytical laboratories

around the world.

PALFORZIA PEANUT ALLERGY IMMUNOTHERAPY:Aimmune CEO On REMS Restrictions, ManufacturingBRENDA SANDBURG brenda.sandburg@informa.com

A immune Therapeutics Inc. is navigating a host of new challenges as it launches Palforzia, the first peanut allergy immunotherapy to be approved by the US Food and Drug

Administration. Most notably, it must get physician practices and individual allergists certified to administer the treatment.

Aimmune President and CEO Jayson Dallas talked to the Pink Sheet about the certification process, part of the company’s Risk Evaluation and Mitigation Strategy (REMS), in an interview in New York last month. He also discussed the complexities involved in manufacturing the food-derived treatment.

Some analysts have speculated that the restriction on admin-istration might slow the uptake of Palforzia and limit its use, but Dallas does not see it as a significant hurdle. He said clinics must go online and certify via a box check-off that they have the experience and staff to do immunotherapy and have access to the emergency allergic reaction treatment EpiPen (epinephrine injec-tion) at all times. The certification pro-cess is similar for physicians, who are not required to go through training.

The US Food and Drug Adminis-tration approved Palforzia [peanut, (Arachis hypogaea) Allergan Powder-dnfp] on 31 January to mitigate allergic reactions, includ-ing anaphylaxis, that may occur with accidental exposure to peanut in patients ages four to 17 years.

Palforzia was associated with a higher rate of systemic allergic reactions and epinephrine use in clinical trials, and to mitigate this risk the agency required Aimmune to implement a REMS. (Also see “Keeping Track: Aimmune’s Peanut Allergen Approved; Novartis’ Inclisiran, Pfizer/Lilly’s Tanezumab, Bayer’s Nifurtimox Submitted” - Pink Sheet, 31 Jan, 2020.)

SETTING PATIENT EXPECTATIONSMembers of FDA’s advisory committee had requested that ad-ditional measures be included in the REMS beyond those sug-gested by the agency, including informed consent and docu-mentation that patients and their families understand they are to continue to avoid eating peanut-containing products. (Also see “Aimmune’s Palforzia Gains US FDA Panel Nod But Faces REMS Restrictions” - Pink Sheet, 15 Sep, 2019.)

The final REMS incorporates the panel’s recommendations.

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Aimmune President and CEO Jayson Dallas

14 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

P O L I C Y P E R S P E C T I V E

Patients must certify that they understand how Palforzia works and will always carry an EpiPen and return to the practice to get new EpiPen prescriptions when they run out or expire.

“They have to understand that for the first couple months they may have allergic reactions to treatment that will go away over time as efficacy gets better,” he said. “This is where setting expecta-tions up front is critical.”

Patients check-off the certification form online in the physician’s office. The patient data goes to a third-party REMS administrator, which submits a report to FDA every six months. Dallas said it is al-most exactly the kind of consent that allergy practices require from children undergoing immunotherapy for grass and pollen allergies.

Once the patient is cleared to receive the product, the powder in the capsules, which consists of peanut flour, is emptied onto semi-solid food, such as applesauce, yogurt or pudding. Patients are given increasing doses in three sequential phases to desensitize them. They receive the initial single day dose escalation in the doctor’s office and then receive a 14-day supply from one of three specialty pharmacies that are certified to distribute it, AllianceRx Walgreens, CVS Specialty, and Optum Specialty Pharmacy. They return to the doctor’s office in two weeks to receive the second dose and then are put on a mainte-nance dose of 300mg daily.

Aimmune’s 80-person field team began meeting with allergists on 4 February to encourage them to incorporate Palforzia into their prac-tice. And the company announced on 16 March that the first patients in the US are being treated with Palforzia. Aimmune Therapeutics Inc. is in uncharted territory as it launches Palforzia, the first treatment for a food allergy ever approved by the US Food and Drug Administra-tion. The company has put together a diverse field team and teamed up with three specialty pharmacies to distribute the oral immuno-therapy, which may provide a model for future food allergy products.

The company launched a REMS website which lists the pre-scribers and healthcare settings that are certified to administer Palforzia capsules.

