Hahn’s Nomination Heads To Full Senate Following Bipartisan … · 2019-12-06 · is a big red...

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Vol. 81 / No. 49 December 9, 2019

DRUG PRICING

Concerns Emerge Over England’s Desire For Even Lower Drug Prices, p. 19

REGULATORY UPDATE

EU Raises Pressure On Pharmaceutical Pollution Of The Environment, p. 8

REGULATORY UPDATE

Real-World Database Studies: Prepare For A Long Journey, IQVIA Advises, p. 16

CONTINUED ON PAGE 4

Hahn’s Nomination Heads To Full Senate Following Bipartisan Endorsement From HELP CommitteeMICHAEL CIPRIANO [email protected]

S tephen Hahn’s nomination to serve as commissioner of the US Food and Drug Administration advanced to the

full Senate following a relatively painless 18-5 vote from the Health, Education, Labor and Pensions Committee on 3 December.

However, a few senators raised con-cerns with Hahn’s noncommittal answers to questions about whether he would support a policy banning non-tobacco e-cigarette flavors raised during his con-firmation hearing.

Sen. Patty Murray, D-WA, the ranking member of the HELP Committee, cited the issue when explaining why she would vote against the nomination.

“I was particularly concerned that when pressed several times by members on both sides of the aisle, Dr. Hahn refused to com-mit to implementing a strong policy to clear non-tobacco flavored e-cigarettes that have not undergone FDA review for the market, like the Trump administration promised to do before it heard from the tobacco indus-try and reversed course,” Murray said. “That is a big red flag for me, and why I will be vot-ing against his nomination.”

Murray also cited concerns about Hahn’s lack of government experience and his public record on FDA policy issues.

Sen. Mitt Romney, R-UT, voted in favor of Hahn’s nomination, but noted he did so “with some degree of concern” over Hahn’s answers to vaping-related questions.

“I had hoped in his hearing that he would express very clearly that he would follow science with regard to vaping,” Romney said. “Specifically that he would place the interest of public health above any other interest, including political interest, and that if for some reason he was directed to take action that was con-trary to his view as a professional and as a scientist and as a doctor, that he would clearly state that he was directed to do so, at the minimum, and perhaps even con-sider resignation.”

“I will vote for Mr. Hahn because I believe he is a solid professional with the right in-stincts and the right record,” Romney add-ed. “But I do intend to insist that he com-municate to us and this committee and to the nation how his decisions are being carried out and being made with regard to this national epidemic.”

Senators Elizabeth Warren, D-MA, Bernie Sanders I-VT, Maggie Hassan D-NH, and Tina Smith, D-MN, joined Murray in oppos-ing Hahn’s nomination.

The Senate HELP Committee advanced Stephen Hahn’s nomination to head the FDA to the full chamber.

A few senators raised

concerns with Hahn’s

noncommittal answers

about whether he

would support a policy

banning non-tobacco

ecigarette flavors.

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Drug Shortages, AMR & Cancer High On New EU Commissioner’s Agendahttps://pink.pharmaintelligence.informa.com/PS141308

The new EU commissioner for health has been given a number of high-priority tasks, including medicines supply and tackling antimicrobial resistance. These topics will be taken up by the European Commission’s advisory body, the Pharmaceutical Committee, in its new work plan.

Richard Torbett to Head Up UK ABPIhttps://pink.pharmaintelligence.informa.com/PS141291

Richard Torbett, who negotiated the UK’s new voluntary pricing scheme, is to be the new chief executive of the ABPI.

Medicare Retail Drug Spending Accelerates In 2018 Despite Price Declineshttps://pink.pharmaintelligence.informa.com/PS141314

Prices for retail drugs across US payers decreased for the first time in years, driven by a drop in generic prices and “little to no growth” in prices for brands.

ANDA Approval Records Will End As US FDA Mops Up Backloghttps://pink.pharmaintelligence.informa.com/PS141304

CDER Director Woodcock says generic approvals remain inflated by applications that languished before FDA’s user fee program began, but as sponsors work through their own backlog of FDA responses, the number of ANDAs cleared by the agency appears likely to fall.

exclusive online contentCO V E R Hahn’s Nomination Heads To Full Senate Following

Bipartisan Endorsement From HELP Committee

U S F D A 4 US FDA Office Of New Drugs Reorg:

Phase 3 Pushed To January

C L I N I C A L T R I A L S 5 Adaptive Clinical Trials: US FDA Offers More Advice

On Bayesian Designs

7 EU Produces More Guidance For Upcoming Clinical Trials Regulation

R E G U L ATO RY U P D AT E 8 EU Raises Pressure On Pharmaceutical Pollution

Of The Environment

16 Real-World Database Studies: Prepare For A Long Journey, IQVIA Advises

M A N U FAC T U R I N G Q UA L I T Y 9 US FDA Mulls Pilot To Examine Separate Review

Pathway For Novel Excipients

10 US FDA Says Data Integrity Remains Challenging For API Manufacturers

12 Differences Put Aside As ICH Finalizes Guide On Post Approval Changes

A D V I S O RY CO M M I T T E E S 13 A Year Of Reconsiderations For US FDA Advisory

Committees

14 Lynparza, Keytruda Supplemental Indications Face US FDA Panel Review

22 Recent And Upcoming FDA Advisory Committee Meetings

D R U G P R I C I N G 19 Concerns Emerge Over England’s Desire

For Even Lower Drug Prices

20 EU Needs More Teamwork On Drug Pricing & Access

inside: 13 6 7

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U S F D A

US FDA Office Of New Drugs Reorg: Phase 3 Pushed To JanuaryMICHAEL MCCAUGHAN [email protected]

T he next phase of the US Food and Drug Administration’s roll-out of a new structure for its

drug review operations will take place in mid-January.

Phase 3 of the four-stage roll-out had been tentatively scheduled to take effect 2 December. However, the FDA announced 25 November that it would pause the process until after the holidays, and Phase 3 is now set for 13 January. The new timeline will “accom-modate the high interest in leadership positions and scheduling interviews during the holiday season …This ad-ditional time also helps us to carefully finalize administrative activities and update applications/submissions.”

The FDA notes that “a large number of candidates have expressed inter-est and applied for division director positions.” The delay may also allow for the FDA to time division director announcements after some potential year-end retirements.

FDA implemented Phase 2 of the re-org in November, with the formal launch of the new Office of Neurology and the reorganized (and renamed) Office of Oncologic Diseases.(Also see “Drug Re-view Reorganization At US FDA Coming Into Focus” - Pink Sheet, 6 Nov, 2019.)

Phase 3 will include the Office of Specialty Medicine and the Office of

Non-Prescription Drugs. “We are still on track for the final phase (Phase 4) to begin in the February/March 2020 timeframe,” the FDA says.

The agency has also confirmed the leadership for each of the new offices within OND, with one notable excep-tion. The selection of the director of the new Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine is still pending. (See table.)

Hylton Joffe (current director of the Bone, Reproductive and Urologic Drug Products Division) and Lesley Furlong (deputy director of Office of Drug Eval-uation IV) had been assigned the leads in setting up the new office, abbreviat-ed as ORPURM. Joffe, however, is now on “detail” as the acting deputy direc-tor of OND (effective 3 December).

Julie Beitz – currently head of the Office of Drug Evaluation III and tran-sitioning to head of the new Office of Immunology and Inflammation – has been acting deputy of OND.

In most cases the leads assigned dur-ing the reorganization process have been confirmed as leaders of the new offices, with a handful of exceptions. For example, Ed Cox was leading the Office of Infectious Diseases reorgani-zation, but left the agency. Gideon Blu-menthal was the lead on OOD, but is retaining his role as deputy in the On-cology Center of Excellence (with OCE head Richard Pazdur as head of OOD simultaneously).

Division of Dermatology and Oph-thalmology Director Kendell Marcus had been working with ODE III Director Julie Beitz on the launch of the new Of-fice of Immunology and Inflammation. However, while Beitz has been con-firmed as OII Director, the deputy role is still pending.

Published online 2 December 2019

Committee chairman Sen. Lamar Al-exander, R-TN, said the full Senate will plan to vote on the nomination “be-fore the end of the year.”

Hahn has received broad support from external stakeholders for the top job at the FDA. Alexander noted dur-ing the vote that the committee re-ceived 13 letters representing nearly 80 organizations supporting Hahn’s nomination.

A letter signed by more than 40 or-ganizations, including the American Society of Clinical Oncology, the Ev-eryLife Foundation for Rare Diseases, and Friends of Cancer Research, stated that Hahn “is the right person to en-sure the FDA keeps pace with science and innovation without sacrificing the safety and efficacy gold standard es-tablished by the agency.”

“As chief medical executive at The University of Texas MD Anderson Cancer Center, he not only has the knowledge and experience gained by managing the cutting-edge research and medi-cal practices of one of the world’s most innovative teaching hospitals, but also firsthand expertise of patient needs and a deep understanding of the breadth of work that needs to be achieved on their behalf,” the letter states.

Hahn also won the endorsement of former FDA commissioners Scott Got-tlieb, Robert Califf, Margaret Hamburg, Andrew von Eschenbach and Mark Mc-Clellan in a letter to Senate leadership.

“We believe Dr. Hahn has the ex-perience and commitment to public health and public service needed to provide this leadership,” the former commissioners said.


