Pharma intelligence Pinkpink.pharmamedtechbi.comSheetVol. 78 / No. 39 September 26, 2016 informa

have described as having major flaws. Sarepta’s Eteplirsen Approved After “The approval of Exondys 51 reflects FDA’s ability to apply flexibility to address challenges we often see with rare, life- Contentious Internal FDA Debate threatening diseases – while remaining Sue Sutter [email protected] within our statutory framework,” Wood- cock said in an email to CDER staff an- DA Commissioner Robert Califf de- nouncing the approval.” ferred to Center for Drug Evaluation “In this case, flexibility is warranted be- Fand Research Director Janet Wood- cause of the life-threatening nature of cock on the accelerated approval of Sarep- the disease; the lack of available therapy; ta Therapeutics Inc.’s Exondys 51 (eteplirs- the fact that the intended population is en) even though her favorable view of the a small subset of an already rare disease; Duchenne muscular dystrophy drug was and the fact that this is a life-limiting dis- opposed by the clinical review team, other ease of children,” she said. “These factors, senior personnel within the drugs center combined with the dystrophin production and the agency’s acting chief scientist. data – and the drug’s low risk profile – led The agency granted accelerated approv- the agency to approve the drug under the al Sept. 19 of eteplirsen, an antisense oli- accelerated approval pathway.” gonucleotide, for treatment of Duchenne Memos released concurrent with the muscular dystrophy (DMD) in patients who “The approval of approval paint a picture of Woodcock tak- have a confirmed mutation of the DMD ing a highly activist role, both before and gene that is amenable to exon 51 skipping. Exondys 51 reflects after NDA submission, in the effort to get The approval followed an unusual ap- eteplirsen approved as the first drug treat- peal by Office of Drug Evaluation I Direc- FDA’s ability to apply ment for DMD, an ultra rare genetic disorder tor Ellis Unger that went all the way to flexibility to address characterized by progressive muscle deteri- the commissioner’s office. Unger and oration and weakness that is often fatal. Woodcock disagreed on the key question challenges we often The CDER director made known her in- of whether the quantity of dystrophin clination to grant accelerated approval produced by eteplirsen is an effect that is see with rare, life- before other reviews had been completed, reasonably likely to predict clinical benefit, threatening diseases was very involved in the advisory commit- such that it can serve as a surrogate end- tee meeting and believed the review team point supporting accelerated approval. – while remaining was not doing enough to take advantage Woodcock – a 30-year agency veteran of the agency’s regulatory flexibility to who has headed CDER for a total of 19 within our statutory speed new treatments to market, the doc- years – clearly put her reputation on the framework,” uments show. line with her aggressive push for acceler- On the other side of the argument were ated approval of eteplirsen, a drug with Woodcock said. Unger and review team members who

limited clinical trial data that FDA officials Rawpixel.com Shutterstock: Continued on page 4

Brought to you by the Editors of Scrip Regulatory Affairs, The RPM Report, Tan Sheet, Gold Sheet, Pink Sheet Daily and Pink Sheet

Consumer Products Regulatory Update Drug Review Profile Tom’s Of Maine Ingredients’ Swedes Explain Why They Zecuity Redesign Got Migraine Efficacy Weighed Against ‘Natural’ Should Have the EMA ‘Gem’ Patch Through FDA, But Burning Claim In NAD, p. 16 After Brexit, p. 24 Continued, p. 20 October 18-19, 2016 The Westin St. Francis, San Francisco, CA Accelerate discovery. Amplify returns.

The BIO Investor Forum is an international biotech investor conference focused on early and established private companies as well as emerging public companies. Now in its 15th year, this elite event brings together angel, venture capital, venture philanthropy, private equity and public investors, research analysts and industry executives in a collaborative setting to explore development and investment opportunities in life sciences. Conference features: • Company presentations given by over 175 early and late-stage private biotech companies and emerging public companies. • Fireside Chats and expert-led panel discussions on the latest market and investment opportunities with emphasis on drug and technology development. • More than 1,700 One-on-One Partnering™ meetings. • Buzz of BIO competition recognizing “Early Stage Entrepreneurs” and “Late Stage Leaders.” • The BIO SPARK Showcase featuring drug development programs that are ready for partnering or venture funding.

Complimentary registration is available for investors. For more information and to register for the event, please go to bio.org/investorforum

ORGANIZED BY: POWERED BY:

Innovation cover 12 18 inside: Cover Sarepta’s Eteplirsen Approved After Contentious Clinical Trials Internal FDA Debate 29 EU Clinical Trials Delayed By Poor Reference Safety Information Regulatory Update 12 Pricey New HCV, Cancer Drugs Push Up Japan’s Patents Health Care Costs 28 New EU Patent System: Only Two More Ratifications 14 As Appraisal Fees Loom, NICE Says No To Industry Needed, But Will The UK Sign Up? Calls For Reform 24 Swedes Explain Why They Should Have The EMA ‘Gem’ After Brexit 26 €20m Action Tackles Poor Uptake Of Joint HTAs Across Europe; Commission Consultation Nears exclusive online content FDA 6 Eteplirsen Review Timeline: CDER Director Was Involved China Regulatory Watch: New Fast-Track Early And Often Designations, CTAs 7 Woodcock’s Consideration of Sarepta Financial Issues http://bit.ly/2cMEZGc Raises Eyebrows China Regulatory Watch is our new snapshot of product-specific Generic Drugs regulatory developments at the China FDA. 19 FDA’s ANDA Approvals 9 EpiPen Generics: Woodcock Explains Injector Studies FDA’s Off-Label Communication Changes Should New Products Start With Payers – PhRMA http://bit.ly/2cXc5lY 25 FDA’s NDA And BLA Approvals PhRMA Senior Counsel Jeffrey Francer offers three-step reform Drug Review Profile approach to loosening FDA’s restrictions, beginning with the 20 Zecuity Redesign Got Migraine Patch Through FDA, ‘low-hanging fruit’ of talking with payers. But Burning Continued Consumer Products Alzheimer’s Drugs and Medicare: A Case For 16 Tom’s Of Maine Ingredients’ Efficacy Weighed Against Pre-Approval Discussions ‘Natural’ Claim In NAD Review http://bit.ly/2d5WzF0 18 Liquid Dosing Accuracy Four-Times Better With Medicare’s Part D plan bidding schedule and uncertainty over Oral Syringes – Study the Alzheimer’s drug pipeline is putting plan sponsors in a difficult situation as they contemplate their 2018 bids. Advisory Committees 10 FDA Oncology Advisory Committee Is Still Pazdur’s Center of Excellence Teva Leads Generic Rivals In First-To-File ANDAs By A Long Shot 11 Pediatric Opioid Development Faces Grim Outlook After http://bit.ly/2cyRLbB Advisory Cmte. Teva has submitted 13 ANDAs with first-to-file opportunities to 30 Recent And Upcoming FDA Advisory Committee Meetings FDA this year, while rivals Mylan, Endo, Sandoz and Indian firm Capitol Hill Hetero each have filed two ANDAs with FTFs, according to public 8 Scrutiny Of EpiPen Pricing Invited By Mylan Lobbying, data released by the agency and further analyzed by Teva. Congressman Says pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 3 New Products

Continued from cover In a July 14 memorandum, Woodcock predict clinical benefit.” believed that Woodcock was overly con- concluded there is evidence from ad- Borio’s memo describes Woodcock’s in- cerned with external pressures on FDA equate and well-controlled trials, and volvement in issues related to the eteplirsen from the DMD patient community, with supportive evidence, that exposure to IND and NDA, including numerous center whom she had interacted frequently, and eteplirsen increases dystrophin protein director briefings and multiple meetings Congress to approve the drug, as well as production in muscle cells. with patient advocacy groups, as well as her with the financial viability of Sarepta if it Evidence from Western blot and other active role in the advisory committee review. received a complete response letter. experiments show that protein in the At the April advisory committee meet- In the end, Califf opted neither to over- range between undetectable and 10% of ing, panelists voted narrowly against accel- rule Woodcock nor convene an indepen- normal is likely to be very important for erated approval and more firmly against dent review of the scientific issues in dis- clinical presentation, she said. Further- regular approval. pute between the director and her staff. more, both the biochemical data and the On June 3, Woodcock requested Sarepta FDA history includes a “consistent prece- eteplirsen clinical data lead to the conclu- provide additional data from an ongoing trial (Study 301) that included compari- sons of biopsy samples obtained at week Woodcock’s involvement in the NDA review 48 to their respective baseline samples. If the data showed a meaningful increase “appears to have upended the typical review and in dystrophin, FDA expected to be able decision-making process,” the board found. to grant accelerated approval within four business days of receiving the data, Wood- cock’s letter stated. sion that an increase in dystrophin produc- dent of final decision-making about medi- The scientific dispute board concluded tion is reasonably likely to predict clinical cal products at the center level,” Califf said that Woodcock had an extensive and early benefit in DMD, she said. in a Sept. 16 memo. role in the NDA review process that was Unger and numerous other FDA staff “Overruling the center director is ex- troubling. “Indeed, her involvement here disagreed with Woodcock’s view that the ceedingly rare and, in my view, would be appears to have upended the typical re- findings on the dystrophin surrogate end- appropriate only if the center director’s view and decision-making process.” point for eteplirsen are reasonably likely to decision could not be supported by the “By all accounts, Dr. Woodcock made clear predict clinical benefit (see box). available data and information,” the com- her views that CDER should lean toward Unger’s appeal was heard by the agen- missioner said. “In the present case, the sci- finding that eteplirsen met the standards cy’s Scientific Dispute Process Review entific uncertainties lead to a situation in underlying accelerated approval nearly from Board, a standing committee chaired by which the decision is a matter of reasoned acting Chief Scientist Luciana Borio. The expert opinion and judgment.” board reviewed the eteplirsen NDA admin- FDA Staff istrative file and interviewed Unger, Wood- Scientific Dispute Board Opposed To cock, an unidentified review team member Appeal … and CDER Ombudsman Virginia Behr. Accelerated Eteplirsen has had a difficult develop- In an Aug. 8 memo to Califf, Borio said the Approval ment and regulatory review, with the ro- board determined the process followed by bustness of the efficacy data underlying CDER gave Unger adequate opportunity to • Office of Drug Evaluation I questions about the drug’s approvability. present his scientific views and that the drug Director Ellis Unger The initial NDA submission included only center considered all relevant evidence. one 12-patient controlled clinical study to • Division of Neurology Products support efficacy. … Sparks Call For review team Despite the questions about clinical ef- Substantive Review • Office of Biometrics ficacy, the drug has garnered an extraor- However, the board urged the commis- dinary amount of support from patients, sioner to conduct “a thorough substan- • Office of Clinical Pharmacology advocates and Congress. tive review of the scientific dispute in this The controversy ended up on Califf’s matter or, in the alternative, to convene a • Office of New Drugs Director desk because Unger, who heads the office panel of relevant experts to conduct such John Jenkins that oversees the Division of Neurology a review and provide advice to the agency Products, submitted a scientific dispute and you, as commissioner, on whether the • Acting Chief Scientist resolution appeal challenging Woodcock’s evidence of the effect of eteplirsen on the Luciana Borio decision to award accelerated approval. surrogate endpoint is reasonably likely to