MANUFACTURING ADVANTAGES AND CHALLENGESThe nature of the product also involves novel manufacturing con-siderations. Dallas said that he had received a lot of questions about how the company was faring with the chemistry, manufacturing and control (CMC) processes, as they pose hurdles for many biotech com-panies in the final stages of FDA review.

Dallas said most manufacturing challenges arise during the pro-duction of the active pharmaceutical ingredient (API), which has to be made at the same quality and scaled up for commercial market-ing. “Our process in a way is fortunate because our API is roasted, de-fatted ground peanut flour. So we don’t have a whole lot of complex-ity and challenge on the API production side or on the ability to scale up or scale down API supplies,” Dallas said.

He noted that the biggest challenge is getting the API accepted as a good manufacturing process drug substance. “We have to do the allergen expression analytic and measure so that every piece of every batch has exactly the right allergenic expression on it,” he said. “That analytic that turns it into drug substance is the most

complicated part of the process.”The product then goes through a sterile manufacturing process

and a comprehensive individual dose measuring process at Aim-mune’s plant. The entire process is based in the US. The peanuts are grown in Georgia, the manufacturing is done in Clearwater, FL, and the packaging is done in Illinois. “It has not been without complex-ity but we have not run into any issues,” Dallas said. “We had an FDA inspection and did very well.”

During a 16 March call with analysts, Dallas acknowledged the im-pact that the coronavirus will likely have on the launch of Palforzia, but he said manufacturing operations remain fully operational and the company has sufficient Palforzia finished product on hand to meet demand for the foreseeable future and expects to remain in a position to continue to produce new product as necessary.

“We don’t have an end date here, but we are able to meet demand for quite some time,” he stated.

RIVAL STUMBLES AGAINDBV Technologies SA, which is looking to be the second entry into the peanut allergy treatment space, is facing another delay with re-view of its Viaskin Peanut patch. On 16 March, DBV announced that FDA had informed the company that during its ongoing review of the BLA it “identified questions regarding efficacy, including the impact of patch-site-adhesion.”

Therefore, the Allergenic Products Advisory Committee that had been slated for 15 May will not take place as scheduled.

DBV said it may submit additional information on patch-site adhesion from its clinical program as well as long-term efficacy results from the three-year open-label extension study, PEOPLE, to answer FDA’s questions. DBV said to its knowledge the target action date of 5 August remains unchanged, but noted that if it submits additional information to FDA, that may constitute a major amendment to the BLA and could extend the target action date.

It’s the second significant review setback for Viaskin Peanut. The company withdrew its BLA in December 2018 after FDA requested additional data on manufacturing procedures and quality controls.The application was resubmitted on 6 August (Also see “Keeping Track: Amarin And Nektar Signal Delays, DBV Returns, And Provention Notches A BTD” - Pink Sheet, 11 Aug, 2019.) and DBV announced in October that FDA had accepted the BLA with a user fee action date of 5 August.

Dallas expressed skepticism that Viaskin Peanut would clear the agency. “It’s a very long reach to believe it is going to be approved,” he said. “None of their data is statistically significant.”

Even if Viaskin Peanut does get approved, Dallas predicted that the patch won’t work in eight of 10 kids who use it. He said the patch in-cludes a miniscule dose and requires proteins to be dissolved in sweat and absorbed. “So the concept of that getting into the body and gen-erating immunity is tricky,” he said. “It’s a problem for all patches.”

CHANGING MEDICAL PRACTICE Dallas has been involved in many high-profile launches over the past 25 years. Prior to joining Aimmune in June 2018, he served as chief commercial officer at Ultragenyx Pharmaceutical Inc., over-seeing the launches of its first two products, Mepsevii (vestroni-

pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 15

dase alfa-vjbk) and Crysvita (burosumab). He also served as general manager of Roche in the UK and head

of global commercial strategy groups focused on oncology, im-munology, and ophthalmology at Genentech Inc., and headed the specialty medicines operating unit for Novartis AG in the US.

The launch of Palforzia differs from his previous work as it breaks totally new ground. “To actually get something approved that is going to rewrite medical textbooks and change medical practice all over the world is just phenomenal,” he said.