CONTINUED FROM PAGE 1

LET’S GET SOCIAL

@PharmaPinksheet

“We are still on track

for the final phase

(Phase 4) to begin in

the February/March

2020 timeframe.”



U S F D A

ADAPTIVE CLINICAL TRIALS: US FDA Offers More Advice On Bayesian DesignsBRENDA SANDBURG [email protected]

T he US Food and Drug Administra-tion’s final guidance on adaptive clinical trial designs includes addi-

tional details on Bayesian design features and more flexibility in trial planning.

The guidance, Adaptive Designs for Clin-ical Trials of Drugs and Biologics, issued on 29 November, is nearly identical to the draft guidance published last year. How-ever, at the request of industry, the agency expanded the section on Bayesian designs and made other tweaks to the document.

The draft document issued in Septem-ber 2018 replaced a 2010 draft guidance. It provided examples of clinical trials with adaptive designs and more details on the

documentation needed for FDA evalua-tion of the adaptive design and completed trial. (Also see “Adaptive Clinical Trial De-signs: US FDA Provides Checklist To Begin Study” - Pink Sheet, 30 Sep, 2018.)

In comments on the new draft guid-ance, the Pharmaceutical Research and Manufacturers of America recommended that FDA provide additional guidance on the use of Bayesian adaptive designs, such as where the agency thinks the principles of Bayesian design approaches differ from other types of adaptive designs.

The final guidance states that in gen-eral, the same principles apply to Bayesian adaptive designs as to adaptive designs

without Bayesian feature. The agency added: “Trial designs that use Bayesian adaptive features may rely on frequentist or Bayesian inferential procedures to sup-port conclusions of drug effectiveness. Frequentist inference is characterized by hypothesis tests performed with known power and Type I error probabilities and is often used along with Bayesian compu-tational techniques that rely on non-infor-mative prior distributions.”

“Bayesian inference is characterized by drawing conclusions based directly on posterior probabilities that a drug is effec-tive and has important differences from frequentist inference,” the guidance states.

The New Offices Of The Office of New DrugsUS FDA has confirmed the leadership for each of the new offices within OND, with one notable exception: the agency says selection of the director of the new Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine is still pending.

OFFICE NAME OFFICE DIRECTOR DEPUTY DIRECTOR

Office of Program Operations (OPO) J. Paul Phillips (Acting) N/A

Office of Regulatory Operations (ORO) Jennifer Mercier (Acting) Pending Selection

OND Policy (ONDP) Keith Flanagan Maarika Kimbrell

Office of Drug Evaluation Sciences (ODES) Chris Leptak (Acting) N/A

Office of Therapeutic Biologics and Biosimilars (OTBB) Sarah Yim (Acting) Pending Selection

Office of Administrative Operations (OAO) Pending Selection Dwayne Keels (Acting)

Office of Infectious Diseases (OID) John Farley (Acting) Pending Selection

Office of Oncologic Diseases (OOD) Rick Pazdur (Acting) Marc Theoret (Acting)

Office of Neuroscience (ON) Billy Dunn (Acting) Pending Selection

Office of Nonprescription Drugs (ONPD) Terri Michele (Acting) Karen Mahoney (Acting)

Office of Specialty Medicine (OSM) Charles Ganley Pending Selection

Office of Cardiology, Hematology, Endocrinology and Nephrology (OCHEN) Ellis Unger Mary Thanh Hai

Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM) Pending Selection Pending Selection

Office of Immunology and Inflammation (OII) Julie Beitz Pending Selection

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





“For trials that use Bayesian inference with informative prior distributions, such as trials that explicitly borrow external information, Bayesian statistical properties are more in-formative than Type I error probability.”

The agency notes that its draft guidance “Interacting with the FDA on Complex In-novative Clinical Trial Designs,” issued in September, provides direction on what in-formation should be submitted to FDA to facilitate the review of trial design propos-als that use Bayesian inference.

The guidance also says that one common feature of many Bayesian adaptive designs is the use of simulations to estimate trial operating characteristics. Because many Bayesian methods themselves rely on ex-tensive computations, “trial simulations can be particularly resource-intensive for Bayesian adaptive designs,” it states.

ADAPTATIONS MAY DEVIATE FROM ANTICIPATED ALGORITHMThe guidance defines adaptive design as a clinical trial design that allows for pro-spectively planned modifications to one or more aspects of the design based on ac-cumulating data from subjects in the trial.

PhRMA also recommended that FDA re-vise the draft guidance to support greater flexibility related to the design, review, and acceptance of adaptive clinical trials, and the nature of allowable adaptations. For example, it said terms used in the guid-ance seem to suggest that adaptations should always follow a specific rigid nu-merical algorithm. PhRMA asked that the guidance make clear this is not required.

FDA added a paragraph that addresses this. “Although we recommend prespecifi-cation of the rules governing adaptations, monitoring committee recommendations might occasionally deviate from the an-ticipated algorithm based on the totality of

the data,” the guidance states. “If this type of flexibility is desired, the prespecified plan should acknowledge the possibility of deviations from the anticipated algorithm, outline factors that may lead to such devia-tions, and propose testing and estimation methods that do not rely on strict adher-ence to the algorithm.”

The agency said that when completely unforeseen circumstances arise, it recom-mends that the sponsor address any po-tential design changes with FDA as soon as possible.

NON-COMPARATIVE ANALYSISFDA added other clarifying sentences to the final guidance. In discussing the con-cept of non-comparative analysis, the document says, “it is possible to include adaptations based on a non-comparative analysis even in open-label trials, but en-suring that the adaptions are completely unaffected by knowledge of comparative data presents additional challenges.”

The agency also slightly modified the section on adaptations based on a poten-tial surrogate or intermediate endpoint. The guidance notes that most adaptive designs rely on ongoing monitoring of the primary endpoint or endpoints. However, in cases where a potential surrogate or intermediate endpoint exists that is corre-lated with the primary endpoint, and the primary endpoint itself is difficult or slow to ascertain, an adaptive design can be based on the potential surrogate or inter-mediate endpoint.

An adaptive design “could be based on a 2-month measurement of patient symp-toms when the primary endpoint is the as-sessment of the same symptom outcome at six months,” the final document states. The draft had specified a 3-month measure-ment and symptom outcome at one year.

REJECTED RECOMMENDATIONSFDA did not make several changes requested by industry. For example, PhRMA and the Biotechnology Innova-tion Organization had recommended that FDA revise the definition of “interim analysis” to be consistent with the Inter-national Council for Harmonisation of Technical Requirements for Pharmaceu-ticals for Human Use (ICH) E9, “Statistical Principles for Clinical Trials.”

FDA retained the definition in the draft guidance that an interim analysis “is any examination of data obtained from sub-jects in a trial while that trial is ongoing and is not restricted to cases in which there are formal between-group com-parisons.” It specifies that the observed data in the interim analysis can include one or more types, such as baseline data, safety outcome data, pharmacokinetic, pharmacodynamic or other biomarker data, or efficacy outcome data.

Vertex Pharmaceuticals Inc. requested that the agency provide greater clarity regarding the regulatory path prior to submission of a special protocol assess-ment (SPA) for a trial with a complex adaptive design, and whether particular aspects of the study would be expected to be agreed upon prior to submission.

The agency did not provide further in-formation in the section on interactions with FDA. Like the draft document, the final guidance recommends that SPAs for trials with complex adaptive designs only be submitted if there has been ex-tensive previous discussion between FDA and the sponsor regarding the pro-posed trial and design.

Comments on the final guidance are due by 2 January.


The guidance defines adaptive design as

a clinical trial design that allows for

prospectively planned modifications to one

or more aspects of the design based on

accumulating data from subjects in the trial.



EU Produces More Guidance For Upcoming Clinical Trials RegulationVIBHA SHARMA [email protected]

T he European Commission has is-sued a new draft template that sponsors can use to explain to

competent authorities their procedures for recruiting subjects to all types of clinical trials, including studies involving incapaci-tated adults and minors, and for obtaining informed consent.

The template has been developed to help sponsors seeking approval of stud-ies under the upcoming EU Clinical Trials Regulation (Regulation (EU) No. 536/2014), which is expected to take effect in 2020. However, it can also be used under the provisions of the existing EU Clinical Trials Directive (Directive 2001/20/EC) before the new regulation kicks in.

In addition, the commission has revised its existing draft guidance on the provi-sions of the CTR to clarify the circum-stances under which initial clinical trial applications, applications for substantial trial modifications and applications for the subsequent addition of a member state concerned may be authorized subject to certain conditions.

Also, an updated form has been pub-lished that sponsors can use to jointly re-quest a clinical trial authorization and an ethics committee opinion under the CTD.

RECRUITMENT & INFORMED CONSENT TEMPLATEThe EU Clinical Trials Expert Group has de-veloped a draft template that sponsors can use to describe their recruitment arrange-ments and/or informed consent proce-dures when seeking trial authorization un-der the CTR. While the template’s use is not mandatory, the commission expects spon-sors to include all the relevant information on recruitment and informed consent in the protocol, as a minimum.

This clarification is in line with the provi-sions of the CTR, which states the protocol should include a detailed description of the recruitment and informed consent proce-

dure, especially when subjects are incapa-ble of giving informed consent. In addition, the CTR requires that, unless described in the protocol, “a separate document should describe in detail the procedures for inclu-sion of subjects” and give a clear indication of the first recruitment action.