4 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 New Products the outset of her involvement,” Borio’s memo of dystrophin produced by eteplirsen at review and advisory committee and her de- states. “By May 4, 2016, she had orally com- the doses studied are reasonably likely to cision to approve before other reviews had municated her intention to grant accelerated provide clinical benefit,” Borio said. been completed. approval for eteplirsen, even though she had Woodcock has had a “hands on” man- not yet seen even the draft review memo- Review Involvement agement style during her entire career at randa from the review team or a decisional Reflects Management Style FDA, Califf said. “She is well known for inter- memorandum from Dr. Unger. Califf’s memo states is it “highly unusual” for a acting with staff at all levels and expressing “Then, when she requested data from center director ‘s decision on a product appli- her opinions.” While her involvement with Study 301 from Sarepta, she communi- cation to be appealed to the commissioner’s the eteplirsen review might have been cated to the sponsor a compressed time- office, and a footnote points out the estab- more intensive than usual, “such a focus frame for CDER’s review. Although she later lished dispute resolution process “does not does fit within a longstanding manage- expanded the timeframe for review when contemplate a substantive decision on the ment approach.” the data proved to be disappointing, she disputed issue by the commissioner.” Furthermore, “it is difficult to argue that apparently analyzed the data on her own, With regard to Woodcock and Unger, Califf CDER has been unsuccessful under her conducted her own additional search of concluded that “qualified experts with exten- leadership,” he continued. “A vast array of the scientific literature, and took only six sive experience in FDA decision-making and new drugs approved during her tenure is or seven business days to orally commu- stellar track records can assimilate the same benefitting patients, including a host of nicate to the review team her decision to scientific evidence and disagree about the significant advances using a variety of ex- grant approval,” the memo states. extrapolation to whether the evidence sup- pedited programs.” Despite the irregularities in process, ports a conclusion that the treatment has Under Woodcock’s leadership, CDER has Woodcock did consider all relevant evi- an effect that is ‘reasonably likely’ to predict enjoyed broad public support, Califf said. dence in reaching her scientific conclusion, clinical benefit.” She has shown “extraordinary courage in the the board found. “Based on her own medi- “Given that I do not have technical exper- face of extreme pressure on many occasions, cal judgment, she simply has a difference tise beyond those already involved in this de- including from Congress, the press, patient of opinion with Dr. Unger – both with re- cision and the record contains adequate evi- and patient advocacy groups and industry. spect to the scientific conclusion and the dence to support her conclusion, I defer to She has taken and supported unpopular de- sufficiency of the underlying rationale.” the judgment of the center director,” he said. cisions when appropriate and is well known Nevertheless, in a section of the memo Contrary to the assertions of Unger and for not relenting to pressure.” titled “Considerations From the Acting Chief other review staff, Califf said he found no ba- “Further, I find no pattern that indicates Scientist,” Borio suggests she shares Unger’s sis for the view that Woodcock was unduly that this decision is part of a trend for low- viewpoint on the underlying scientific issues. influenced by involvement with the patient ering the standard for drug approval – a “By any meaningful objective standard community or other external pressures. trend that would be unacceptable in any … the overall evidence derived from Califf also addressed the concerns raised event,” Califf said. eteplirsen’s limited clinical development by the review board with regard to the CDER program does not support that the levels director’s involvement in the early stages of Published online September 19, 2016

Optimize clinical trial design with Trialtrove’s new Standard of Care service

RequeST a deMO! citeline.com/products/trialtrove/

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 5 FDA Eteplirsen Review Timeline: CDER Director Was Involved Early And Often Sue Sutter [email protected]

DA review documents released in connection with the ac- “The center director’s direct involvement with this drug, com- celerated approval of Sarepta Therapeutics Inc.’s Exondys 51 pared to other development programs, has been unprecedented,” F(eteplirsen) describe Center for Drug Evaluation and Re- Unger said. search Director Janet Woodcock’s involvement with review activi- In his memo refusing to disturb Woodcock’s decision to grant ac- ties during the IND and NDA stages of the Duchenne muscular celerated approval, FDA Commissioner Robert Califf said that while dystrophy drug. the CDER director’s involvement was “more intensive than usual,” In his appeal to the Scientific Dispute Process Review Board, Of- it fit within her longstanding “hands on” management approach. fice of Drug Evaluation I Director Ellis Unger lists a total of 15 center Below is a list of the center director briefings and other key director briefings associated with eteplirsen’s development, more events in the review of the eteplirsen NDA, as drawn from agency than half of which occurred prior to NDA submission. Some of the documents. briefings during the IND stage also included discussion of other DMD drugs under development. Published online September 19, 2016

Date Action

IND Chronology 3/13/2013 End-of-Phase II meeting 7/17/2013 Center director briefing 10/18/2013 Center director briefing 10/28/2013 Center director briefing (continuation of 10/18/2013 meeting) 11/17/2014 Center director briefing 2/6/2014 Center director briefing 3/5/2014 Center director briefing 3/19/2014 Sponsor meeting with CDER director on study design and path forward 4/2/2014 Center director briefing

NDA Chronology 6/26/2015 Eteplirsen NDA submitted 12/9/2015 Center director briefing 1/13/2016 Center director briefing 1/22/2016 Originally scheduled meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (postponed due to snowstorm) 2/10/2016 Center director briefing 4/15/2016 Center director briefing 4/25/2016 Advisory committee meeting; panel votes 7-6 there is not substantial evidence from adequate, well-controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit, and 7-3 (3 abstentions) that clinical results of a single historically controlled study do not provide substantial evidence of efficacy 5/4/2016 Center director briefing to discuss the advisory committee meeting and plan of actions for the NDA; CDER Director Janet Woodcock informs review team she intends to grant accelerated approval

6 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 FDA

Date Action 5/24/2016 ODE I Director Ellis Unger meets privately with Woodcock to discuss eteplirsen decision 5/31/2016 Center director briefing to discuss reviews and initial draft of Woodcock’s decisional memorandum based primarily on the data from Study 201/202 6/3/2016 In a letter signed by Woodcock, FDA requests additional data from Study 301, including comparisons of biopsy samples at baseline and week 48; if results show a meaningful increase in dystrophin by Western blot analysis, FDA expects to be able to grant accelerated approval within four business days of receiving the data 6/27/2016 Sarepta submits requested data 7/5/2016 In email to Woodcock, Unger requests formal appeal to the commissioner 7/6/2016 Center director briefing on levels of dystrophin observed in ongoing trial and whether they can be interpreted as reason- ably likely to predict clinical benefit and used as a surrogate endpoint 7/11/2016 Woodcock provides draft of her final decisional memo to review team for comments 7/14/2016 Woodcock finalizes her decisional memo 7/16/2016 Unger finalizes his decisional memo 7/18/2016 Unger files scientific dispute resolution appeal 8/8/2016 Acting chief scientist’s memo says Scientific Dispute Process Review Board finds Unger had an opportunity to present his scientific views; board encourages FDA Commissioner Robert Califf to conduct a substantive review of the scientific dispute or convene a panel of relevant experts 9/16/2016 Califf memo defers to Woodcock on eteplirsen’s accelerated approval 9/19/2016 Eteplirsen receives accelerated approval under brand name Exondys 51

Woodcock’s Consideration of Sarepta Financial Issues Raises Eyebrows

Derrick Gingery [email protected]

DER Director Janet Woodcock gave a candid opinion of the decision to approve Exondys 51 indicate that Woodcock “was look- importance of the approval of the Duchenne muscular dys- ing at the broader picture for the development of these types of Ctrophy drug Exondys 51 (eteplirsen), as well as the health of drugs in very limited patient populations” and said “there needed its sponsor, Sarepta Therapeutics Inc., during FDA’s internal battle to be some path forward for such innovative products.” over the decision. Woodcock suggested that “Sarepta in particular ‘needed to be Woodcock admitted to colleagues that the company may need capitalized.’” the product approved for its financial health as well as drug develop- “Dr. Woodcock cautioned that if Sarepta did not receive accel- ment in the space, an issue that is not supposed to play a role in FDA erated approval for eteplirsen, it would have insufficient funding decision-making. to continue to study eteplirsen and the other similar drugs in its The issue emerged because Woodcock overruled the review pipeline,” according to a memo from Acting Chief Scientist Luciana team’s decision against approving Exondys 51 even though there Borio on the scientific dispute resolution appeal. Documents out- were questions about its efficacy. Woodcock’s decision was appealed lining the appeal were posted Sept. 19 along with the Exondys 51 ultimately to FDA Commissioner Robert Califf, who sided with her. label and approval letter. Sarepta also gained a pediatric rare disease priority review “[Woodcock] stated that, without an approval in cases such as voucher as a result of the approval. It and the required confirma- eteplirsen, patients would abandon all hope of approval for these tory studies could affect the company’s health going forward. types of products and would ‘lapse into a position of’ self-treatment.” Documents outlining the extraordinary appeal of Woodcock’s Woodcock’s statement about the impact on the drug develop- pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 7 FDA

ment may hold some merit. Duchenne drug development could plication that Sarepta’s financial health played a role in the decision. have been in trouble with another denial. “I was troubled by statements … that Dr. Woodcock’s decision If Exondys 51 had not been approved, Sarepta could have faced to approve eteplirsen may have been inappropriately motivated severe financial problems. Its stock price plummeted after FDA’s by concerns over the sponsor’s financial well-being,” Califf wrote in Peripheral and Central Nervous System Drugs Advisory Commit- a footnote. “I have discussed this issue directly with Dr. Woodcock, tee voted against a recommendation that the evidence presented who said that she was aware of the financial pressures on the com- warranted accelerated or full approval. pany, but that her decision was based on the science. And another proposed Duchenne candidate, BioMarin Phar- “Based on the record of our conversation, I am satisfied that her maceutical Inc.’s drisapersen, already had received a complete re- decision is indeed based on her scientific evaluation of the evidence.” sponse letter. Woodcock has been among FDA’s strongest proponents of flex- ibility when it comes to reviewing drugs for orphan diseases like Califf ‘Troubled’ Duchenne. The agency also has a long track record of flexibility Califf did not determine that Woodcock “succumbed to pressure with evidentiary standards for orphan product approvals. from the patient community, the public, the press, or others” in over- ruling the review division. But he also was concerned about the im- Published online September 19, 2016

Capitol Hill Scrutiny Of EpiPen Pricing Invited By Mylan Lobbying, Congressman Says Cathy Kelly [email protected]

ylan Pharmaceuticals Inc. invited Lobbying For covered by insurance plans the painful scrutiny it is receiving Sales without member cost Mfrom Congress over the pricing if Mulvaney referred to com- sharing under a provision its EpiPen emergency allergy treatment by pany lobbying at the state of the Affordable Care Act. engaging with legislators to pass laws that and federal level aimed at The list for children cur- advance its business interests, Rep. Mick expanding access to EpiPen rently includes immuniza- Mulvaney, R-SC, told CEO Heather Bresch at through schools. “There are tions and a range of health a House Oversight & Government Reform laws in 11 states now that screening tests. Committee hearing Sept. 21. require schools to have epi- The effort is part of the The hearing was the first to be held on nephrine available in some company’s initiative for Mylan’s pattern of large price increase for immediately deliverable expanding access to treat- EpiPen (epinephrine auto injector) since fashion,” he noted. Rep. Mick Mulvaney, R-SC ment, Bresch maintained. acquiring the product in 2007. But it fol- The US Congress passed But it has also been criti- lows a spate of letters and public state- a law in 2013 which “gave this wonderful cized as a way of shifting costs to payers. ments from bipartisan members of the financial incentive to all of our schools to House and Senate aimed at challenging have this product in the schools,” he added. European Market Better the pricing decisions. “The White House called it the EpiPen bill.” Mulvaney said the discussion at the hear- “I was as uncomfortable with some of The law authorizes HHS to give federal ing was not focusing on issues of real the questions (asked by members) as I’m asthma grant funding preference to states importance to the pricing debate, such sure you were,” Mulvaney said to Bresch. that maintain an emergency supply of as why there aren’t more competitors to “But I have to defend both my Republican epinephrine (essentially, EpiPens), permit EpiPen on the market. and Democratic colleagues because you trained personnel of the school to admin- Instead, he said, Bresch “talked about asked for it. ister epinephrine, and develop a plan for your profit margins with people who have “This is my message: If you want to come ensuring trained personnel are available to no clue what that means. We talked about to Washington, if you want to go to state cap- administer epinephrine during all hours of distribution facilities. We talked about itols to lobby us to make [taxpayers] buy your the school day. cost of goods sold. We talked about board stuff, this is what you get. You get a level of Some members also questioned Mylan’s meetings. We talked about your salary.” scrutiny and a level of treatment that would efforts to get EpiPen added to the list of “I wish we were talking instead … about ordinarily curl my hair but you asked for it.” preventive health care services that must be why Mylan can charge $600 for [EpiPen] or