Aimmune, previously called Allergen Research Corporation, was established in 2011 with seed funding from the nonprofit group Food Allergy Research & Education. The group held a research re-treat earlier that year with members of the food allergy commu-nity to reach a consensus on the future of food allergy research. Aimmune said the participants, which included members of the pharmaceutical industry and representatives of the FDA and the National Institutes of Health, decided to focus on oral immuno-therapy, the practice of giving a small amount of the allergen pro-tein with a gradual increase in dose to desensitize a patient.

On 16 March, Aimmune announced its analysis of ARC004, the open-label follow-on trial to the 52-week pivotal PALISADE trial. The data had been scheduled to be presented at the American Academy of Allergy, Asthma & Immunology’s annual meeting in Dallas, which was cancelled due to the COVID-19 pandemic. The company said the analysis showed that patients tolerated more peanut protein, experienced fewer adverse events and continued immunomodulation as evidenced by reductions in peanut-specific immunoglobuin (IgE) blood levels after an additional 56 weeks of daily treatment with Palforzia.

Aimmune has a Phase III study underway to expand the indica-tion for use in children aged 1 to less than four years. Last month it licensed AIMab7195, an investigational anti-IgE monoclonal anti-

body with three mechanisms of action, from Xencor Inc.. The com-pany’s goal is to see if a larger proportion of patients can achieve remission from their food allergy more quickly with concomitant therapy with AIMaB7195 than on immunotherapy alone.

GAINING REGULATORY CONFIDENCE Dallas said getting the first food-derived medicine through the FDA’s robust review process “gives us a lot of comfort that our concept and the platform of characterized oral immunotherapy actually works and we can show it works and we can persuade regulators that it is a valuable therapeutic option for people with food allergies.”

The company has two additional products in the pipeline, AR201 in Phase II for treatment of egg allergy, and a single ther-apy for treatment of allergies to five tree nuts (walnuts, hazel-nuts, cashews, pistachios and pecans) in pre-IND development. Dallas said this is a new challenge in terms of how you make a multitherapeutic in a single product and deal with regulators. But he said doing a development program for five nuts would take too long and be too complicated and be clinically quite challenging for individuals to desensitize five different times to five different things.

“We think it’s much more elegant to do it in one,” he said.The experience gained in getting Palforzia through regulatory

authorities, past payers and convincing physicians to give it to pa-tients will provide the company important lessons that will help it with the additional programs.

Next up, though, is the expected approval of Palforzia in Europe at the end of the first quarter. Dallas said the company will launch in Germany first, as other countries require a product to obtain re-imbursement prior to marketing.

Published online 16 March 2020

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Biosimilar Competition: Still More Focus On FDA Than FTCMICHAEL MCCAUGHAN pinkeditor@informa.com

T he workshop on biosimilar competition hosted by the US Food & Drug Administration and the Federal Trade Com-mission certainly helped send a message about the impor-

tance of assuring robust competition in the market for biologics. It just might not have been the intended message. The formal purpose of the 9 May meeting was to showcase a

new collaborative effort between FDA and FTC to assure a “level playing field” in the marketplace, building on a joint statement be-tween the two agencies declaring a shared purpose and outlining responsibilities related to biosimilars within their at times overlap-ping jurisdiction over prescription drug marketing. (Also see “FDA/FTC’s Hot Ticket: Biosimilar Workshop On How To Boost Market, From Education To Lawsuits” - Pink Sheet, 12 Mar, 2020.)

B I O S I M I L A R S

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B I O S I M I L A R S

But the clearer implicit message of the event was to reinforce the reality that FTC is unlikely to play much of a role in shaping the adoption of biosimilars in the near term – beyond drawing public attention to the issues.

The meeting also began by unintentionally underscoring the higher priority placed on the topic by FDA than FTC. FDA Commis-sioner Stephen Hahn opened the meeting and expressed his ap-preciation to FTC colleagues for traveling from downtown to the White Oak FDA campus. However, he then turned the podium over to FTC chief of staff Tara Koslov, rather than the scheduled presen-tation by FTC Chair Joseph Simons.

Hahn’s remarks did continue his rhetorical embrace of the bio-similar agenda mapped up by his predecessor. He invoked former Commissioner Scott Gottlieb by name and summarized the meet-ing agenda as intended to fulfill what Gottlieb described as assur-ing a free market with “no shenanigans.”