For information on the recruitment pro-cess, the template includes a section cov-ering all trials as well as separate sections for trials that would recruit incapacitated adults and minors. For informed consent procedures, there are separate sections

covering clinical trials where consent wit-nessed by an impartial witness will likely be used, trials in an emergency situation, and cluster trials.

CONDITIONAL TRIAL AUTHORIZATIONThe commission has also updated its questions & answers document to clarify, among other things, “what should be understood by conditions” within the context of the CTR, which allows an ini-tial clinical trial application, a substantial amendment or the addition of a member state concerned to be authorized subject to certain conditions.

The updated guideline states that such conditions would relate to an issue already identified in the “request for information” by member states assessing the clinical trial application. (Also see “EU Explains How Info Requests Will Be Managed Under Clinical Trials Regulation” - Pink Sheet, 11 Nov, 2019.) When all member states concerned are in agreement, conditions can be used to:

• Request additional data not available at the time of the authorization of the clinical trial, such as data needed for later parts of the trial that does not pre-vent the start of the trial.

• Indicate aspects that the sponsor needs to fulfil after authorization, such as submission of minutes of the safety data monitoring board meetings.

A clinical trial can be authorized subject to conditions only for issues that, by their nature, cannot be fulfilled at the time of authorization. The guideline also clarifies that the setting of conditions is only possi-ble in case of trial applications with a posi-tive benefit-risk balance. “This means that if the benefit-risk balance is not positive at the time of the authorisation, the applica-tion should be rejected,” it adds.

Published online 29 November 2019

An EU group

has developed

a draft template

that sponsors can

use to describe

their recruitment

arrangements and/

or informed consent

procedures.




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

EU Raises Pressure On Pharmaceutical Pollution Of The EnvironmentIAN SCHOFIELD [email protected]

T he EU’s Pharmaceutical Committee, an advisory group of experts in public health, is to set up a new group to look at how environmental considerations can best be taken into

account at various stages of the human pharmaceutical life cycle. Another EU body, the European Parliament’s environment and

public health committee (ENVI), has called on the EU member states and the European Commission to make clear what mea-sures they intend to take to reduce the risk posed to the environ-ment by pharmaceuticals.

The moves are part of efforts to progress the commission’s March 2019 communication on a “Strategic approach to phar-maceuticals in the environment,” which outlines the steps the EU needs to take to tackle the problem of pharmaceutical contami-nation of the environment.

In the communication, the commission said there was enough evidence to justify action being taken to reduce the contamination risk. This would need to involve all relevant stakeholders along the pharmaceutical life cycle, including member state authorities, in-dustry, health professionals, patients, farmers and the water indus-try. (Also see “EU Calls For Action To Reduce Environmental Impact Of Pharmaceuticals” - Pink Sheet, 12 Mar, 2019.)

THREE KEY PATHWAYSThere are three key pathways by which active pharmaceutical in-gredients (APIs) can have an environmental impact: normal human and animal excretion of medicinal products (accounting for about 90% of total emissions), waste water discharge from API manufac-turing plants, and improper disposal of unused or expired medi-

cines by consumers.The Pharmaceutical Committee met earlier this month to discuss

follow-up actions to the strategic approach, including the setting up of the ad hoc group. In a background note for the meeting, it said that the approach had six action areas:

• Increase awareness and promote the prudent use of phar-maceuticals, for example by promoting the development of guidelines for health professionals on the prudent use of medicines that can pose a threat to the environment.

• Reduce wastage and improve waste management. This could include optimizing pack sizes so medicines can be dispensed in quantities that better match patient needs, and safely extend-ing expiry dates so fewer medicines have to be thrown away.

• Support the development of pharmaceuticals that are intrinsi-cally less harmful for the environment, and promote “greener manufacturing.”

• Improve environmental risk assessment and review. This could be done, for example, by improving public access to risk as-sessment results and toxicological threshold for medicines.

• Expand environmental monitoring.

• Fill other knowledge gaps.

It said the ad hoc group would focus on sharing best practices on how environmental considerations are taken into account in the life cycle of human medicines, and could also produce guid-ance and recommendations in relation to the list of actions.

The outcome of the ad hoc group’s work will be “discussed and endorsed in the Pharmaceuticals Committee,” it said. With this is mind, it has asked member states to “present their views and in-form the Commission on their participation in this group” and their “willingness to take the leading role.”

It said the commission’s health directorate (DG SANTE) would help to start up the group’s work by arranging a first physical meet-ing, with follow-up meetings to be organized via teleconferences.

The matter is also on the agenda of the Pharmaceutical Commit-tee’s next meeting on 17 December.

TWO QUESTIONS AND A MOTIONMeanwhile, at its 2-3 December meeting, the ENVI committee considered a motion for a resolution on this issue, with a deadline for tabling amendments of 29 January 2019. It has also tabled two separate questions for oral answers in parliament about the next steps for the strategic approach.

One of them, aimed at the commission, asks: “What legislative




and non-legislative measures is the Commission intending to take in order to reduce the risk from pharmaceuticals in the envi-ronment? What is the timeline for those measures?”

The other one is intended for the Council of the EU (member state ministers): “What is the Council’s position concerning the strategic approach and the actions put forward by the Commis-sion? What legislative and non-legislative measures is the Council intending to support in order to reduce the risk from pharmaceu-ticals in the environment?”

The council mentioned the strategic approach at a meeting in June this year, when it highlighted the “growing evidence that specific pharmaceuticals and their residues found in the soil and water pose a risk to the environment and to human and animal health,” and the need for more research to better understand the extent of the risk.

OTHER PHARMACEUTICAL COMMITTEE ITEMSThe Pharmaceutical Committee will debate a number of other topical questions at its 17 December meeting, including the evalu-ation of the EU legislation on orphan and pediatric medicines, mar-ket failures in the antimicrobials area, updates from the EU/Orga-nization for Economic Cooperation and Development project on access to medicines, the hospital exemption for advanced therapy medicinal products, and enhancing oversight of the global manu-facturing and supply chain for APIs.

Members will also discuss the new ICH quality (Q12) guideline, which was adopted at a recent meeting in Singapore. (Also see “Dif-ferences Put Aside As ICH Finalizes Guide On Post Approval Changes” - Pink Sheet, 2 Dec, 2019.)


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

US FDA Mulls Pilot To Examine Separate Review Pathway For Novel Excipients JOANNE S. EGLOVITCH [email protected]

T he US Food and Drug Administration is seeking input on whether to launch a pilot program to evaluate the safety of novel excipients through an independent review process.

Industry proponents argue that such a process would spur de-velopment of much-needed novel excipients.

The agency made this announcement in a notice scheduled for publication on 5 December in the Federal Register.

The FDA only reviews novel excipients for safety as part of an investigational new drug application (IND), a new drug application (NDA), or a biologics license application (BLA).

The agency said that a separate review path for reviewing and approving those deemed novel excipients would “obviate the need for FDA review of the excipient” in the context of an IND, an NDA or a BLA.

The FDA expects that excipients reviewed and approved un-der this program, after they are used in approved formulations, would be listed in its Inactive Ingredient Database.

The agency said that stakeholders have been encouraging the agency to establish an independent review program for novel excipients. The notice said that “proponents of an FDA novel excipient review program believe FDA’s recognition of a novel excipient would reassure drug developers that the novel excipient can be used in a drug development program while minimizing the risk that safety concerns would be raised by FDA during application review.”

Proponents told the FDA that drug developers were averse to us-ing such novel excipients when they have not been approved for use in formulations, even if they have potential public health benefits.

The International Pharmaceutical Excipients Council (IPEC) has long advocated for establishing a separate and independent pathway for novel excipients outside of drug and biologics review processes, and made the case for the need for such a pathway at a 2015 June meeting with the FDA. (Also see “FDA Suggests Use of Biomarker Qualification Program as Possible Model for Approving Novel Excipients” - Pink Sheet, 25 Sep, 2015.) Such reviews would be supported by user fees.

At the meeting, the Innovation and Quality Consortium told the FDA that two thirds of manufacturers surveyed said they need more novel excipients to promote the development of innova-tive delivery systems, such as the oral absorption of peptides and proteins and the delivery of inhalation drugs, as well as to ensure peptide and protein stability and to prevent protein aggregation.

IPEC officials did not immediately respond to questions about the FDA’s novel excipients announcement.

The FDA said that if the agency decides to go forward, the pilot program would review a limited number of submissions.

The agency is seeking comments on the following:

• What drug development challenges do drug sponsors en-counter that could be addressed by using novel excipients?

• Can stakeholders identify examples (specific or general) of novel excipients that have potential public health benefits?

The deadline for public comment is 5 February. All submissions must refer for docket No. FDA-2019-N-5464.






US FDA Says Data Integrity Remains Challenging For API ManufacturersJOANNE S. EGLOVITCH [email protected]

M akers of active pharmaceutical ingredients need to work on improving the integrity of their

manufacturing data, if recent US Food and Drug Administration warning letters are any indication.

In recent years, FDA warning letters were more likely to cite data integrity issues if they went to API manufacturers than if they went to drug product manufacturers, according to data presented by Donald Ashley, director of the Office of Compli-ance in the FDA’s Center for Drug Evalua-tion and Research, on 5 November at the Association for Accessible Medicines’ GRx-Biosims meeting in North Bethesda, MD.