8 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Capitol Hill

$300 for a generic” when “this same exact rector for regulatory programs at the Cen- takes a long time to get this stuff approved. product costs between $100 and $150 in Eu- ter for Drug Evaluation and Review, testi- … If you can really charge $600 for the stuff rope,” he pointed out. Mulvaney noted one fied at the hearing about the agency’s new and people are paying for it, why aren’t reason the treatment is so much cheaper 10-month approval timeline for generic more people rushing to get a piece of this abroad “is because there are nine different applications, Mulvaney acknowledged. huge market? Because it’s too hard to get people making the stuff in Europe because “But that makes me wonder how long the darned stuff approved.” it’s easier to get drugs approved” there. [reviews] really took before this became a FDA’s Douglas Throckmorton, deputy di- huge national deal,” he said. “My guess is it Published online September 21, 2016

EpiPen Generics: Woodcock Explains Injector Studies Derrick Gingery [email protected]

or potential EpiPen competitors, it appears FDA’s require- would work for them.” ments to fix problems with the device may not be extensive. Auvi-Q has been approved, but it was voluntarily recalled after po- F Center for Drug Evaluation and Research Director Janet tential problems with the device delivering the proper dose. Woodcock outlined to Senators Sept. 21 the potential steps that could be involved to ensure injector issues, such as ensuring it de- Device Patents The Issue, Woodcock Says livers the proper dose, were resolved. Indeed, it is the injector device that seems to present the biggest prob- While she did not mention any potential sponsors that may be lem for a generic EpiPen. affected, Woodcock described what could be the process that Teva Woodcock said the agency has approved four auto-injectors, but Pharmaceutical Industries Ltd., as well as Sanofi, might be able use to an EpiPen ANDA must include a similar device while not violating help their potential alternatives to Mylan NV’s EpiPen (epinephrine) its patents. reach the market and hopefully force price competition. “It’s not easy to make a generic that doesn’t infringe upon those EpiPen’s heavily criticized price increases also was the subject of patents and still works,” she said. a House Oversight and Government Reform Committee hearing The device has four patents listed in the Orange Book, which do not the same day. expire until 2025. Along with the public shaming of Mylan, members of Congress Teva submitted an ANDA for an EpiPen generic and had a device have written the company asking for justification of the price increase. prepared that was similar but not identical to EpiPen. Legislators have also asked FDA for an explanation of why generic Mylan filed a citizen petition as part of a fight to keep it off the -mar competition has not entered the market. ket, arguing that a generic should not be approved unless compara- During Woodcock’s appearance at the Senate Appropriations Ag- tive performance tests show that patients can operate the Teva device riculture, Rural Development, FDA and Related Agencies Subcom- with EpiPen instructions. mittee hearing on FDA’s role in the generic market, Ranking Mem- Mylan’s petition also included a study conducted by a third party ber Sen. Jeff Merkley, D-Ore., pushed the line of questioning, asking comparing a prototype Teva injector device to EpiPen that conclud- about FDA’s requirements for a generic EpiPen. He wanted to know ed patients could not use it like an EpiPen. whether FDA was a barrier to generic competition in the space. Teva later said its ANDA received a complete response letter with Merkley also asked what would be required for a company to re- major deficiencies. submit an application after the product was pulled from the market because of a manufacturing problem with its injector device, an ap- Auvi-Q Would Not Need Prioritization parent reference to Sanofi’s Auvi-Q epinephrine product. Merkley also asked whether an EpiPen generic application could Woodcock emphasized that she was answering in theoretical be prioritized under FDA rules, given the volume of pending ge- terms, and said the company would have to prove to FDA that the neric applications on its books. injector device works as intended, but likely would not have to con- Woodcock said that should the Auvi-Q application be resubmitted, duct clinical trials that would take years. it would be an NDA and therefore be subject to prescription drug user “Depending how they change their auto-injector, they might have fee review goals, which already are speedy. to do a human factor study again to make sure people can use it FDA also has the ability to expedite an ANDA for EpiPen using its properly,” Woodcock told the subcommittee. “Or they might not, de- policies to push first-generics and competitors for sole-source drugs to pending on if the change was just inside, they might not have to do the market as quickly as possible. that. But if the change was how you went about injecting yourself, they might have to test that again on people to make sure that it Published online September 21, 2016

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 9 Advisory Committees

FDA Oncology Advisory Committee Is Still Pazdur’s Center of Excellence

Michael McCaughan [email protected]

he Oncologic Drugs Advisory Com- broader public interested in cancer drug actually been demonstrated.” mittee’s unanimous rejection of development – of exactly what “substantial” Pazdur returned to the theme in the com- T Spectrum’s proposed bladder can- means in looking for substantial evidence mittee discussion period. He explained to cer therapy apaziquone followed a tried- of efficacy in oncology. the committee that they were being asked and-true template for cancer drug reviews first to vote on whether there is substantial in the “Breakthrough” era. Two Failed Trials Prompts evidence of efficacy and only then to dis- A new drug application with clear prob- A Lesson On ‘Substantial cuss clinical meaningfulness of the results, lems was brought to the meeting largely Evidence’ because “you can’t get into a discussion of a to allow FDA’s negative review to be aired Apaziquone was studied for use in non-mus- risk benefit analysis unless we are confident publicly. And along the way, Office of He- cle invasive bladder cancer, a setting where there is a treatment effect here.” matology & Oncology Products Director FDA agrees there is a need for therapies that Richard Pazdur uses the application to may prevent or delay recurrence of tumors “It Should Not Be ‘Safe And drive home a broader message about can- that require surgical removal. Apaziquone Maybe Effective’” cer drug development. is chemically related to mitomycin, which is “We realize there is a need for drugs, as has Pazdur openly acknowledges that FDA’s already used (off-label) in the setting. been expressed by the open public hearing,” Oncologic Drugs Advisory Committee Unfortunately, both of Spectrum’s Phase Pazdur said. However, “these drugs should (ODAC) is largely reserved for “problem” III trials failed to show statistical signifi- be safe and effective. It should not be ‘safe applications; there is, in his view, generally cance. Spectrum argued nevertheless that and maybe effective,’ or ‘safe and I wish it was little justification for the delay necessitated the committee should assume that the 6% effective.’ … There is a regulatory obligation.” by an advisory committee stop when a reduction in recurrence rate seen in both Pazdur drew a contrast between a treat- new drug for cancer could get to market trials is a reasonable estimate of the ben- ment for an advanced, highly metastatic even a few weeks faster. efit of the therapy. The company argued cancer and the current setting – where the But, through the years, Pazdur has also that waiting five years for approval would therapy is intended for low-grade tumors used the ODAC meeting as an opportunity mean as many as 100,000 avoidable resec- in a disease with a relatively long course of to offer important messages to sponsors. tion procedures (20,000 per year), each of progression. Drug developers have learned to pay care- which exposes patients to considerable “We have approved drugs on single-arm ful attention to those meetings for insights discomfort and potential adverse events studies with a response rate in very metastat- into Pazdur’s thinking on topics like the lim- like bladder perforation. ic disease,” he said, because “we know there is its of progression-free survival endpoints, In addition, the sponsor argued, FDA ap- a treatment effect there because the disease efficacy bars in different disease settings, or proval of apaziquone would greatly increase doesn’t go away on its own.” However, “this is the expectations for accelerated approval. use of the instillation treatment. Spectrum a different situation” and so “the need to rely The recent news that Pazdur is transi- noted that mitomycin is often in short sup- on the statistics is much greater here.” tioning to a new role at FDA – leading an ply, and can be expensive to source in com- Pazdur, however, also made clear that FDA “Oncology Center of Excellence” to inte- pounded versions. In addition, the company is not demanding that apaziquone or any grate cancer reviews across the traditional maintains, urologists are generally less will- other NMIBC agent meet some pre-speci- FDA drug, biologic and device centers – ing than oncologists to use therapies off-la- fied efficacy threshold for approval. “There raises questions about how long that tradi- bel, and so an FDA approved agent would in- is no comparative efficacy standard,” Pazdur tion can continue. crease treatment in accordance with clinical stressed. You don’t have to show it better The Sept. 14 apaziquone review suggests practice guidelines that already recommend than mitomycin.” However, “you have to an- that, for the moment, nothing is changing. instillation with resection. swer do you believe there is an effect here.” When the meeting began with the usual One of Spectrum’s consultants summa- The committee unanimously agreed vot- introductions around the table, Pazdur was rized the case for approval as “the drug ed that the trials failed to meet the efficacy there, and identified himself simply as “Rich- didn’t fail. The trial did.” bar, and that results from another (ongoing) ard Pazdur, Office Director.” That summary brought a response from trial will be necessary before approval. And, when the key points in the discus- Pazdur. “We all wish for new drugs,” Pazdur sion came, he didn’t miss a chance to weigh said. The question is “Is there an effect here? From the editors of the RPM Report. in, reminding the committee – and the It is not the wish of an effect, but what has Published online September 20, 2016

10 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Advisory Committees Pediatric Opioid Development Faces Grim Outlook After Advisory Cmte. Michael Cipriano [email protected]

he shoring up of FDA’s guidelines on pediatric opioid devel- sampling for pharmacokinetic and safety analyses. But there was opment looks like it could be a long way off, as three of the virtually no conversation about an innovative solution. Jennifer Hig- T agency’s advisory committees struggled to provide con- gins, a consumer representative on the panel, briefly addressed the crete recommendations to fill in the topic’s gaps. topic, suggesting an education campaign targeting parents. FDA laid out several issues in conducting clinical trials for opi- “[The difficulty of enrollment] is something that I find particular- oids in pediatric populations in the briefing documents leading ly frustrating,” Higgins said. “I think with the right educational cam- up to the Sept.15-16 joint meeting of the Anesthetic and Analge- paign, if there was such a thing, to have an educational campaign sic Drug Products Advisory Committee, the Drug Safety and Risk educating parents about the benefits of trial participation, I think Management Advisory Committee and the Pediatric Advisory will go a long way in boosting those enrollment rates.” Committee. One panelist even suggested changing the conversation entire- ly. Samuel Maldonado, vice president and head of pediatric drug Committee member Sarah Hoehn development at Janssen R&D LLC and a non-voting industry repre- sentative of the Pediatric Advisory Committee, proposed studying summed up the tone of the meeting the condition of pain even before studying drugs. “I am still puzzled, because based on the comments, we don’t best when she said, “the more know the condition [of pain] itself. We need to have a taxonomy I talk about this, the more I have of the condition. This is not a single entity. It is many entities, some that cannot diagnose in the newborn period,” Maldonado said. no great answers.” Funding And Fear: More Unanswered But panelists offered only marginal feedback to solve longstand- Concerns ing problems. Sarah Hoehn, an associate professor of pediatrics at Another major barrier to pediatric opioid development has been a the University of Kansas School of Medicine and a member of the lack of funding for investigator initiated trials. Steven Weisman, the Pediatric Advisory Committee, summed up the tone of the meet- medical director of pain management at the Children’s Hospital of ing best when she said, “the more I talk about this, the more I have Wisconsin and a speaker at the meeting, said funding sources to do no great answers.” these studies continue to be “a real challenge.” Extrapolation of efficacy was one major topic of discussion, since “[Studies] are not going to get done unless we make this enough practice allows studies to be smaller and enroll fewer patients. But of a priority that there are monies available outside of pharma to extrapolation does also have its limits, even though it can benefit do some of these studies,” he said. studies that focus on safety and pharmacokinetics rather than ef- Weismen also said that investigators are also fearful of being ficacy. For example, if exposure of a drug is lower in children when negatively represented for their work by the media. He cited an ex- compared to adults, it is unclear whether extrapolation of efficacy ample of a pain group that planned to study oxycodone for acute from adults is appropriate. Feedback from panelists on the subject pain management in infants from six to 24 months of age. How- was largely inconclusive. ever, the group put the trial on hold because of the fear of reper- “It hurts my heart to say we can’t extrapolate, but I don’t think cussions from the media. we can,” Hoehn said. “To do a full efficacy trial we know is incredibly Charles Emala, vice-chair for research at Columbia University’s challenging. But to not do any efficacy I think is also problematic. Department of Anesthesiology and a member of the Anesthetic I think we have to find something in between,” she added. “I don’t and Analgesic Drug Products Advisory Committee, echoed the know what that is.” concerns about funding, adding that investigator initiated studies on the topic that are submitted to the National Institutes of Health What Should We Be Talking About? are not very well received. Emala also called on FDA to work in con- The cliché of “more research is needed” was a phrase that was com- cert with NIH on pediatric opioid development, noting that there monly used by the committee members throughout the two days is also frustration when priorities of one federal agency don’t get of the meeting. transmitted to another. Enrollment is another major issue in pediatric opioid develop- “I think at the end of the day, great plans will remain great plans ment. Parents often have concerns that their child will be harmed, unless there active efforts at the federal level to have these types of receive less effective treatment or need to undergo extensive blood studies funded,” Emala said. pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 11 Advisory Committees