Several other speakers highlighted that comment by Hahn as a gratifying statement of ongoing interest – though it was apparent-ly extemporaneous and not included in the published statement released by FDA.

It also is a reminder of the long gestation period for even this first small step. Gottlieb included collaboration with FTC as one plank in FDA’s Biosimilar “Action Plan” announced in 2018. The two-year process to draft a shared statement by FTC and FDA on priorities in biosimilar competition (and to convene the meeting itself ) is il-lustrative of the timelines involved.

FTC’S TIME LAG Koslov’s opening remarks (formally attributed to Simons by FTC) also indirectly underscored the time lag that is essentially inherent in the process FTC has to follow to bring cases.

“One way the FTC promotes competition in pharmaceutical markets is by conducting industry studies,” Koslov began. While undoubtedly important and informative, that is not a message that is likely to prompt any marketer to change behavior for fear of im-minent action.

“Another way the FTC promotes competition in pharmaceuti-cal markets,” Koslov continued, “is by vigorously combating anti-

competitive conduct.” Now there is a message that might change behavior. However, she continued with an example: “The Com-mission for example has a long record of successful enforcement actions against brand and generic drug manufacturers seeking to game the Hatch-Waxman process by entering into anticompetitive reverse-payment agreements.”

The emphasis in that statement should probably be on the “long” record, rather than the “successful” actions.

Koslov immediately cited the “landmark decision by the Su-preme Court in FTC v. Actavis” as a case in point. That 2013 ruling was a decade in the making, following extensive FTC study, in-vestigation and litigation attempting to block “reverse payment” (a.k.a., “pay for delay”) patent settlements. (Also see “Pay-For-Delay Deals May Be Smaller After Supreme Court Okays FTC Suits” - Pink Sheet, 24 Jun, 2013.)

And, even after the partial victory at the Supreme Court, it took another five years for FTC to win an award for damages from the marketer of the brand (Androgel) at the heart of the case. (Also see “FTC Wins $448M Ruling Against AbbVie For Sham Litigation Rather Than Pay-For-Delay Deal” - Pink Sheet, 2 Jul, 2018.)

That marketer, coincidentally, was AbbVie Inc. – now the central target for political complaints about overzealous evergreening in the biologics market with Humira. The Androgel saga should make very clear that if anyone is counting on FTC to accelerate the time-line for entry of biosimilar Humira(now set for 2023 via multiple patent settlements), they are likely to be disappointed.

TEMPLATE FOR ADVERTISING SUITS After those opening statements, the day-long meeting heard nu-merous discussions of potential avenues to accelerate competition in the biosimilars market. Many focused on actions FDA could take, like streamlining the pathway for interchangeable biosimilars, re-visiting its naming policies, etc. Many more focused on actions the Centers for Medicare & Medicaid Services or Congress could take to enhance reimbursement and formulary coverage.

Remarkably few suggestions were actually for FTC. In fact, one of the few was a suggestion that the commission issue guidance outlining a case for deeming false and misleading advertising by “monopolists” (as most innovator brands would be considered) to be inherently actionable under anti-competitive statutes like the Lanham Act.

The intent of that proposal is not so much for FTC to act, but to make it easier for biosimilar marketers to bring cases on their own (and, perhaps, for the threat of those cases to deter the advertisers in the first place).

That idea is largely premised on the expectation that biosimi-lar competition will continue to pit large, well-capitalized firms against each other – the way Pfizer Inc. is litigating against Johnson & Johnson over Remicade competition.

In those kinds of markets, both sides are likely to appeal to FTC as a referee. But like any good competition, the players only want the referee to keep things fair – not interfere with the game itself.

Published online 18 March 2020

The two-year process to draft

a shared statement by FTC and

FDA on priorities in biosimilar

competition (and to convene the

meeting itself) is illustrative

of the long timelines involved.

pink.pharmaintelligence.informa.com March 23, 2020 | Pink Sheet | 17

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

Gilead’s Robust Expanded Access For Remdesivir Signals Confidence In Study EnrollmentSARAH KARLIN-SMITH sarah.karlin-smith@informa.com

T he US Food and Drug Administra-tion has granted about 250 US CO-VID-19 patients expanded access to

Gilead Sciences Inc.’s investigational anti-viral remdesivir, the agency said Thursday. That relatively high number suggests the agency and Gilead may not be concerned about compassionate use detracting from patient enrollment in clinical trials needed for regulatory approval.