Ashley discussed other non-compliance trends in the API supply chain as well, such as inadequate testing for impurities and the obfuscation by API repackers of API suppliers’ identities.

DATA INTEGRITY TIP OF THE ICEBERG Ashley said that in the agency’s inspec-tions of API makers, data integrity breach-es are considered one of the “more serious problems” found by investigators.

When the agency finds data integrity problems, this is often the “tip of the ice-berg” and likely to mask other serious good manufacturing practice problems.

According to the FDA, data integrity de-ficiencies were noted in 40% of warning letters going to pharmaceutical manufac-turers of all types from fiscal year 2016 to FY 2019. (See chart.)

Yet data integrity is more of a pro-nounced problem for API manufacturers. Ashley reported that from FY 2015 to FY 2019, 72.5% of all warning letters to API manufacturers had data integrity viola-tions, compared to just 50% of warning letters to prescription drug manufacturers and 42.8% of warning letters to multiple drug manufacturers. Only 30% of warning letters to manufacturers of over-the-coun-

ter drugs addressed data integrity infrac-tions during this four-year period.

Ashley said that to ward off data integrity problems, manufacturers must ensure that all laboratory, analytical and quality data are complete, consistent and accurate.

The warning letter to solvent recycler Lantech Pharmaceuticals Ltd. in August 2019 was representative of some of the data integrity issues troubling the agency. (Also see “US FDA Warning Letter Draws In-dian Solvent Recycler Into Valsartan Crisis” - Pink Sheet, 16 Aug, 2019.)

The FDA said the firm “failed to imple-ment adequate controls to ensure the in-tegrity of data generated at your facility,” and the firm “admitted to routinely delet-ing recovered solvents gas chromatogra-phy data older than three months perma-nently, without any backup.”

The administrator also “had full access privileges to computerized systems, in-cluding editing, deleting, modifying data, and audit trails. Additionally, the firm ad-mitted to routinely deleting recovered sol-vents gas chromatography (GC) data older than three months permanently, without any backup.”

API REPACKERS CHASTISED FOR LACK OF TRANSPARENCY Ashley discussed another worrisome trend involving repackers of APIs to which agen-cy enforcement officials have been call-

ing attention in recent months. (Also see “US FDA Pressing Repackers To Disclose API Suppliers In Case Quality Issues Arise” - Pink Sheet, 25 Sep, 2019.) (Also see “First-Ever OTC Inspections Drove Surge Of FDA Warning Letters In FY 2019” - Pink Sheet, 5 Nov, 2019.) The problem is with companies that do not show customers the source of the APIs they repack. He said that “we have sent multiple warning letters to API repackag-ers and relabelers and have placed many of them on import alert for obfuscation of supply chain information.”

In the summer, the FDA issued three drug GMP warning letters to drug repack-agers of APIs for omitting the names of the original manufacturers of the API to cus-tomers, a common practice in the API sec-tor that the agency wants to stop. (Also see “FDA Warning Letters Hit Three Repackers For Failing To Identify Original API Makers“ - Pink Sheet, 3 Jul, 2019.)

He said that the most common scenario is of firms failing to obtain and retain docu-ments with the identity of the original manufacturer and the certificate of analy-sis. Another scenario is that APIs are being repackaged with an inadequate certificate of analysis as some companies are using their own data for the certificate of analysis instead of the original copy.

Ashley said that both scenarios “compro-mise supply chain accountability and visibil-ity and put patients at risk.” This is especially problematic where repackaged opioids are involved, he noted.

Ashley advised manufacturers to consult the International Council on Harmoniza-tion’s Q7 guideline on good business prac-tices for handling of APIs. It specifies that agents, brokers, distributors, repackers or relabelers should transfer all quality or regu-latory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or inter-mediate manufacturer.

ICH Q7 also says the agent, broker, trader,

Nearly three-quarters of

warning letters to API

manufacturers over the

last few years cited data

integrity issues.




distributor, repacker or relabeler who sup-plies the API or intermediate to the custom-er should provide the name of the original API or intermediate manufacturer and the batch numbers supplied.

THIRD TREND IS NOT TESTING FOR IMPURITIES Ashley said that another trend is inad-equate testing of APIs for the presence of impurities. He said impurities such as the ni-trosamines found in certain blood pressure medications and more recently the heart-burn medicine ranitidine have been the source of more than 50 major recalls and multiple warning letters and import alerts.

Manufacturers can control these risks by having a “good knowledge of their processes and by understanding the chemistry [of their ingredients] and us-ing risk assessments tools to understand what types of impurities may be present in their APIs.”

Ashley said manufacturers should con-sult the following ICH guidance docu-ments to better understand how to con-trol impurities:

• ICH Q3A Impurities in New Drug Substances

• ICH Q3B(R2) Impurities in New Drug Products

• ICH Q3C Impurities: Residual Solvents

• ICH Q3D Elemental Impurities

• ICH M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogens.


Data IntegrityWarning letters continued to raise data integrity concerns.

Distribution of data integrity warning letters by drug type, FY 2015-FY 2019.

FY = October 1 to September 30

Source: FDA

Intelligence with a Global Perspective

www.pharmaintelligence.informa.com

100

90

80

70

60

50

40

30

20

10

0FY2016 FY2017 FY2018 FY2019

YES NO

API

YES 58

NO 22 RX

YES 28 NO 33

OTCYES 38

NO 128

Multiple

YES 6NO 8




Differences Put Aside As ICH Finalizes Guide On Post Approval ChangesVIBHA SHARMA [email protected]

T he International Council for Harmonisation has finalized three key guidelines at its latest meeting in Singapore, in-cluding the highly-debated quality guideline (ICH Q12) on

lifecycle management of post approval changes.The other two guidelines that have been finalized are the ICH

E9(R1) addendum to defining the appropriate estimand for a clini-cal trial/sensitivity analyses, and the ICH M9 guideline on biophar-maceutics classification system-based biowaivers.

Both the ICH E9(R1) and M9 guidelines “represent important ar-eas of work,” said the ICH. The E9(R1) addendum aims to improve the planning, design, analysis and interpretation of clinical trials by providing a structured framework and harmonized standards on the choice of estimand. (Also see “ICH Consults On Harmonized Standards For Choosing Estimands In Clinical Trials” - Pink Sheet, 11 Sep, 2017.) The ICH M9 provides recommendations to support bio-pharmaceutics classification of medicinal products and waiver of bioequivalence studies. (Also see “M9 Biowaivers Guidance Nearly Harmonised During ICH Meeting” - Pink Sheet, 10 Jul, 2019.)

At the Singapore meeting, progress was also made on several new guideline topics such as adaptive clinical trials, with concept papers and business plans being finalized for them.

Q12 FINALIZATION ‘NOTEWORTHY’Regarding the Q12 guideline, the ICH said its finalization was “par-ticularly noteworthy.”

The Q12 guideline complements other ICH quality guidelines – Q8 through Q11 – and aims to promote innovation and continual improvement in the pharmaceutical sector, and to strengthen quality assurance and reliable product supply, including proactive planning of global supply chain adjustments, the ICH explained.

The journey to ICH Q12’s finalization has not been an easy one. The draft version was strongly criticized by the EU and US phar-maceutical industry earlier this year due to concerns about its in-compatibility with the established legal framework in certain ICH regions, including the EU. (Also see “Lack Of Harmonization In ICH Q12 Draft Guideline Draws Fire In US” - Pink Sheet, 11 Apr, 2019.)(Also see “EU Pharma Slams ICH Proposal For Selective Adoption Of Quality Guideline” - Pink Sheet, 9 Jan, 2019.)

Specifically, the industry had complained that the lack of a glob-al framework for some core concepts of ICH Q12, like “established conditions” and “product lifecycle management,” could result in different regional regulatory interpretations, thus posing a risk of divergence across countries.

The European Commission had also raised legal objections

relating to the Q12 guideline because of its possible impact on variation-related fees received by national competent authorities (NCAs) in EU member states. As Q12 foresees a substantial reduc-tion in variation-related workload, this would have affected the income received by NCAs for processing variation applications on behalf of the European Medicines Agency. (Also see “EMA Fee Revisions Expected To Resolve EC’s Objections To ICH Q12 Guide-line” - Pink Sheet, 2 Oct, 2019.) A way forward was found when the European Commission announced plans to review the EMA’s fee system. (Also see “Keep It Simple: EU Consults On Future Design Of EMA’s Fee System” - Pink Sheet, 19 Sep, 2019.)

ADAPTIVE TRIALS AND OTHER GUIDESThe ICH assembly also adopted finalized concept papers and busi-ness plans relating to several new ICH guideline topics:

• E20 Adaptive Clinical Trials - Although the EU and US authori-ties have issued a reflection paper and draft guidance for adaptive clinical trials respectively, these advisory documents are not fully harmonized. For example, there are differences in terminology and in principles for the design, conduct, analysis and interpretation of adaptive clinical trials. The ICH E20 guideline, which is expected to take around three or four years to complete,, would address these differences, and its primary focus would be on confirmatory clinical trials.