An Ethical Framework Purdue Fends Off Attacks On OxyContin Chris Feudtner, director of the Department of Medical Ethics at the The unofficial spokesprescription of the opioid epidemic, Oxy- Children’s Hospital of Philadelphia and a speaker at the meeting, Contin (oxycodone controlled release), did not go undiscussed provided panelists with a proposed ethical framework for consid- at the meeting, as guest speaker Edwin Thompson, president ering pediatric opioid policy. The framework aimed to account for of Pharmaceutical Manufacturing Research Services, slammed pediatric patients taking opioids in a prohibited and harmful man- FDA for approve the Purdue Pharma LP drug on the “false be- ner, as well as those enduring inadequately severe pain. lief” that it has abuse deterrent properties. Thompson argued Policy considerations should first start with “a full accounting of against conducting pediatric studies of extended-release opi- the current situation” by identifying the variety of problems that oids, citing the ethical principle of scientific necessity and the are causing the opioid epidemic, Feudtner said. uncertain benefits. He further called for the removal of pediatric “Narrow depictions of the situation and problems are ethically labeling from OxyContin. problematic. Deeply problematic,” Feudtner said. “If we think we Purdue’s Stacy Baldridge defended the product’s labeling, point- are fighting a small little brush fire when in fact there is a whole ing to the company’s clinical trials of OxyContin with pediatric pa- forest fire going on, we are going to make huge mistakes that are tients at the meeting, noting that subjects were carefully selected, not going to help anybody, and are ultimately going to be hurtful. as well as an enrollment rate of 7.6%. Additionally, 40% of pedi- Feudtner also cautioned against simplistic thinking at the popu- atric patients prescreened but not enrolled either failed to meet lation level, noting that it does not convey the true complexity of requirements related to minimum dosage or duration of use. the situation. “Simple solutions for complex problems may work, Baldridge also said in a statement to the Pink Sheet that Purdue but we owe it to people to be clear that we are not really sure,” is not promoting to pediatricians or other prescribers the pediatric Feudtner said. safety and dosing information for OxyContin. “So while individual deliberations in the office of the pros and “While we are not promoting the indication, we believe it is criti- cons of opioid therapy for severe pain is demanding, deliberation cal for prescribers to have the necessary safety information when regarding population level implications is orders of magnitude making prescribing decisions,” Baldridge said. “It is important to more complicated and less certain,” he added. study treatments for children with pain so that doctors can make He further stressed that the needs in severe pain cannot be lost good, evidence-driven decisions.” in the efforts to restrict access to opioids as a way to curb the opi- oid epidemic. Published online September 19, 2016

Regulatory Update Pricey New HCV, Cancer Drugs Push Up Japan’s Health Care Costs Ian Haydock [email protected]

he latest official figures for medical JPY7.9tn, accounting for around 19% of while Opdivo was first launched in Sep- costs under Japan’s national health the total, and an 11% increase in reim- tember 2014. Tinsurance (NHI) system have served bursed medicine costs to JPY5.98tn, which Given the two HCV drugs’ close to 100% to focus mass media attention in the coun- hit the local headlines. efficacy rates for reducing HCV to undetect- try on the increased use and cost of new Coming in for particular scrutiny were re- able levels, the uptake of both in Japan – and highly effective, but also expensive, cent huge sales increases for specific prod- where around 1.1 million people are chroni- drugs for hepatitis C and cancer. ucts including Gilead Sciences Inc.’s hepatitis cally infected with the virus – has been high The country’s total health care costs C virus (HCV) therapies Sovaldi (sofosbuvir) and rapid. Initial reimbursement prices under the NHI scheme – which applies and Harvoni (sofosbuvir and ledipasvir), and were set at JPY61,799.30 per 400 mg tablet to all citizens – rose by 4% to JPY41.46tn Ono Pharmaceutical Co. Ltd./Bristol-Myers for Sovaldi and JPY80,171.30 for Harvoni. ($405.88bn) in the fiscal year ended March Squibb Co.’s PD-1-targeting antibody for Gilead reported first half sales in Japan 31, 2016, an actual increase of JPY1.5tn, cancer Opdivo (nivolumab). of $1.33bn for Harvoni, roughly triple those the new data from the Ministry of Health, in the previous year’s period, while Sovaldi Labor and Welfare show. HCV And Cancer also grew strongly to $373m. But it was the jump of around 9% The first two products were launched in Opdivo was approved for the first time (JPY680bn) in total prescription costs to May and September respectively last year, worldwide in Japan, in July 2014, for unre-

12 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Regulatory Update

the figures, but are likely to further concen- trate policy makers’ attention on the spike in government-paid drug costs arising from new therapies introduced over the past few years.

Industry Views The pharma industry has not surprisingly been steadfastly opposed to any expan- sion of price reductions, with major as- sociations including PhRMA arguing that drugs help offset or avoid other medical costs within the system, while supporting policy moves to encourage increased ge-

Shutterstock: Daimond Shutter Daimond Shutterstock: neric use. Before the company was hit with the Japan conducts biennial revisions of drug reim- price cuts, Gilead President Dr. John Mil- ligan also pointed out during a visit to Ja- bursement prices every other April, with the aim of pan that as Sovaldi and Harvoni effectively aligning reimbursement prices with actual (discounted) “cure” HCV, their initial high costs to the system reflect pent-up demand and will market levels, based on a nationwide survey. steadily decline as patient numbers fall. Japan is furthermore considering the sectable metastatic melanoma, a relatively els, based on a nationwide survey. There gradual adoption of some type of formal small patient population, with reimburse- are also other defined mechanisms to con- health technology assessment, but initially ment prices at launch of JPY729,849 per trol rising NHI drug costs, notably one-off this is only being retrospectively applied 100mg/10mL infusion and JPY150,200 per cuts for big-selling products for which sales to selected marketed drugs to determine 20 mg/2mL. have expanded rapidly beyond official es- if their prices are appropriate. But while the initial patient population timates at the time of reimbursement. The local and international industry is was limited, it has expanded sharply with Under new such rules implemented cautious over the HTA plans, warning that subsequent local approvals of Opdivo for this April, price cuts of up to 25% can be systems in other countries are laced with non-small cell lung cancer (NSCLC) last De- applied to products with annual sales of shortcomings and advising that a holistic cember and just recently for renal cell car- JPY100-150bn for which sales have grown approach that considers medicines’ broad benefits is needed. cinoma. Fiscal first quarter sales of Opdivo to at least 1.5 times the initial projection, The increasing use of expensive drugs (to June 30) surged to JPY25.2bn, and the while cuts of up to 50% can be levied on may also add to medical and public sector total number of new patients treated as of drugs with sales of more than JPY150bn demands for increased transparency in the mid-July was around 8,600, Ono noted in that have expanded by at least 1.3x initial price-setting process for novel products. its results for the period. official forecasts. While the methodology is already clear (al- The firm is currently forecasting Opdivo Under these rules, Sovaldi and Harvoni’s beit highly complex) and released publicly, sales of JPY126bn for the fiscal year ending prices were slashed by around 32% in April. the “cost-plus” approach applied to new next March 31, within which NSCLC will ac- Even so, with health and drug costs drugs without comparators relies in part count for most of the figure. looking set to continue rising, it seems on manufacturers’ undisclosed estimates While patient out-of-pocket co-pay- likely that the latest ministry figures will of R&D and manufacturing costs, to which ments (usually 30%) for expensive drug prompt continued evaluation of pricing a system of premiums is applied. treatments in Japan are capped depend- and reimbursement mechanisms. These Innovative companies have so far been ing on income, the NHI health care system have already been coming under scrutiny quiet on this issue but R&D-based associa- still has to bear the full cost of the drugs. since April by the Ministry of Finance’s Fis- tions say they would like to see the contin- cal System Council, which is tapping into uation of Japan’s current reimbursement Policy Steps testimony from medical experts and re- pricing system, which they view as encour- Japan conducts biennial revisions of drug portedly considering further extraordinary aging innovation. reimbursement prices every other April, price cuts for selected drugs next year. with the aim of aligning reimbursement The new official data make no commen- From the editors of PharmAsia News. prices with actual (discounted) market lev- tary or recommendations with respect to Published online September 19, 2016 pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 13 regulatory update