FDA said the data collected from the ex-panded access program might contribute to its understanding of the drug, but con-trolled clinical trials will be needed to make a safety and efficacy determination.

However, some experts are concerned that expanded access requests may be slowing the progress of clinical research and determinations of whether remdesivir should be used to treat COIVD-19.

“We have to get well done studies en-rolled and completed rapidly because the number of people who could be affected by those findings is rising very rapidly, so each day lost due to a patient not going on a study and instead receiving a treat-ment under compassionate use actually harms other patients,” Peter Bach, director of Memorial Sloan Kettering’s Center for Health Policy and Outcomes, told the Pink Sheet. “This is always the case but here the harms compound because the number of people who could benefit or not is rising exponentially.”

The National Institute of Allergy and Infectious Diseases is running a Phase II adaptive trial of remdesivir. The study enrolled its first patient on 21 February in Nebraska and aims to enroll nearly 400 patients. While the study will initially com-pare remdesivir to placebo, it is a platform trial that can be adapted to evaluate ad-ditional treatments. Once a therapy is proved efficacious it becomes the control arm for need candidates. (Also see “CO-VID-19 Study Of Gilead’s Remdesivir Using Ebola-Style Adaptive Platform Trial” - Pink

Sheet, 17 Mar, 2020.)Gilead’s Phase III studies of remdesivir

for COVID-19 are primarily focusing enroll-ment in Asia where the virus originated.

NIAID did not respond by press time to a request for the number of patients

enrolled in the trial. NIAID, along with Gil-ead and FDA did not respond to questions about how the parties were balancing ex-panded access requests with the need to ensure sufficient and speedy patient en-rollment in clinical trials.

Gilead’s general policy on compassion-ate use requests for all medicines says pa-tients must not be eligible or able to par-ticipate in clinical trials of the drug, noting that receipt of investigational medicines through clinical trials is preferable because such trials generate data regarding the drug’s safety and efficacy.

For remdesivir, Gilead is assessing com-passionate use requests on an “individual basis.” At a minimum patients must be hospitalized with confirmed COVID-19 infection and “significant clinical mani-festations,” according to the policy, last updated on its webpage on 26 February. Gilead also requires that compassionate use requests be submitted by a patient’s treating physician.

The company also did not say whether it is fulfilling any other US compassionate use re-quests under the right-to-try law, which lets companies provide experimental medicines with much more limited FDA oversight.

FDA Commissioner Stephen Hahn said during a press conference of the White House’s coronavirus taskforce Thursday

that “the really positive” thing about com-passionate use is that it lets FDA give a drug rapidly to a doctor and a patient, “but it allow us to collect the data,” that is needed “to make the appropriate decision about safety and effectiveness.”

Later in the briefing, however, he clari-fied that clinical trials will provide the data “that are going to inform the deci-sions that are ultimately made about safety and efficacy.” The agency did not respond to requests for more informa-tion about if and how it may be working with Gilead and expanded access recipi-ents to collect data that could be useful as part of an NDA.

“This is an unprecedented situation. This is a really significant time,” Hahn said. “And one thing that, with the President’s leader-ship, FDA has done is said, ‘Okay, how do we approach these extraordinary times with extraordinary measures, knowing that we have a sacred trust with the Ameri-can people about safety and efficacy, but still, at the same time, enable these treat-ments to get into patients?”’ And that’s what we’re doing.”

A new Coronavirus Analytic Solution in-cluding comprehensive integrated data on clinical trials, pipeline, market events and in-sights from across Pharma Intelligence’s suite of products, updated daily, is now available. Contact Duncan Emerton, PhD; Director, Custom Intelligence & Analytics for details. Duncan.Emerton@informa.com (Separate purchase required.)

Published online 19 March 2020

Gilead is assessing compassionate use requests on

an “individual basis.” At a minimum patients must

be hospitalized with confirmed COVID-19 infection

and “significant clinical manifestations.”

18 | Pink Sheet | March 23, 2020 © Informa UK Ltd 2020

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