• E6(R3) Good Clinical Practice (GCP) - The guideline would address the application of GCP principles to the increasingly diverse trial types and the data sources being employed to support regulatory and health care related decision-making on drugs. It would provide flexibility, whenever appropriate, to facilitate the use of technological innovations in clinical trials. When complete, E6(R3) will be composed of an overarching principles and objectives document, Annex 1 (interventional clinical trials), and Annex 2 (additional considerations for non-traditional interventional clinical trials). The overarching




principles and objectives document and Annex 1 will replace the current E6(R2).

• E2D(R1) Post Approval Safety Data Management: Defini-tion and Standards for Expedited Reporting – This initiative involves revisiting the definitions and standards for the management of post approval safety information in order to support appropriate safety surveillance and actions.

• Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin – The ICH wants to revise its existing Q5A(R1) guideline to reflect new biotechnology product types, as well as advances in manufacturing technology, analytical methods for virus testing and scientific knowledge that have occurred since publication of the original document in 1999. The revised guideline is expected to be finalized by November 2022.

• S12 Nonclinical Biodistribution Studies for Gene Therapy Products – Existing guidelines issued by various regula-tory authorities contain different expectations on the biodistribution (BD) assessment of gene therapy products, which creates a challenge for both regulators and indus-try. The ICH guideline would provide harmonized advice on a number of issues, including the definition of BD, the need for and timing of BD studies, BD study design com-ponents, assay methodologies for assessing BD, what BD data is required to justify the selection of most relevant species for nonclinical pharmacology and safety studies, and interpretation of BD data to help inform aspects of clinical trial design.

• M12 Drug Interaction Studies – There is lack of harmonization among regulators on what drug-drug interaction (DDI) stud-ies are required. This could result in additional studies being undertaken by companies and different clinical interpretations across regulatory agencies. The ICH guideline would result in harmonized advice on in vitro and clinical DDI study require-ments, design considerations and interpretation of the find-ings. The new guideline is expected to be finalized by 2023.

THREE MORE ICH GUIDELINESThe ICH assembly also approved “concept paper outlines” for two other guidelines, which received in principle support at the last ICH biannual meeting in June 2019. These related to ICH M13 on bioequivalence for immediate-release solid oral dosage forms, and the revision of the ICH Q9 guideline on quality risk management.

In addition, a working group is being established to initiate work on a new document to be added to the ICH Q3 series of guidelines that deal with impurities in drug substances. The new document, ICH Q3E, would deal with the assessment and control of extract-ables and leachables for pharmaceuticals and biologics.

The ICH assembly took stock of these guidance documents at its meeting in Singapore, which took place from 16 to 20 Novem-ber. Also at the meeting, representatives from Brazil’s ANVISA were elected to the ICH management committee. (Also see “Brazilian Regulator Wins Place On ICH Management Committee” - Pink Sheet, 21 Nov, 2019.)

The next ICH meeting is due to take place from 23 to 27 May 2020, in Vancouver, Canada.


A Year Of Reconsiderations For US FDA Advisory Committees MICHAEL MCCAUGHAN [email protected]

T he US Food & Drug Administration will be convening an advisory com-mittee to review Correvio Pharma

Corp.’s anit-arrhythmic drug vernakalant in December – a dozen years after the Cardio-vascular & Renal Drugs Advisory Committee first considered the product for approval.

That 2007 meeting ended in a vote in favor of approval of the IV therapy for conversion of atrial fibrillation to normal sinus rhythm. The FDA, however, ended up rejecting the application – due to safety concerns, including potential signals of pro-

arrhythmic effects. That decision came in 2008, when FDA still issued “approvable” let-ters, making it seem possible that the drug would reach the market relatively soon.

That didn’t happen, obviously. At the time, the drug – developed by Correvio’s predecessor company Cardiome Pharma Corp. – was licensed to Astellas Pharma Inc. Despite the setback at the FDA, Mer-ck & Co. Inc. stepped in in 2009 to license global rights to therapy, and then assumed US rights as well when Astellas gave up on the project after a patient death led to a

clinical hold. Merck in turn gave up on the drug in 2012.

In the meantime, though, vernakalant was approved in Europe under the trade name Brinavess. And now the FDA is ask-ing the Cardio-Renal panel to meet on 10

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





Lynparza, Keytruda Supplemental Indications Face US FDA Panel ReviewSUE SUTTER [email protected]

The US Food and Drug Administra-tion will close out 2019 with a two-day Oncologic Drugs Advisory

Committee meeting encompassing four applications – two for supplemental indi-cations and two original submissions – in mid-December.

On the morning of 17 December, ODAC will discuss the addition of a pancreatic cancer indication for AstraZeneca PLC and Merck & Co. Inc.’s PARP inhibitor Lynparza (olaparib). In the afternoon, the panel will take up Merck’s supplemental biologics license application for use of the PD-1 in-hibitor Keytruda (pembrolizumab) in non-muscle invasive bladder cancer, according to a Federal Register notice that will publish on 4 December.

The meeting marks the first visit to ODAC for Keytruda, initially approved in 2014.

The agency said it was unable to pub-lish notice of the 17 December meeting at least 15 days ahead of time “due to techni-cal issues.”

“Because the agency believes there is a need to bring these issues to public discussion and qualified members of the committee were available at this time and already scheduled to participate in the meeting, the agency concluded that

it was in the public interest to hold this meeting without the customary 15-day public notice,” the notice states.

ODAC will kick off its 18 December meeting with Celgene Corp.’s (now Bristol-Myers Squibb Co.) BLA for luspatercept in myelodysplastic syndromes, followed by Epizyme Inc.’s NDA for tazemetostat in epithelioid sarcoma, according to a Federal Register notice that will publish 3 December.

The busy year-end schedule will more than double ODAC’s workload for prod-uct-specific reviews during the first 11 months of 2019.

The panel has weighed in on only three drug applications so far this year: Karyo-pharm Therapeutics Inc.’s Xpovio (selinex-or) for multiple myeloma; Daiichi Sankyo Co. Ltd.’s Turalio (pexidartinib) for symp-tomatic tenosynovial giant cell tumor;

Dec. to review what is technically a resub-mission of the NDA for the drug.

It is in many ways an apt way for the FDA to wrap up the year, given the preponderance of advisory commit-tee meetings in 2019 that amounted to second-chances for panels to opine on applications that had been considered years earlier.

Most recently, the Endocrinologic & Metabolic Drugs Advisory Committee voted in favor of a cardiovascular out-comes claim for Amarin’s fish-oil derived Vascepa triglyceride therapy – six years after rejecting a claim based on triglycer-ide data alone. (Also see “Amarin’s Vascepa Positioned For Broad CV Risk Reduction Claim Following US FDA Panel Nod” - Pink Sheet, 14 Nov, 2019.)

Earlier in the year, the Pulmonary Allergy Drugs Advisory Committee revisited a dif-ferent 2013 review, for the inhaled cystic fibrosis therapy Bronchitol (mannitol). (Also see “Bronchitol Gets Narrow Approval Vote From Advisory Cmte., Leaving US FDA Host Of Issues To Consider” - Pink Sheet, 8 May, 2019.)

The Bone, Reproductive & Urologic Drugs Advisory Committee also held a re-review of sorts when it met to discuss the continued marketing status of AMAG Pharmaceuticals Inc.’s Makena. Thirteen years after initially considering the applica-tion, the panel voted that it no longer sees substantial evidence of efficacy for the pre-term labor therapy. (Also see “Makena With-drawal Dilemma: Advisory Cmte. Split Offers No Clear Direction For US FDA” - Pink Sheet, 29 Oct, 2019.)

But none of those meetings comes close to the longest gap between discus-sions of the same topic by the same com-mittee during 2019. That honor goes to Antimicrobial Drugs Advisory Committee, which met April to discuss the continued marketing status of injectable bacitracin. The committee voted that the approved indication should be withdrawn – just as it did 35 years ago when it met to consider the DESI status of the product in 1984. (Also see “Injectable Bacitracin’s Lone Indication Should Be Revoked, US FDA Panel Says” - Pink Sheet, 28 Apr, 2019.)


The meeting marks

the first visit to ODAC

for Keytruda, initially

approved in 2014.




and Daiichi’s quizartinib for acute myeloid leukemia. (Also see “Karyopharm Selinexor Approval Likely Awaits BOSTON Trial, But US FDA Promises To Move Quickly” - Pink Sheet, 26 Feb, 2019.) (Also see “Quizartinib Looks Like A Good Drug, ODAC Says, But Needs Another Efficacy Trial Before Approval” - Pink Sheet, 14 May, 2019.)(Also see “Dai-ichi’s Pexidartinib: Potential Patient Impact Drives Advisory Cmte. Recommendation” - Pink Sheet, 14 May, 2019.)

Xpovio received accelerated approval, Turalio won regular approval, and quizar-tinib garnered a complete response letter.

LYNPARZA SHOWS BENEFIT ON PFS BUT NOT OSAstraZeneca and Merck are seeking a new indication for Lynparza tablets for mainte-nance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated metastatic adenocarcinoma of the pancreas whose disease has not pro-gressed on first-line platinum-based thera-py. Olaparib currently is approved for ovar-ian and breast cancer indications.

The sNDA for pancreatic cancer was sub-mitted in June and received a priority re-view, with a December user fee goal date. The application is based on results from the 154-patient Phase III POLO trial that evalu-ated olaparib 300mg tablets twice daily versus placebo as a first-line maintenance monotherapy for patients with gBRCAm metastatic adenocarcinoma of the pancreas.