As Appraisal Fees Loom, NICE Says No To Industry Calls For Reform

Vibha Sharma [email protected]

he UK pharmaceutical industry is hoping that a proposal Independent consultant Leela Barham thinks that the consulta- by health technology assessment body NICE to charge for tion on the fee-based model should not be seen as an opportunity T technology appraisals will allow companies to discuss po- to drive reforms to NICE’s methods “as the case for that needs to tential reforms to HTA processes, but NICE has stated clearly that be made on its own merit.” However, she believes that moving to a there will be no negotiations on this front. fee-based system “might help to hold NICE to account” and the aim Also, it is expected that the proposed fee-based system will add should be drive improvements to that end. In Canada, for example, to the business complexities of bringing new medicines to the she pointed out that fee reductions are offered to companies if market, especially for drugs that are to be used in a very limited the health technology assessment body CADTH does not issue a patient population where the revenue gain may be close to the timely recommendation. cost of getting the product appraised. Catchpole, however, believes there is a case for reform. The pro- The National Institute for Health and Care Excellence has said file of the medicines pipeline, he pointed out, is changing as a result that it will not consider changes to its current methods in return for introducing a fee-based system for technology appraisals. At “We need to find a way for NICE present, these appraisals do not involve any costs for pharmaceu- tical and medtech companies as they are funded by the govern- to responsive to industry’s ment. NICE is considering moving to a full cost-recovery model as government bodies have been asked to reduce their reliance on requirements, while maintaining grant-in-aid funding. The Association of the British Pharmaceutical Industry’s Value and proper independence” Access Director Paul Catchpole told the Pink Sheet that the APBI was – Paul Catchpole “happy to explore with NICE, in principle, the merits of charging for [technology] appraisals, but in return for that the industry is keen of the new kinds of medicines already coming to the market, such to see NICE progressing with some reforms and changes that the as stratified medicines for more targeted groups of patients, regen- industry thinks would be important in order to ensure that NICE’s erative medicines, advanced therapy products and medicines for processes are fit for purpose for the medicines of the 21st century.” rare diseases. “In that context, the industry is keen to ensure that Catchpole said there was a range of areas that the industry would NICE can maintain its leadership in HTA… by ensuring that the way like NICE to consider as part of an “evolutionary journey” and that the it evaluates medicines is up to date” and can tackle the challenges quality-adjusted life year (QALY) – the threshold against which medi- that such new types of medicines pose to evaluative methods and cines are judged regarding value for money – “is a very key area.” processes, he said. Catchpole is mindful of the fact that NICE’s credibility comes “NICE will not negotiate its methods as a from the fact that it works independently and carefully balances result of its cost recovery activities.” the needs of different stakeholders, including patient groups and NICE, however, told the Pink Sheet that during the consultation, sponsors of technology. “Nevertheless, if only the industry is pay- “companies are being given the opportunity to comment on the ing for appraisals and other groups are not, then I think we do need cost-recovery proposals only. NICE will not negotiate its methods to find a way for NICE to listen and be responsive to industry’s re- as a result of its cost recovery activities.” quirements, while maintaining proper independence”,” he said. In the consultation document, NICE clarifies that the introduc- Ensuring NICE’s independence is critical and Barham points out tion of charges will not have an effect on its methods. “NICE will there are already some who feel that NICE is not independent continue to develop its methods independently. Industry will con- enough as it is. “I suspect that [the introduction of a] fees will be tinue to be given the opportunity to be involved and consulted, a further driver of scrutiny of what NICE does and who is involved and the introduction of a direct payment relationship will not con- and in what way: that is no bad thing as it is not necessarily a con- fer any more right to influence NICE’s methods than currently ex- flict of interest so much as a vested interest that needs to be trans- ists,” the HTA body says. parent so that all stakeholders are aware,” she told the Pink Sheet. Nevertheless, NICE states that its fee proposals will be reviewed NICE is not alone in charging companies for HTA related activi- in the light of the report of the government’s Accelerated Access ties. Several other countries, such as Australia, Canada and more Review, “which may contain recommendations for changes to the recently Ireland, have introduced charges for some elements of the processes NICE uses for its technology evaluation programmes”. pricing and reimbursement processes, albeit at much lower rates

14 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Regulatory Update than those proposed by NICE, said Christian Hill, managing direc- Proposed charges by NICE tor of consultancy firm MAP BioPharma. “These fees have not noticeably deterred companies from mak- ing submissions in those countries, but it is something that must Type Of Technology Appraisal Proposed Fee be transparently justified, as market access is a very expensive pro- cess already, and increasing those costs may at best delay patient Single Technology Appraisal (STA) £142,000 access and at worst could make some medicines unavailable,” Hill Highly Specialised Technology (HST) told the Pink Sheet. Barham, who has looked at the fees charged by HTA agencies in Abbreviated Technology Appraisal (ATA) £99,000 Australia and Canada, said these examples are still relatively new Rapid review and despite initial concerns it seems that these fee systems are at the very least feasible. The jury is still out on whether they are desir- able or not, she added. Multiple Technology Appraisal – standard £210,000

Will Some Companies Prefer To Skip NICE Multiple Technology Appraisal – complex £282,000 Appraisals? NICE said it would start charging companies for the cost of under- Source: NICE consultation document taking technology appraisals and highly specialized technology appraisals once it secures the necessary approvals and the regula- tions governing NICE have been changed. “We anticipate that to Fees “Add Another Dimension” be in 2017/18,” a NICE spokesperson said. Catchpole believes the introduction of HTA fees would add anoth- Specifically, NICE is planning to charge £142,000 ($188,000) for er dimension to the business of bringing medicines to the market, a single or a highly specialized technology appraisal (see table for especially in cases where the medicine is targeted for a very limited full details). There will be no reduced charges for small companies. patient population. “It is certainly possible that when you start to However, to help small companies with their cash flow, NICE said get down to very small numbers of patients, then the potential re- it would look into charging small companies in instalments rath- turn for companies from marketing those medicines in those indi- er than upfront. This is line with similar arrangements offered by cations may not be that far away from the charge that has been put medicines regulator MHRA, it explained. in place for the NICE appraisal in the first place,” he said. So will the introduction of a fee-based system result in some com- This, he said, is something that the companies will have to weigh panies skipping the NICE appraisal process altogether? There is un- up in terms of the business case on whether to go through a na- certainty on how this might play out. The NICE spokesperson clari- tional reimbursement submission with NICE versus the commer- fied that even under the present system, companies have the option cial returns that the company will get in the long run if the propos- of not getting their products appraised, and under the fee-based als go ahead as presently proposed. system they can continue to “decide whether or not to they want Given that the fees proposed by NICE are relatively high in com- to make a submission [to NICE] for their product [to be appraised].” parison to the fees used by other HTA agencies in Australia and Barham said this already happens. Quoting from NICE statistics Canada, Barham said it is more likely that companies will try even for March 1, 2000 to July 31, 2016, she pointed out that 26 compa- harder to ensure that they put in the best submission they can. nies chose not to submit their products to NICE. While it is unlikely that the introduction of a fee-based system Ever since the fee proposals have been announced, Hill said skip- will have a negative impact on the reimbursement of medicines ping NICE appraisals “is certainly already on companies’ minds, and on the National Health Service, Hill pointed out that there are con- several subscribers to our online market access services have con- cerns among his clients on this front that his company will take up firmed that this is likely to be the case,” he said. with NICE “so that NICE can fully consider the potential unintended However, Hill pointed out that avoiding NICE appraisal may not consequences of its proposals.” make things easier for companies as they have few options to Barham believes that the introduction of a fee-based system ensure patient access to their products. “Avoiding a NICE review will bring greater transparency to the cost of technology apprais- would mean that commissioning arrangements would be needed als “and that might bring further scrutiny on whether they need to in the absence of guidance. Even with positive NICE guidance, this cost as much, as well as whether they offer value for money.” has sometimes been problematic, such as with Hepatitis C medi- NICE will accept industry feedback on its proposals until Sept. cines due to the high early budget impact, despite being highly 30. Based on the comments received, NICE said it would further cost effective in the long term. Therefore, if companies have to put develop its proposals, which will then be subject to Department of themselves at the mercy of NHS England and CCG commission- Health and Treasury approval. ing prioritization, then they may be in store for a lengthy delay to access, well beyond what they might have experienced had they From the editors of Scrip Regulatory Affairs. Published online submitted to NICE appraisal,” he explained. September 22, 2016 pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 15 Consumer Products Tom’s Of Maine Ingredients’ Efficacy Weighed Against ‘Natural’ Claim In NAD Review Malcolm Spicer [email protected]

review of advertising for Colgate- NAD also considered the use of “natural” Palmolive Co. Tom’s of Maine anti- claims in a 1999 review of Tom’s of Maine Aperspirant highlights a challenging Natural Mouthwash, finding the “pure question for firms marketing certain kinds simple ingredients from nature claim” was of “natural” products – compliance with an supported where all the active ingredients FDA ingredient requirement might conflict were naturally sourced but approximately with their “natural” claims. 1% of the product was a non-natural emul- The issue is highlighted in a National Ad- sifying agent. vertising Division recommendation pub- However, claiming its antiperspirant is lished Sept. 20 that the company change “naturally dry” is misleading by implying the name of its Tom’s of Maine brand’s Natu- that natural ingredients are responsible for rally Dry Antiperspirant. Colgate is appealing the product’s effectiveness when the active the recommendation, arguing that a class ingredient is extensively chemically pro- action settlement on the brand’s “natural” cessed, the attorneys said. claims should be a stop sign for a review by While Colgate referred to the product in- NAD, the investigative arm of the NAD Ad- As a Tom’s of Maine brand gredient list and a definition of natural on name, Naturally Dry vertising Self-Regulatory Council, the Tom’s of Maine website as disclosures Antiperspirant makes an Unilever PLC challenged the product’s unsupported express that should resolve any consumer confu- claims of “Naturally Dry,” “It really works. Natu- message “that natural sion, NAD attorneys said those statements rally,” and “Natural Powder,” arguing that the ingredients are responsible for are not clear and conspicuous and do not aluminum chlorohydrate for wetness control the dryness provided by this appear in close proximity to the main claims. in Tom’s of Maine Naturally Dry is not natural, antiperspirant,” NAD says They also point out the disclosures contra- but is formed from reacting aluminum in- dict that the antiperspirant is “naturally dry” gots with hydrochloric acid under controlled by stating the product’s active dryness in- conditions. With aluminum chlorohydrate, gredient is a non-natural, heavily processed Tom’s of Maine is compliant with FDA’s re- aluminum salt, which consumers seeking quirement that antiperspirants contain an natural products might wish to avoid. aluminum salt-based active ingredient. While FDA has oversight authority for Colgate is appealing NAD attorneys’ rec- antiperspirant formulations and manu- ommendation to the National Advertising ARSC procedural facturing, the agency has not taken on Review Board, the appellate panel of ASRC, whether firms can support making natural which is part of the Council of Better Busi- rules stop a NAD claims for the products. It will look at the ness Bureaus. potential need for a rulemaking for “natu- As a Tom’s of Maine brand name, Natu- review when litigation ral” labeling on dietary supplements and rally Dry Antiperspirant makes an unsup- other food products after reviewing com- ported express message “that natural in- already has resolved ments in a docket it opened in November gredients are responsible for the dryness arguments over 2015 on questions including whether a provided by this antiperspirant,” NAD says. public health concern will emerge if the challenged claims, agency does not substantially expand its Natural In NAD’s Bailiwick regulation of use of the term. NAD attorneys noted previous reviews in- but not when a The Federal Trade Commission, mean- cluding a 2012 decision that McNabb Nu- while, dipped its toes into natural claims traceuticals LLC’s claim of “sunscreen for skin settlement does not enforcement earlier in 2016 with actions that prefers no chemicals” for its Sunology against five companies making unsup- Sunblock is adequately disclaimed and is not address the claims. ported all-natural and 100% natural claims likely to be misleading with the explanation in online advertising for personal care “active ingredients derived from nature.” products, including sunscreen.

16 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Consumer Products

NAD Jurisdiction Disputed result in inconsistent guidance on the ad- alterations generally are not “natural” in For NAD, the key procedural issue is wheth- vertising claims, a court order approving a the way consumers expect them. er an earlier class action settlement on the litigation settlement is unlikely to produce Since acquiring 84% of Tom’s of Maine antiperspirant’s claims precludes a review. inconsistent guidance particularly where, shares in 2006 for $100m cash, Colgate The US District Court for the Southern Dis- as in this case, the settlement did not re- has expanded the brand from the health trict of Florida approved a settlement to a quire changes to the challenged advertis- and specialty trade channel to traditional class action that alleged false advertising in ing claims,” according to NAD attorneys, retail channels and has established its claims that Naturally Dry Antiperspirant and who determined they “retained jurisdic- lines as key drivers across its oral and skin other Tom’s of Maine products are natural. tion to review the challenged claims on care sectors. The attorneys contend the January 2016 their merits.” In the class action settlement, Tom’s settlement did not consider the accuracy of Maine committed $4.5m to refunding of the claims. Colgate argues that the ad Brand Change ‘Burden’ Noted consumers for natural product purchases claims in the NAD review “are identical to The attorneys did not downplay the sig- across its portfolio excluding toothpastes those” targeted in the litigation. nificance of recommending that Colgate – sunscreens, body washes, shampoos and “That litigation was fully resolved by a change the name of Naturally Dry Antiper- lip care products as well as deodorant/an- court order,” the New York-based personal spirant, saying they are “cognizant of the tiperspirants and other items – between and oral care product giant says in a report burden placed on an advertiser when [a March 25, 2009 and Sept. 23, 2015. on the NAD review. NAD] decision affects the product name.” Appeals of NAD recommendations are NAD’s attorneys say a judge consider- However, NAD will recommend a prod- heard by five-member National Advertis- ing a proposed settlement in class action uct name change, “even in the absence of ing Review Board panels made up of ad- litigation alleging false advertising weighs extrinsic evidence of consumer confusion, vertising and marketing experts, including whether the settlement is fair, not whether if the product name itself conveys a mes- professors and executives, from outside the challenged ad claims are misleading. sage that is false or misleading,” they said. the organization that the CBBB appoints “A court-ordered settlement in class ac- The review concluded that “naturally on a rotating basis. The panels generally tion litigation takes into account the fair- dry” as it appears in Tom’s of Maine adver- align with conclusions from reviews by ness of the results and the fairness to the tising and on product packaging conveys NAD attorney’s and ASRC’s Electronic Re- class, but the court does not make findings an unsupported express message “that tailing Self-Regulation Program. as to the truthfulness of the advertising natural ingredients are responsible for the In changes to ASRC’s procedures ad- claims at issue,” according to NAD attorneys. dryness provided by this antiperspirant.” opted in late 2015 from recommendations ARSC procedural rules stop a NAD re- Agreeing with Unilever’s challenge, the by an American Bar Association working view when litigation already has resolved attorneys said ingredients derived from group, NAD attorney’s role in appeals is arguments over challenged claims, but not nature that undergo significant chemical limited to being available to answer ques- when a settlement does not ad- tions, no longer representing the dress the claims. advertiser or challenger making “While a court order evaluating We have an online page focused an appeal or submitting briefs. the truthfulness of the same ad- on the consumer drugs sector. vertising claims would result in du- From the editors of the Tan Sheet. Find it at: https://pink.pharmamedtechbi.com/consumer-drugs plicative proceedings and might Published online September 19, 2016

Clinical Trial Landscape Whitepaper By Christine Blazynski

Reviewing the landscape of clinical trials that completed in 2015, the disease areas with successful outcomes, and the companies that backed them.

Download your copy now! citeline.com/category/whitepapers/

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 17 Consumer Products Liquid Dosing Accuracy Four-Times Better With Oral Syringes – Study Eileen Francis [email protected]

esearchers question the accuracy of dosing using cups commonly in- Rcluded with liquid drugs after find- ing 84% of parents measure the wrong amount of medicine and are four times more likely with cups than syringes to dose inaccurately. The percentage of attempts with er- rors per parent when using a cup reached 43%, but 16.7% with a 0.2mL syringe and 16.2% with a 0.5mL oral syringe, accord- ing to a study, which found that cups “are most frequently included” with OTC prod- ucts, published in the journal Pediatrics following research led by H. Shonna Yin, New York University School of Medicine Department of Pediatrics. “Recommending oral syringes over cups, particularly for smaller doses, would “Recommending oral syringes over cups, be part of a comprehensive pediatric la- particularly for smaller doses, would be part of beling and dosing strategy to reduce medication errors,” Yin and her colleagues a comprehensive pediatric labeling and dosing concluded. Conducted between August 2013 and strategy to reduce medication errors.” December 2014, the research included 2,110 parents of children ages 8 and – Pediatrics study younger recruited from three urban pe- diatric outpatient clinics in Atlanta, New ‘Greatest’ Error, Cups For tion of syringes in the test bearing fewer York and Stanford, Calif. Small Dosing dosage markings on them did not lead to In the randomized, controlled trial, The researchers also found the use of dos- more errors. “It may be that parents benefit subjects randomly assigned into five ing cups “greatly” increased the risk of er- so much form using a syringe over a cup groups were asked to measure medicine rors, especially with smaller dose amounts, that the added benefit of simplifications of using various devices. Each parent mea- and overall led to more than four times the markings is not discernible.” sured nine doses of medication in three risk for error compared with syringes, the Although the strength of associations amounts – 2.5 mL, 5 mL and 7.5 mL – us- study reported. differed somewhat by health literacy and ing three tools in random order, a cup and “One reason why cups may be inferior language, the study “clearly identified cer- two oral syringes. to syringes is that the same distance along tain improvements that could be made to The groups differed by pairings of mea- the side of the tool represents a greater labels and tools to enhance dosing accu- surement units stated on product labels volume for cups than for syringes,” the re- racy for parents,” the researchers reported. and tools that contained a mix of millili- searchers noted. For example, in a cup, the The researchers point out that with a ter and teaspoon measurements, includ- distance of 1 mm might contain a volume significant number of parents making ing some with both on either the label of 0.8 mL, but on a syringe, the same mea- dosing errors using oral syringes, they or tool. The outcome measured dosing surement could hold 0.1 mL, they noted. recommend more intensive education of errors, determined by pediatricians using The researchers also said “when a cup is consumers by physicians, pharmacists and a pharmacy-grade electronic digital pre- not held at eye level, it may appear to be other health care providers, including the scription scale to compare the measured filled to a particular marking when it is not.” use of pictures and demonstrations. does with a reference weight. They also discovered that the simplifica- FDA included both cups and syringes

18 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Consumer Products in a 2011 final guidance that advised OTC sociation notes that the CHPA Educational were used with concordant milliliter-only la- drug firms to provide a dosage device with Foundation provides information to con- bels and tools, parents made one or two errors their products and suggested using either sumers on accurate dosing of OTCs and on average across the nine trials. teaspoons/tablespoons or metric mea- that FDA regulates drug product labels The American Academy of Pediatrics has surements on both a product’s label and and dosing devices. suggested dosing orally administered pre- its dosing device. “Knowing how to properly treat chil- scription liquid medicines exclusively with The mention of cups as appropriate deliv- dren with over-the-counter medicines is labels and delivery tools marketed with mil- ery devices also was included in guidance so important, and this study underscores liliters to avoid confusion and dosing errors for liquid acetaminophen pediatric prod- the need for parents to practice great at- associated with common kitchen spoons, ucts that FDA published in August 2015. tention and care every time they give their the study authors point out. The academy The guidance created more room for in- children medicine,” said Anita Brikman, CH- also recommended dosing liquid medi- novation than allowed in the draft versions PA’s vice president, communications and cines to the nearest 0.1 mL, 0.5 mL or 1 mL. by omitting a recommendation against public affairs, and executive director of the AAP’s position is consistent with that potential use of droppers and including a foundation, in a statement. of the American Pharmacists Association, statement that CDER will consider alterna- which in March adopted a policy on la- tives to calibrated cups and oral syringes. Teaspoon-Only Labeling: beling and measurement of oral liquid Rx The agency also recommended marketers More Errors medications to move away from “outdat- of those products include an appropriate The researcher noted their study was the ed” dosing cups and teaspoons in favor of delivery device including a calibrated and first to examine, within an experimental oral syringes and cups that measure only labeled oral syringe or dosing cup. study, whether altering specific label and in the metric system. The policy entails us- According to the researchers, several dosing-tool attributes can reduce parent ing milliliter as the standard unit of mea- studies have found that cups are associ- liquid medication dosing error rates. sure for oral liquid medications. ated with higher rates of parent errors, but The researchers found that 84% of par- “Our findings suggest that health care they were limited in scope with respect to ents made more than one dosing errors in providers should encourage oral syringe the range of dose amounts tested and as- their nine trials and that most errors were use for the measurement of liquid medica- pects such as complexity of tool markings, in the form of over-dosing; more with 2.5- tions, particularly when small doses are rec- said the researchers. and 7.5mL dose amounts, compared with ommended; this change would probably “Previous studies have demonstrated the 5-mL dose amounts. benefit all families, regardless of health liter- superiority of syringes to cups when a 5mL Use of a teaspoon-only label, paired with a acy and language,” said the researchers. dose was tested. Our study is unique in that tool marked with milliliter and teaspoon units, we examined a range of doses,” they said. was associated with more errors than pairing From the editors of the Tan Sheet. Published The Consumer Healthcare Products As- milliliter-only labels and tools. When syringes online September 20, 2016

Generic Drugs FDA’s ANDA Approvals

Sponsor Active Ingredient Dosage; Formulation Approval Date Mylan Levetiracetam 500 mg/5 mL (100 mg/mL); injectable, IV infusion 9/16/2016 Kremers Urban Buprenorphine HCl/ naloxone HCl EQ 2 mg base/EQ 0.5 mg base and EQ 8 mg base/EQ 2 mg 9/19/2016 base; sublingual tablet Aurobindo Darifenacin HCl 7.5 mg and 15 mg; extended-release tablet 9/19/2016 MacLeods Valsartan 40 mg, 80 mg, 160 mg and 320 mg; tablet 9/20/2016 Acella Brompheniramine maleate/ 2 mg/5 mL, 10 mg/5 mL and 30 mg/5 mL; oral syrup 9/20/2016 dextromethorphan hydrobromide/ pseudoephedrine HCl Accord Spironolactone 25 mg, 50 mg and 100 mg; tablet 9/20/2016 Tentative Approvals Aurobindo Dolutegravir 50 mg; tablet 9/20/2016

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 19 Drug review profile / An inside look at key lessons learned from recent FDA approvals.

Zecuity Redesign Got Migraine Patch Through FDA, But Burning Continued

Brenda Sandburg [email protected]

DA thought burning and scarring effects with NuPathe Inc.’s mi- sents a very small fraction of the migraine population, but also a graine therapy Zecuity could be addressed with a redesign that very disabled subgroup,” he added. Fadded technology to ensure proper placement of the patch, but The transdermal route bypasses the gastrointestinal system, pro- persistent adverse events reported during the battery-powered trans- viding an alternative means of delivering sumatriptan to migraine dermal system’s short time on the market suggests that the agency’s patients who might not be able to tolerate oral medications. The confidence that the problem had been fixed was misplaced. iontophoretic technology allows the drug to transfer through the FDA reviewers initially opposed approval of Zecuity, an ionto- skin without needles. phoretic transdermal system that delivered the venerable migraine Clinical reviewer Nushin Todd also gave the migraine patch a drug sumatriptan (GlaxoSmithKline PLC’s Imitrex and generics), muted endorsement. “Overall, the benefits derived from Zecuity in part because the patch caused burning and scarring in clinical marginally outweigh its risks of causing numerous adverse events trial subjects. At FDA’s recommendation, the sponsor redesigned at the application site,” he said. the product, and when the redesigned version was approved, the agency did not require a warning about those risks in labeling. “Overall, the benefits derived from FDA approved Zecuity on Jan. 17, 2013, for the acute treatment of migraine with or without aura in adults, making it the only Zecuity marginally outweigh its patch approved for the indication. NuPathe waited to commer- cialize the drug-device combination product until it could scale risks of causing numerous adverse up manufacturing and find a domestic partner. Teva Pharmaceu- events at the application site” tical Industries Ltd. acquired NuPathe in 2014 and launched Ze- cuity in September 2015. – FDA clinical reviewer Nushin Todd It was soon after Zecuity was launched that FDA learned that the modifications to the patch design were inadequate. FDA an- More than half of the patients (57%) in two long-term safety nounced in June 2016 that “a large number of patients” had report- studies sustained a treatment-emergent adverse event, Todd not- ed burns or scars from the patch, and Teva voluntarily suspended ed. The vast majority of AEs were related to application site con- marketing of the product. ditions, most commonly pain and pruritis. He also pointed to the In response to a Freedom of Information Act request, FDA pro- high rate (59%) of discontinuation in the studies, mostly due to vided a list of cases generated by the FDA Adverse Event Reporting withdrawal of consent and adverse events. System (FAERS). The list includes more than 600 reports of burns, “Modifications made to the device portion of the product have miti- including 23 reports of first- and second-degree burns. In addition, gated the risks for potential severe burns and scarring that occurred in there were more than 140 separate reports of “sunburn.” some patients in the clinical program,” Todd concluded. “Local adverse events from use of the product, however, remain numerous.” Zecuity’s Marginal Benefit-Risk Ratio FDA’s review team found Zecuity to be effective in relieving mi- Device Modifications graines, but they did not express much enthusiasm for the product Zecuity is a disposable, single-use, co-packaged drug/device and expected it would be used by a limited number of patients, combination product that delivers 6.5 mg of sumatriptan over review documents show. four hours. The drug portion consists of a reservoir card that has “There is no definite evidence that this product addresses an two reservoir pads, one containing sumatriptan and the other unmet medical need,” FDA Division of Neurology Products Deputy containing a salt solution. The device portion is an electrode Director Eric Bastings, who served as the review team leader, said patch containing positive and negatively charged electrodes in a summary review of the application. “Patients with prominent connected to a programmed circuit. Patients remove the top nausea already have several non-oral alternatives, including a na- foils protecting the drug reservoir and electrodes and apply the sal spray, and a subcutaneous formulation for self-administration electrodes over the drug reservoir. The patch is applied to the with an autoinjector, or with a needleless device.” upper arm or thigh and drug delivery is activated by pushing “Nevertheless, the product may offer benefit for patients who a button. After four hours, the system is automatically deacti- have prominent nausea or vomiting and who cannot tolerate or vated by the preprogrammed circuit. are unwilling to use the marketed formulations of sumatriptan,” FDA recommended that the product be redesigned after pa- Bastings commented. “Arguably, that subgroup of patients repre- tients experienced burns and scarring in the clinical trial. Nu-