The results, which were presented at the American Society of Clinical Oncology an-nual meeting in June and published in the New England Journal of Medicine, showed a near doubling in progression-free surviv-al with olaparib. (Also see “AZ/Merck & Co’s Lynparza POLO Study ‘Practice Changing’ For Pancreatic Cancer Subgroup“ - Scrip, 3 Jun, 2019.) There was a statistically sig-nificant 3.6-month improvement in pro-gression-free survival, with a median of 7.4 months for olaparib compared to 3.8 months for placebo (HR 0.53 [95% CI 0.35-0.82], p=0.004).

More than twice as many Lynparza-treated patients showed no disease pro-gression at one year (34% vs. 15%) and two years (22% vs. 10%) compared to the placebo group.

An interim analysis of overall survival, at a data maturity of 46%, showed no dif-ference between the olaparib and pla-cebo groups (median 18.9 months vs. 18.1 months), according to the NEJM publi-cation. There also was no significant be-tween-group difference in health-related quality of life.

The incidence of grade 3 or higher ad-verse events was 40% in the olaparib group and 23% in the placebo group.

KEYTRUDA PURSUES ANOTHER BLADDER CANCER CLAIMMerck also is seeking approval of Keytruda for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ with or with-out papillary tumors who are ineligible for or have elected not to undergo cystectomy.

The sBLA is undergoing priority review with a January target action date, Merck said.

The filing is based on results from KEY-NOTE-057, a Phase II, single-arm study of 103 patients. The data were first presented at the European Society for Medical Oncol-ogy 2018 Congress.

Patients received Keytruda 200mg every three weeks until unacceptable toxicity, per-sistent or recurrent high-risk NMIBC or pro-gressive disease. An interim analysis of the study’s primary endpoint showed a com-plete response rate of 38.8% at three months with Keytruda. Among the 40 patients who achieved complete response, 80.2% had a

CR duration of at least six months.Grade 3/4 treatment-related AEs oc-

curred in 13 (12.6%) patients; one death was considered treatment-related, and immune-mediated AEs occurred in 19 (18.4%) patients.

In May 2017 Keytruda received acceler-ated approval for treatment of patients with metastatic urothelial cancer (mUC) who are not eligible for cisplatin-contain-ing chemotherapy.

However, in June 2018 the FDA narrowed this indication based on findings of lower survival associated with use of Keytruda monotherapy compared with platinum chemotherapy in previously untreated mUC patients with low expression of the PD-L1 biomarker. The accelerated approval indi-cation currently is limited to mUC patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. (Also see “US FDA Fine-Tunes Tecentriq, Keytruda First-Line Blad-der Cancer Accelerated Approval Indications” - Pink Sheet, 21 Jun, 2018.)

Keytruda also holds regular approval for mUC patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

CELGENE EYES SECOND INDICATION FOR REBLOZYLODAC will review Celgene and Acceleron Pharma Inc.’s Reblozyl (luspatercept–aamt) for myelodysplastic syndromes (MDS) ane-mia just a little over a month after the ery-throid maturation agent received approval for beta-thalassemia-associated anemia. (Also see “Keeping Track: Biosimilars, Novel Ap-provals, And Ebola” - Pink Sheet, 10 Nov, 2019.)

The application seeks approval for treat-ment of adults with very low- to intermedi-ate-risk MDS-associated anemia who have ring sideroblasts and require red blood cell transfusions.

Celgene submitted the original applica-tions for the MDS and beta-thalassemia in-dications in April 2019. The latter received a priority review and was approved 8 No-vember. The MDS indication, which is the

The MDS application is

based on data from the

229-patient MEDALIST

trial, in which 37.9% of

patients treated with

luspatercept achieved

transfusion independence

versus 13.2% on placebo.




larger of the two markets, is undergoing a standard review, with a user fee date in April 2020.

The MDS filing is based on data from the 229-patient MEDALIST trial, in which 37.9% of patients treated with luspater-cept achieved transfusion independence versus 13.2% on placebo.

On the secondary endpoint of hema-tologic improvement-erythroid (HI-E), the response rate was 52.9% for luspatercept versus 11.8% for placebo. (Also see “’Totality Of Data’ Make A Case For Luspatercept In Beta-Thalassemia, MDS” - Scrip, 3 Dec, 2018.)

Treatment-emergent adverse events were balanced between the arms. Progres-sion to acute myeloid leukemia occurred in four patients (2.0%) in the luspatercept arm and one (1.3%) in the placebo arm.

EPIZYME TAKES ACCELERATED APPROVAL PATHEpizyme will seek to convince ODAC that the limited available data justify acceler-ated approval of tazemetostat as the first

drug to treat epithelioid sarcoma.The sponsor is seeking approval of the

first-in-class EZH2 inhibitor for patients with metastatic or locally advanced epi-thelioid sarcoma not eligible for curative surgery. (Also see “Keeping Track: A Busy Week For Regenerative Medicine, A Surprise Priority Review For Vascepa, And Tazemeto-stat Aims For Accelerated Approval” - Pink Sheet, 1 Jun, 2019.) The NDA was submit-ted in May and received a priority review, with a 23 January user fee date.

The filing is based on data from 62 patients enrolled in the epithelioid sarcoma cohort of an open-label, single-arm, Phase II trial.

The fully enrolled cohort included 24 treatment-naive patients and 38 relapsed/refractory patients, who were administered 800mg of tazemetostat orally twice daily. As of a September 2018 data cutoff, a total of 15% of patients achieved an objective re-sponse, with a disease control rate of 26%.

The majority of treatment-emergent ad-verse events were grade 1 or 2, with only 13% of patients experiencing grade 3 or

higher treatment-related AEs.Nevertheless, safety concerns could

come into play at the advisory commit-tee review. Tazemetostat was the subject to a partial clinical hold in 2018 following a safety report of a pediatric patient de-veloping a secondary T-cell lymphoblastic lymphoma; the hold subsequently was lifted. (Also see “Tazemetostat Setbacks Hit Epizyme“ - Scrip, 3 Aug, 2018.)

To support full approval, Epizyme plans to conduct global confirmatory trial in the front-line treatment setting comparing tazemetostat in combination with doxo-rubicin versus placebo plus doxorubicin in approximately 150 patients. The primary efficacy endpoint will be progression-free survival, and secondary efficacy endpoints will include overall survival, disease control rate, overall response rate and duration of response. The confirmatory study will in-clude a safety run-in that is expected to begin in the second half of 2019.


REAL-WORLD DATABASE STUDIES: Prepare For A Long Journey, IQVIA Advises BRIDGET SILVERMAN [email protected]

“R eal-world database studies are a long journey,” IQVIA Real World Solutions UK associate principal Paola Nasuti ob-served in an interview with the Pink Sheet.

“The data sciences have evolved over time,” she observed, re-flecting the “constant evolution in the way we access data, the way we analyze them, the way we conduct the studies.” Ten years ago, “we were analyzing claims data, reimbursement data,” she observed. Today “we are conducting external comparator stud-ies. We are using these data in more novel ways.”

With the multiplicity of data available, it is “very important to use the right methods,” Nasuti said, and to “answer specific re-search questions with a high degree of rigor.”

Nasuti is an author of a recent white paper from IQVIA, “Real World Database Studies: Eight Key Steps To Success.” The con-sultants take a regulatory science approach, focusing on the process and precepts that should produce retrospective data-base studies with “robust, reliable results.” (See graphic, p. 17.)

IQVIA is a key participant in efforts to incorporate real-world

data (RWD) and real-world evidence (RWE) into regulatory de-cision-making. Company researchers are working with the US Food and Drug Administration, the European Medicines Agency and many initiatives “to improve the way we conduct studies, to improve the transparency around how these studies are con-ducted, the methods we used, and the way we report the find-ings in the public domain,” Nasuti noted.

“It’s still a work in progress,” she commented.The 21st Century Cures Act directs the FDA to develop policy

on use of RWE in regulatory decision-making – an ambitious


“ We need to be mindful that we

cannot make the database studies

too complex, too much something

like clinical trials.”




regulatory science initiative that includes an effort to replicate clinical trials using RWD from claims data along with multi-pronged efforts to work through standards and processes with stakeholders.

The agency released a framework for assessing RWE for ef-fectiveness in December 2018, but draft guidance is not ex-pected until December 2021. (Also see “Real-World Evidence: US FDA Framework Emphasizes Data Fitness And Study Quality” - Pink Sheet, 9 Dec, 2018.)

The framework is particularly hesitant about the utility of retrospective observational studies using RWD. The FDA not-ed that the literature offers some examples where observa-tional and randomized trials reached similar conclusions, but weighed them against countervailing examples “when effects identified in observational studies could not be reproduced in randomized trials or when the effect sizes differed in direc-tion or magnitude.” (Also see “US FDA Is Hesitant About Using Observational Studies In Real-World Evidence Framework“ - Pink Sheet, 6 Dec, 2018.)

Some themes have already arisen in the limited FDA experi-ence with RWE that align with the recommendations of the IQVIA white paper. At a recent meeting on RWE hosted by the Friends of Cancer Research and Alexandria Real Estate Equities, Aetion pres-ident and chief scientific officer Jeremy Rassen identified data is-sues as a major stumbling block to adoption of RWE.