20 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Drug review profile

Pathe modified the patch to include a “pad detection system,” a plastic surgeon to discuss cosmetic repair for the discoloration. which includes a pre-programmed microprocessor that conducts FDA criticized the company’s attribution of the lesions to “improp- a series of diagnostic tests to verify pad placement, skin resis- er application.” tance and device functionality prior to drug delivery. If the pads FDA also noted that there were three adverse event reports of are misaligned or missing, the system prevents pad activation. severe burns and two reports of moderate burns in long-term safe- Todd noted that 647 modified patches were tested in two ty studies, and one report of “mild scar.” clinical studies and reportedly were 100% effective in detecting “In addition, we cannot rule out that your database includes ad- misaligned or absent medication pads and preventing patch ditional cases of permanent skin lesions that were not described activation. in your summary of clinical data,” the agency said. “Unless you can provide evidence that cases of significant administration site ad- Safety, Usability Concerns Behind Extensive verse events (e.g., burn, scar, discoloration or abnormal pigmenta- Complete Response Letter tion) in your database ultimately resolved, we believe that the risk While burning and scarring would cause the removal of Zecuity of skin lesions (in particular with permanent sequelae) is not justi- from the market, those adverse events were only one of many con- fied by the benefits of the product.” cerns about product design that FDA communicated to NuPathe. FDA said it was not able to estimate the exact incidence of ad- The complete response letter (CRL) the agency issued on Aug. 29, verse events because they were often reported by non-specific 2011, is notable for its length. The CRL cites nine concerns with clin- terms, such as “site reactions,” or “adverse drug reactions.” It direct- ical data, six concerns with microbiology – and 71 issues related to ed the company to re-examine and recode the adverse events. product quality. The agency also cited the high rate of discontinuation in long- FDA had already told NuPathe that the fundamental design of term safety studies (55%) and noted that the most common reason Zecuity was not acceptable in a May 2011 chemistry, manufactur- the company gave for discontinuation was “withdrawal of consent.” ing and controls (CMC) information letter. But FDA said the company did not include the reasons for with- The CMC letter previewed many of the issues cited by the CRL. drawal of consent in its database and pointed out that withdrawal “A lack of uniformity of drug formulation distribution, and issues is often due to an adverse event. with drug formulation containment, safe disposal procedures, and patient usability raise concerns about the safety and efficacy of the One Reviewer Opposed Approval product,” the information letter stated. The sponsor resubmitted the Zecuity NDA in July 2012 with modi- The agency said the amount of drug on the drug-containing pad fications that persuaded the review team to recommend approval was not evenly distributed and that variable amounts of the drug – with one exception. Non-clinical pharmacology/toxicology re- remained on the reservoir side after pad transfer. “This lack of uni- viewer Charles Thompson recommended a “not approvable” ac- formity may result in variable amounts of drug transferred from the tion, saying the sponsor’s nine-month dermal toxicity study was packaging to the patient, which has potential safety and efficacy inadequate and that the company had not provided sufficient in- implications,” the agency said. formation to warrant a waiver for a dermal carcinogenicity study. FDA reviewers also cited the complicated assembly of the trans- Supervisory pharmacologist Lois Freed agreed with Thompson’s dermal system, saying it could increase the chance for exposure to conclusion that the sponsor had not provided sufficient nonclinical the drug formulation. They recommended that the sponsor con- data to support approval of the NDA. However, in a Jan. 14, 2013, duct a comprehensive risk analysis identifying the use-related and memo Freed said that since the clinical team had determined that medication error risks with the iontophoretic system. Zecuity provided clinical benefit, particularly in migraine patients NuPathe’s response did not quell FDA’s concerns. CMC review- who cannot take sumatriptan orally, the nonclinical deficiencies ers followed up with a discipline review letter in July 2011 stating could be addressed with post-marketing requirements. that the agency “remains unconvinced” that the lack of formulation Review team leader Bastings explained that the key question containment, the drug formulation, and the large quantity of re- was whether Zecuity had a clinical benefit that would justify al- sidual drug after use “do not pose a safety risk to the patient, health lowing the product to be marketed before the nonclinical studies care provider, children, or pets.” were conducted. Given the vast experience with other formulations of sumatrip- FDA Skeptical Of NuPathe’s Improper tan and the absence of a signal of carcinogenicity with the other Application Explanation routes of administration, he concluded that it was acceptable to FDA also cited inadequate chronic dermal toxicity testing and the have the sponsor conduct nonclinical studies as post-market- risks of burning and skin discoloration. “We have serious concerns ing requirements. The agency required an in vivo repeat-dose about the potential for your product to cause severe burns and dermal-painting study of sumatriptan in an appropriate mouse permanent skin lesion,” the complete response letter said. model using various permeation enhancers and a dermal carci- The agency noted that the company’s summary of clinical safety nogenicity study in mice. described several cases of patients who experienced permanent As for the product’s safety, Bastings said the sponsor provided skin lesions, including one patient who had a consultation with adequate engineering evidence to support that the pad-detec- pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 21 Drug review profile tion system will operate as expected and the review team agreed dose of Zecuity or placebo; 454 subjects were included in the it was sufficient to address the burn/scarring issue. However, he intent-to-treat population. The primary endpoint was absence said that given the lack of clinical experience with the redesigned of headache pain two hours after patch activation. The trial also product, the sponsor would be required to report all postmarket- included three key secondary endpoints looking at relief of other ing cases of burns and scarring as 15-day safety reports. migraine symptoms: absence of photophobia, phonophobia and nausea two hours after activation. REMS Deemed Unnecessary The patch was superior to placebo across all endpoints. Forty of NuPathe itself had been cautious about the product’s safety risks the 226 subjects (17.7%) in the Zecuity-treated group reported no and proposed a Risk Evaluation and Mitigation Strategy, which in- headache at two hours compared with 21 of 228 (9.2%) subjects cluded a Medication Guide and other elements. These other ele- in the placebo-treated group. For the secondary endpoints, 116 of ments were redacted in FDA’s July 2011 REMS review document. the patients in the Zecuity group (51.3%) v. 83 (36.4%) in the pla- The Division of Neurology Products had concluded that the cebo group were free of photophobia at two hours after activation; product did not require a REMS to mitigate the well-known risks 125 (55.3%) in the Zecuity group v. 89 (39%) in the placebo group were free of phonophobia; and 189 (83.6%) in the Zecuity group v. 144 (63.2%) in the placebo group were free of nausea. The Zecuity NDA was filed under the The study looked for dermal effects of Zecuity, but burning and 505(b)(2) pathway, allowing NuPathe scarring are not among the effects described in approved labeling. The only dermatologic concern in the label’s warnings and precau- to rely on FDA’s prior findings of tions section is allergic contact dermatitis, based on 4% ACD rate in open-label studies out to one year. safety and efficacy for Imitrex tablets The label does advise users to remove the patch if they experi- ence “a powerful burning sensation during use.” and subcutaneous injection. Labeling also does not address review team concerns about ef- ficacy data in non-white patients. The label states that “analyses of associated with sumatriptan, which were to be included in the pro- the relationship between age, race, gender, or BMI and response posed labeling, the Office of Surveillance and Epidemiology’s Divi- showed no significant differences in response rates.” sion of Risk Management noted. Bastings, however, observed that the efficacy results in non- The Division of Risk Management deferred comment on the white patients in the pivotal study appeared questionable. Sub- proposed REMS since FDA was to issue a complete response letter. group analyses of the non-white population, which included 19% The CR letter said the agency did not believe a Medication Guide of the study population, “indicate that in non-white subjects, Zecu- would be sufficient to mitigate the risks, as significant skin toxicity ity was no better than placebo for the primary endpoint: 12.5% vs. occurred in clinical trials despite patients being instructed how to 11.4%, p=0.87 (according to the sponsor analysis),” he said. use the product. But the agency said it had not yet determined if Additional analyses from the sponsor “do not provide a very other REMS elements would be necessary. convincing argument of efficacy in non-white patients,” the team FDA’s approval letter does not mention a REMS. The agency’s leader said, “with the caveat that the study was not powered to es- chief safety concern at the time of approval seemed to be the risk tablish efficacy in that subgroup.” of cancer. FDA said it had determined that an analysis of sponta- neous postmarketing adverse events would not be sufficient to Will Teva Try Another Redesign? identify an unexpected serious risk of the carcinogenic potential of Teva’s 2014 acquisition of NuPathe for $144m was part of Teva’s Zecuity and required the two postmarketing studies in mice. The strategy to focus on pain and respiratory disease as its core thera- agency also required studies of Zecuity in adolescents with a his- peutic areas. Teva also said that the acquisition of the company, tory of migraine. and specifically of Zecuity, would leverage Teva’s commercial ex- pertise in marketing complex products, such as its multiple sclero- Labeling Identifies Allergic Dermatitis As sis drug Copaxone (glatiramer). Chief Skin Concern The question now is whether Teva will redesign the product a sec- The Zecuity NDA was filed under the 505(b)(2) pathway, allowing ond time and seek to return it to market. The company said it is work- NuPathe to rely on FDA’s prior findings of safety and efficacy for ing with FDA to explain and characterize the adverse reactions and Imitrex tablets and subcutaneous injection. Only one pivotal ef- determine the feasibility of bringing the product back to the market. ficacy study was required for approval, and it was a single-dose It has not yet determined the root cause of the burning and scarring. study, leaving the Zecuity dataset with less safety experience than And FDA, having been burned by one redesign that did not a new molecular entity would need to provide. Controlled and solve the problem, may be more cautious in accepting further data uncontrolled data in the NDA came from a total of 796 patients on Zecuity safety. treated with Zecuity. The pivotal efficacy study randomized 530 subjects to a single Published online September 16, 2016