“If you read the reviews, a lot of the criticisms are about the data or the generalizability of the populations – missing data, selection bias, things like that – but also about the way that the data are analyzed,” Rassen observed. “These issues are re-ally important to work through.” (Also see “Real-World Evidence: Sponsors Look To US FDA Drug Reviews For Potential Pitfalls” - Pink Sheet, 7 Oct, 2019.)

NOT A CLINICAL TRIAL “We need to be mindful that we cannot make the database stud-ies too complex, too much something like clinical trials,” Nasuti said. “We should not overcomplicate the objective of the study, which is to improve the quality of drug development.” That goal “is not going to be met if these studies become too complex.”

Real-world database studies “need to be different from clini-cal trials,” she said. “The key objective is to re-use data that are already collected for other purposes,” like medical claims and pharmacy records.

In fact, the “growing access to different types of data sources” is one of the biggest challenges facing the RWD field, she said.

“We have more and exciting new types of data,” she said. “I think the challenge is to make sure that we understand the data we are using.” She pointed out that diagnostic and drug use codes often differ between locations.

“That’s why we highlight in the white paper the right collabo-ration with the right partner,” she said.

Nasuti highlighted I-O Optimise, a multinational real-world research initiative in lung cancer, as an example. It’s an “innova-tive study leveraging multiple, different real-world data sources and involving multi-disciplinary teams of experts across Eu-rope” that was described in a March 2019 paper by Simon Ek-man, Karolinksa University Hospital, Sweden, et al. published in Future Medicine.

“The research objectives of this program span from epide-miology, standard of care, safety, patient-reported outcomes to exploring health-related quality of life of patients with lung cancer,” she reported.

I-O Optimise is a collaboration between Bristol-Myers Squibb Co., IQVIA, and real-world data source (RWDS) owners. An external scientific committee comprised of a multidisci-plinary team of experts, including clinicians/oncologists, epi-demiologists, health economists and RWDS owners, “provide continuous insights and guidance on the latest medical and epidemiologic knowledge, to ensure deployment of the most rigorous methodological approaches during data analyses and to ensure that research outputs are independently veri-fied,” the Future Medicine article explained.

I-O Optimise had considered a total of 594 RWDS for inclusion

RETROSPECTIVE STUDIES: 8 KEY STEPS

1. Define the study objectives

3. Develop the protocol

5. Build the statistical analysis plan (SAP)

7. Conduct the analyses

2. Identify the data source(s)

4. Apply for ethics approval

6. Extract the data

8. Report the results

RETROSPECTIVE STUDIES: 8 KEY STEPS




by the October 2018 cut-off date for the article; 173 made it to the shortlist. Only 36 were selected for initial assessment, and only 12 were selected for full assessment. Reasons for exclusion included lack of continuous data collection, overlap with other data sources, limited sample size, unsuitable database structure or content, and refusal to participate.

“It was, and continues to be, important to acknowledge the challenges that could be faced when conducting analyses across these RWDS,” Ekman et al. concluded. “Indeed, some of the main concerns related to the conduct of multi-data source initiatives appear to be related to incomplete/missing data and methodological differences.”

The authors look outside oncology for another example, pointing to the “recently established Real world Outcomes across the Alzheimer’s Disease spectrum for better care: Multi-modal data Access Platform (ROADMAP) initiative, designed to optimize real-world data generation in Alzheimer’s disease,” where “a noted challenge is the lack of standardized outcomes across the different data sources.”

THE IMPORTANCE OF A GOOD FOUNDATION “The first important step is to understand the rationale for con-ducting the study,” the IQVIA white paper advises. “The study objectives should be clearly defined and documented in scien-tific prose as a hypothesis that can be tested or proven, with a description of how this might be achieved through an epide-miologic study.”

“It is important to bear in mind that if the detail contained in the objectives is insufficient, the detail contained in the meth-odology will be equally insufficient, leaving the project vulner-able in terms of the overall strategy,” the white paper says.

The next step, assessment of the suitability of a RWDS for a study, “calls for both knowledge of the database and a clear vision of the study design, data components and operational requirements,” the paper states.

“Before selecting a database, the team should give careful consideration to the diverse and heterogenous nature of RWD and uniqueness in both the content (e.g., parameters available, diagnositic coding) and context of the source (e.g. healthcare setting, purpose of data collection, geographic representati-tiveness, duration of patient enrollment in the database).”

“Consulting a database expert who has a deep understand-ing of the sources can inform this process and help to place the database within the context of the heathare environment,” the paper advises.

With rationale and data sources established, a study protocol can be designed, “built on formal epidemiological principles.”

ALL RWD IS LOCAL The fourth step, applying for ethics approval, “can be a lengthy process,” the white paper cautions. Different countries have dif-ferent ethical requirements for retrospective database studies, so “it is important to consider any local rules and regulations.” Local representation is necessary for multidisciplinary teams designing and overseeing RWD studies.

The next steps on the IQVIA matrix, build the statistical analy-sis plan (SAP) and extract the data, turn to specialists with local or specific knowledge. The SAP “should be written by an expe-rienced statistician who is familiar with the database,” the white paper says. “A data preparation plan should be created, provid-ing an unambiguous set of instructions to the programming team to operationalize the study objectives.”

Data extraction should then be “executed by a database ex-pert with sufficient knowledge of the structure, content and context of the database as well as a solid understanding of the healthcare system from which the data is derived.”

Analysis of RWD studies is typically “faster than clinical trials,” Nasuti commented. The white paper suggests a range “between a few weeks and a few months in most cases.” Nonetheless, “each step in a retrospective database study can take consider-able time.”

The white paper repeatedly emphasizes the range of exper-tise needed to analyze and report real-world database studies. “The reporting of real-world studies requires various skillsets and should be based on feedback from a multi-disciplinary team of data scientists,” the white paper says.

The research team should have “a deep understanding of the content (e.g., parameters available, diagnostic codes used) and context (e.g., local healthcare setting, purpose of data collec-tion) of the data source,” IQVIA wrote. “Especially in the case of multi-country, multi-database studies, database experts with country-specific experience should also be involved to ensure correct interpretation of differences across geographies.”

INVEST IN PLANNING TIME The IQVIA white paper responds to the need for “rigorous meth-ods” in the burgeoning RWD and RWE fields, Nasuti indicated.

Given the emphasis on planning in the eight-step rubric de-vised by IQVIA, it is not surprising that Nasuti identified as a key challenge for the field as the need “to make sure that before conducting any kind of database studies we allow enough time for planning.”

“Data are not always accessible,” she cautioned. In Europe es-pecially, countries have imposed restrictions on how healthcare data can be used. “These require a lot of time, a lot of planning.” The work of multidisciplinary RWD study teams starts “well in advance” of a study.


An IQVIA white paper repeatedly

emphasizes the range of expertise

needed to analyze and report real-

world database studies.


D R U G P R I C I N G

Concerns Emerge Over England’s Desire For Even Lower Drug Prices LEELA BARHAM [email protected]

T he commercial framework that England’s National Health Service has proposed to help the NHS strike deals with companies signals a desire by the NHS to drive drug prices

down even further, according to industry sources.“It’s now clearly in the public domain, for those who didn’t know,

that NHS England want to get companies to price below the cost-effectiveness threshold,” said one industry insider.

The insider, who was part of the negotiations on the UK’s 2019 Voluntary Scheme for Branded Medicines Pricing and Access (VPAS), said that the framework would also not allow companies to hold NHS England to account.

A similar stance was taken by market access consultant Tim Richardson, who said the framework showed NHS England to be “a hard bargainer.”

A second industry insider, who works at a top five pharma com-pany and has almost 30 years of experience in selling to the NHS, sees little value in the framework, saying: “It’s a tick-box exercise.”

These sentiments are in contrast with official lines welcoming the framework from the UK pharmaceutical industry body, the ABPI, and other key parties to the VPAS, under which the commer-cial framework is a deliverable.

The VPAS, which came into effect in January this year, has been agreed by the UK government, NHS England and the ABPI, and provides a framework for managing branded medicines spend. (Also see “Metrics For Measuring UK Pricing Scheme Success: Good Start But More Work Needed” - Pink Sheet, 28 Oct, 2019.)

BUILDING ON LESSONS LEARNEDThe NHS’s commercial framework was launched for public consul-tation on 1 November, with a 10 January 2020 deadline for com-ments. (Also see “Fair Pricing A Key Feature Of NHS England Drug Funding Proposals” - Pink Sheet, 11 Nov, 2019.)

According to the 33-page consultation document, the frame-work promises to deliver faster market entry and support for up-take and adoption – but only for medicines that are deemed to be priced fairly and responsibly.

NHS England also expects companies to agree to prices that are lower than those that achieve the UK’s cost-effectiveness threshold of between £20,000 to £30,000 cost per quality adjusted life year (QALY).

According to the commercial medicines director for NHS Eng-land, Blake Dark, there are no new proposals in the new frame-work, “but it is a guide on how best to work fairly with the NHS.”

The framework builds on lessons from deals already struck for Biogen’s Spinraza (nusinersen) for spinal muscular atrophy, Roche’s Hemlibra (emicizumab) for hemophilia, and Vertex Pharmaceuticals’ Orkambi (lumacaftor/ivacaftor) and Symkevi (tezacaftor/ivacaftor) for cystic fibrosis. (Also see “UK Rare Dis-

ease Drug Review Reform Urged As Spin-raza Finally Gets NICE OK” - Pink Sheet, 16 May, 2019.) (Also see “At Last: Vertex Strikes CF Deal In England” - Pink Sheet, 24 Oct, 2019.)

GREATER CLARITY BUT NO NEW OPPORTUNITIESAccording to consultant Richardson, there is value in having all op-tions set out. “It is useful to have it all in one place, it’s still a bit of a minefield to find your way around NICE [National Institute for Health and Care Excellence] and NHS England processes,” said Rich-ardson, who is managing director at Pharma Access to Health.

However, he sees no real new opportunities in the framework, which he describes as “strikingly underwhelming. It just reinforces what has always been said, companies should go and talk to NICE and NHS England.”

The first industry insider, who wished to remain anonymous, sees a missed opportunity for industry in having NHS England write the framework. “From an industry perspective, it was a miss not to have the framework in the VPAS itself. A commitment for NHS England to write it later, that was a loss for industry.”

The second insider, who also wished to remain anonymous, claims that because NHS England wrote the document it was inevi-table that the framework would not allow companies to hold NHS England to account. “NHS England don’t want a process that would hold them to account. If you can’t agree, then where do you go?”

By contrast, Leslie Galloway, chairman of the Ethical Medicines Industry Group, believes that the framework brings some clarity and “provides the clearest route to commissioning to date.”

For Galloway, the fact that the framework emphasizes the need to engage is useful because “it suggests a degree of flexibility de-pending upon the relationship that companies are willing to de-velop with NHS England.”

The ABPI too has welcomed the framework’s publication and has signalled that it will keep working with NHS England. “We look forward to taking part in the engagement process to ensure that the framework meets the needs of all stakeholders includ-ing patients, NHSE, NICE and industry,” it said on its website. The association did not respond to a request from the Pink Sheet for further comment.

NHS ENGLAND WILL DRIVE A HARD BARGAINAs well as being unimpressed with the commercial framework, the second industry insider expressed disappointment over the wider VPAS deal. “The whole idea is that if you [as the company] give NHS England additional value – with a price that would get below £20,000 per QALY – then NHS England will give you flexibil-ity.” There is frustration with that as the starting point: “it’s not at





the low end of the cost-effectiveness threshold that you need the flexibility, it’s at the high end.”

Meanwhile, the first insider argues that the commercial frame-work is making it clearer that NHS England is pushing for bargain prices and that NHS England wants to get companies to “price be-low the cost-effectiveness threshold.”

CHANGES TO THE COST PER QALY?According to this industry source, the push for lower prices is

a direct result of empirical work that has estimated that the cost per QALY threshold should be closer to £15,000, rather than the £20,000 to £30,000 used for treatments for common diseases. “There has been a plan brewing for a long time to get to around £15,000 per QALY as a result of Karl Claxton’s work.”

Claxton, professor of economics at the University of York and one of the authors of that empirical work, supports the direction that the framework is taking. According to Claxton, “NHS England push-

ing for a better deal, one that gets below the current threshold, is strongly supported by existing evidence of the health effects of NHS expenditure. There is harm being done to NHS patients when the NHS is paying too much for drugs.”

That argument is presumably a reason why industry has not been able to convince the UK government to raise the threshold, and sug-gests that even keeping it the same is a win from its perspective.

POOR SIGNAL TO INDUSTRYAnother frustration, according to the first industry insider, is the

mixed signals coming from the government, which acknowledges that “the medicines bill is underwritten by industry” but is “attack-ing us even further. It’s sending a poor message to boards. There is no link between the ambitions to support the life sciences industry and the commercial environment.”


EU Needs More Teamwork On Drug Pricing & AccessIAN SCHOFIELD [email protected]

T he European Commission is step-ping up its efforts to improve ac-cess to medicines by calling on EU

member states to cooperate more strate-gically in areas like pricing and reimburse-ment and health technology assessments, and to maximize the potential savings from generics and biosimilars.

In the “State of Health in the EU – Com-panion Report 2019,” the commission says that the product life cycle of medi-cines “reveals ample scope for member state cooperation in ensuring safe, ef-fective and affordable therapies, includ-ing everything from rational spending to

responsible prescribing.”The report, which was produced in as-

sociation with the Organization for Eco-nomic Cooperation and Development (OECD), looks at five areas: medicines access, vaccine hesitancy, gaps in health system accessibility, digital transforma-tion of health promotion and disease pre-vention, and the skills mix.

It draws a number of conclusions and recommendations based on the 2019 country health profiles that were draft-ed for the latest version of the “State of Health in the EU” cycle, which was initi-ated by the outgoing health commis-

sioner, Vytenis Andriukaitis.In his introduction to the report, Andriu-

kaitis, who will be succeeded as health commissioner on 1 December by Stella Kyriakides, says: “It is the ultimate aim of the State of Health in the EU cycle to sup-port member states in constantly improv-ing the effectiveness, accessibility and re-silience of their health systems. This robust country-specific and cross-EU knowledge now feeds into both national policymak-ing and EU level cooperation.”

In the section on medicines access, the report says that while selective funding of cost-effective, affordable medicines is




“key to safeguarding sustainable access to medicines in the EU,” national health policymakers have “struggled to strike a balance between ensuring accessibility to medicines, providing incentives for phar-maceutical innovation and ensuring the fiscal sustainability of health spending.”

While it acknowledges the importance of the pharmaceutical sector in encour-aging innovation and economic growth in the EU, it says that most countries have “challenges related to the affordability of pharmaceuticals,” as payers find it difficult to devise affordable and equitable access schemes for medicines with increasingly high prices.

This, it declares, has “further exacerbat-ed existing concerns from member states about the appropriateness of the current R&D model, as well as the future fiscal sus-tainability of current levels of pharmaceu-tical expenditure.”

PRICE DISCUSSIONS, MANAGED ACCESS DEALSThe commission believes there is plenty of mileage in cross-border cooperation initia-tives. It notes that “some member states have taken up cross-country collaborative approaches in recent years. These may result in joint procurement and joint pric-ing (and reimbursement) negotiations for specific medicines, in addition to collabo-ration in other areas such as information sharing, HTA or horizon scanning.”

Among ongoing initiatives are the BeN-eLuxA coalition, the Valletta Declaration and the Nordic FINOSE collaboration. Un-der these projects, pricing and reimburse-ment continue to be a competence of the participant countries, “but there is a keen interest in continuing the communication and exchange of information at EU level, for instance via a future platform for mutu-al exchange and learning,” the report says.

Noting the commission’s proposal for a regulation that would strengthen HTA cooperation on health technology assess-ments in Europe, which is currently going through the EU legislative process, the re-port says this would help member states make “timely, evidence-based decisions related to patient access to new medicines and other health technologies while at the

same time reducing the administrative burden borne by the industry.”

Another idea for closer cooperation ex-plored in the report is addressing what the commission sees as an imbalance in the relationship between pharmaceutical companies and national authorities when it comes to pricing and reimbursement discussions on new medicines.

“The inclusion of new products in the basket of covered services usually requires both parties to negotiate on the condi-tions for a product to enter a market,” the report says. “A first step towards balanc-ing the bargaining power of stakeholders consists of bridging information gaps that may put payers at a disadvantage in the pricing and reimbursement negotiations with manufacturers.”

It suggests that fostering more coop-eration among EU countries in this regard “could offer promising opportunities to im-prove the affordability of medicines through more transparent pricing and greater com-petition among manufacturers.”

A cooperative approach could also prove beneficial in the area of managed access deals. The report says that the arriv-al of new, high-cost medicines for smaller populations requires a “critical reflection on the need to redesign existing payment models, in particular with a focus on in-stalment plans to smoothen out upfront purchasing costs and pay-for-performance approaches to ensure high-value care is provided.” Expertise “can be pooled at EU level in this regard,” it adds.

GENERICS AND BIOSIMILARSThe potential cost savings from generic and biosimilar medicines, which of course are another key lever in containing drug costs, are addressed, albeit briefly, in the report.

It says that biologicals “already make up around a quarter of pharmaceutical ex-penditure,” but the uptake of biosimilars shows a mixed picture, with the uptake of biosimilars across member states varying wildly within the same interchangeable product class. “This high variance hints at a large untapped potential for efficiency gains for several countries,” it declares.

Published online 29 November 2019

“Payers find it

difficult to devise

affordable and

equitable access

schemes for

medicines with

increasingly

high prices”

– European

Commission report




EDITORS IN CHIEF Ian Haydock (Asia)Eleanor Malone (Europe)Denise Peterson (US)

EXECUTIVE EDITORSPOLICY AND REGULATORYMaureen Kenny (Europe)Nielsen Hobbs (US)

COMMERCIALAlex Shimmings (Europe)Mary Jo Laffler (US)

ASIAAnju GhangurdeVibha RaviJung Won ShinBrian Yang

EUROPENeena Brizmohun Francesca BruceAndrea Charles

John DavisKevin GroganAndrew McConaghieIan SchofieldVibha SharmaSten Stovall

USMichael CiprianoBowman CoxJoanne EglovitchEileen FrancisDerrick GingeryJoseph HaasMandy JacksonCathy KellyJessica Merrill Leah Samuel Brenda SandburgBridget SilvermanMalcolm SpicerSue Sutter

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