22 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Drug review profile

Zecuity Clinical Development Timeline Date Action IND Chronology (#74877) 10/18/2006 Pre-IND meeting 11/24/2009 Pre-NDA meeting 3/4/2010 Pre-NDA meeting on chemistry, manufacturing and controls NDA Chronology (#202278) 10/29/2010 NDA submitted under 505(b)(2) pathway 3/9/2011 FDA rejects proposed tradename Zelrix due to orthographic, phonetic and product characteristic similarities with the marketed drug Salvax (salicylic acid) and the discontinued topical product Lidex (fluocinonide). 5/16/2011 CMC review team sends NuPathe information request letter stating that the fundamental design of its product is not acceptable and recommends that the company conduct a comprehensive risk analysis 6/10/2011 NuPathe submits response to FDA’s 5/16/2011 letter 7/15/2011 CMC team issues discipline review letter saying it remains unconvinced that the lack of formulation containment, the drug formulation and large quantity of residual drug after use do not pose a safety risk 8/29/2011 Complete response letter (CRL) issued on the PDUFA goal date 11/9/2011 End-of-review meeting 7/16/2012 NuPathe resubmits NDA 11/6/2012 FDA finds tradename Zecuity acceptable 12/21/2012 FDA discipline review letter says company has not provided an adequate response to nonclinical deficiencies conveyed in CRL 1/17/2013 Zecuity approved 9/2015 Teva launches Zecuity 6/13/2016 Teva voluntarily suspends marketing

Zecuity Reviewers Clinical Nushin Todd

Statistics Jingyu (Julia) Luan

Clinical Pharmacology Jagan Parepally, Michael Bewernitz

Pharmacology/Toxicology Charles Thompson

Biopharmaceutics Tapash Ghosh

Microbiology Stephen Langille

Chemistry, Manufacturing and Controls Caroline Strasinger, David Claffey

Center for Devices and Radiological Health Geeta Pamidimukkala

Cross-Discipline Team Leader Eric Bastings

Regulatory Project Manager Lana Chen

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 23 Regulatory Update Swedes Explain Why They Should Have the EMA ‘Gem’ After Brexit Ian Schofield [email protected]

ith the UK still undecided as to building a new research hospital in Stock- when to trigger formal negotia- holm’s life science quarter that will work with Wtions on its departure from the research labs and life science firms. EU, a Swedish government official has out- The biopharmaceutical industry is in- lined his reasons why the European Medi- vesting heavily in the life sciences, often cines Agency should relocate from London with state support. GE Healthcare, for ex- to Sweden post-Brexit. ample, is jointly investing with the govern- Several countries other than Sweden ment in a new biotech production facil- have already registered their interest in ity due to open in 2018, while the private hosting the EMA, including Austria, Den- Wallenberg Foundation has allocated mark, France, Italy, Ireland, Poland and SEK320m ($37m) to the Wallenberg Center Spain*. At issue is not only what they can for Protein Research, in collaboration with offer the EMA by way of a science base, uni- Uppsala University, other academic cen- versity network, regulatory expertise and ters and AstraZeneca. so forth, but also what advantages those AstraZeneca itself, Lönnberg noted, is countries might derive from having the building a new biological medicines pro- EMA on their territory. duction facility in Södertalje, to the south- Anders Lönnberg, life sciences coordina- west of Stockholm. With planned invest- Shutterstock: PRILL Shutterstock: tor for the Swedish government, believes ments of $285m, the facility is expected his country is ideally placed to host the “The EMA would be to supply drugs for clinical trial programs agency, which he describes as a “gem”. In an run by AZ and Medimmune, its biolog- interview with the Pink Sheet, he said that like a gem in the ics R&D arm, from the end of 2018, and Sweden has a strong national regulator in to produce products for commercial use the Medical Products Agency, a number of whole life science once it is fully operational by 2019. well-known universities, an established life “So you have the whole network neces- sciences infrastructure with strengths in IT cluster here” sary for tomorrow’s pharmaceuticals here,” and mobile technology, and a solid biologi- Lönnberg noted, adding that the pharma- cals manufacturing base. came to relationships with the EMA. “Com- ceutical industry in Sweden has already Lönnberg, who is also advisor to the Swed- panies tend to think they get a good ser- come out in support of having the EMA ish prime minister’s Innovation Council, said vice when there is a lot of collaboration on its territory. “The Swedish [industry as- that having the agency in Sweden would of- between the national agency and the EU sociation] LIF was first out, before the gov- fer numerous scientific and regulatory ben- agency,” he observed. ernment actually, so they are in favor, and I efits, not least because the MPA is already Lönnberg also highlighted Sweden’s meet several big pharmas every week and closely involved in the work of the EMA and strong and well established life sciences they are in general very positive.” the EU regulatory network, and would also environment. It has a network of universi- serve to attract outside investment. ties with life science capabilities – including Strengthening Swedish Life Two national agencies – the UK MHRA the Karolinksa Institute and the Karolinska Sciences and the Swedish MPA – currently lead the University Hospital – as well as private and Lönnberg said that part of his task as life sci- field in terms of work done on behalf of public R&D capabilities (such as the Uppsa- ences coordinator is to get those working in the EU regulatory network, handling about la Clinical Research Center), biobanks and industry, healthcare and academia to work 30% and 25% of centralized rapporteur- registers, and a strong biopharmaceutical together on common priorities and pro- ships respectively, he said. industry presence. pose ideas for strengthening the sector. Noting that the MHRA has had a lot of in- “Look at the top rated universities in Eu- “We have three aims,” he said: to improve put into the work of the EMA, he said that rope,” Lönnberg said: “Four are British, the the quality of healthcare, to use and dis- when the UK left the EU, the MPA would be fifth is the Karolinksa. If the UK leaves, the perse new technologies more quickly, and “by far the largest agency” in the EU and Karolinska will be the top university for medi- to bring more revenues to the healthcare this would stand it in good stead when it cal studies in the EU.” The Karolinska is also sector by transforming Swedish inventions

24 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Regulatory Update into innovation, developing new treat- research new compounds in the future, public health area: the European Centre ments, medtech products and pharma- you can shorten the time span for devel- for Disease Prevention And Control, which ceuticals, and bringing them to the inter- opment which is now 12-15 years. And of is located in the Stockholm area. The ECDC national market.” course Sweden has one of the best IT and gathers, analyses and disseminates data So how would having the EMA help mobile sectors.” on more than 50 communicable diseases Sweden achieve these aims? “It would be Sweden is putting a lot of money and ef- and conditions, and one of its most impor- like a gem in the whole life science cluster fort in getting all its various IT systems to tant tasks is to offer scientific advice and here,” Lönnberg said. “I also think it would work together, and next month a new bill guidance to the member states. Might this attract more investment from outside is to be presented that will aim to connect not hinder Sweden’s bid to host the EMA? pharma firms, the Japanese have said that, data systems for diagnosis, biobanks, and “Yes, it is a drawback that we host an but of course we must not forget that it is so on, Lönnberg said. “So we would have an agency, but so do several countries,” Lön- also 900 jobs and, with the multiplier ef- excellent base to try out the data we need nberg acknowledged. “On the other hand fect, three or four times that. Then there is to monitor how new drugs work in the real there is a natural link between EMA and also the network of some 4,500 scientists world – this is very important for the EMA, ECDC and we have a lot to win in Europe all around Europe that are connected to we can follow patients everywhere.” by locating them in the same place.” the EMA. That is impressive brainpower.” On a practical level, Lönnberg noted He believes it would also help to boost that for some, having the agency in Swe- *The Pink Sheet will be contacting gov- the uptake and acceptance of new tech- den would mean “a bit of a longer trip, ernments in these countries to elicit their nologies in the Swedish healthcare system. and there are not as many flights” as there views on why they are well suited to host “You can say that life sciences are merging are to London. the EMA. with IT and mobile technology. IT and big Another possible barrier is that Sweden data will have a great impact on how you already has an EU agency working in the Published online September 20, 2016

New Products FDA’s NDA And BLA Approvals Below are FDA’s original approvals of NDAs and BLAs issued in the past week. Please see key below chart for a guide to frequently used abbreviations

Sponsor Product INDICATION CODE Approval Date New Drugs Bayer Kyleena Levonorgestrel-releasing intrauterine system 19.5 mg for the 5 9/16/2016 (levonorgestrel prevention of pregnancy for up to five years Sarepta Exondys 51 Treatment of Duchenne muscular dystrophy in patients who have a con- P, 1 9/19/2016 (eteplirsen) firmed mutation of the DMD gene that is amenable to exon 51 skipping

Janssen Invokamet XR Once-daily fixed-dose combination therapy of the SGLT2 inhibitor cana- 4 9/20/2016 (canagliflozin/ gliflozin and metformin HCl extended-release for first-line use as an ad- metformin HCl) junct to diet and exercise to improve blood glucose control in adults with type 2 diabetes when treatment with the two medications is appropriate Silvergate Epaned (enalapril Oral solution formulation of the ACE inhibitor to treat hypertension in 5 9/20/2016 maleate) adults and children older than one month to lower blood pressure; symp- tomatic heart failure; and asymptomatic left ventricular dysfunction Key to Abbreviations Review Classifications NDA Chemical Types P: Priority review 1: New molecular entity (NME); 2: New active ingredient; 3: New dosage form; S: Standard review 4: New Combination; 5: New formulation or new manufacturer; 6: New indication; O: Orphan Drug 7: Drug already marketed without an approved NDA; 8: OTC (over-the-counter) switch; 9: New indication submitted as distinct NDA – consolidated with original NDA; 10: New indication submitted as distinct NDA – not consolidated with original NDA

pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 25 regulatory update €20m Action Tackles Poor Uptake Of Joint HTAs Across Europe; Commission Consultation Nears Neena Brizmohun [email protected]

he 77 organizations from 29 European countries working vergence in the way HTA is done throughout Europe.” Such con- under the EUnetHTA collaboration to create a sustainable vergence, the commission continued, “is expected to contribute to T network for health technology assessments across the Eu- access to innovation and provide stimulus for industries to develop rope are seeking to understand why not enough countries are us- innovative technologies.” ing their joint HTA reports and how to address this problem. The commission commented that JA2 had “optimized the way In addition, the European Commission told the Pink Sheet that it HTA bodies can work together and produce joint output…[and] it was preparing to consult “soon” on how cooperation on HTAs across also developed common IT tools, templates and methodologies” Europe can be sustained after 2020, when EUnetHTA’s third and final which facilitate joint work. Joint Action (JA3) ends. JA3 (2016-2020) is a €20m initiative that started in June 2016. It will Increasing national uptake of the joint explore, among other things, why as of March this year only three member states on average had implemented into their national deci- reports will be key to justifying any sion-making processes a joint assessment from among the 15 joint re- ports EUnetHTA produced during its Joint Action 2 (2012-2015) phase. support devoted to HTA cooperation and Joint assessment reports comprise structured information for rapid or full HTAs and they are produced by two or more countries and/or ensuring the sustainability of activities organizations working together to prepare shared products or agreed – European Commission outcomes. The reports cover topics such as using canagliflozin for the treatment of type 2 diabetes mellitus and the use of sorafenib for treating thyroid cancer. The aim is for countries to implement the re- ports into their national or regional setting, thereby promoting good JA3 is expected to facilitate 35 early dialogues between develop- practices in HTA processes across Europe, avoiding duplication and ers and HTA bodies that will help industry better understand how helping HTA bodies use their time and resources effectively. to design their studies in terms of HTA requirements, it added, not- ing that JA2 had so far facilitated over 20 early dialogues. Uptake Must Improve If HTA Cooperation Is To Increasing national uptake of the joint reports, though, will be Continue “key” to justifying any support devoted to HTA cooperation and EUnetHTA has so far produced 20 joint assessment reports for drugs ensuring the sustainability of activities, the commission told the and medical devices and, according to the commission, it plans to Pink Sheet. produce 80 joint reports during JA3. The latest update from the net- Notably, EUnetHTA has received around €35.5m in funds since work’s database shows that as of March 21, 2016, 18 countries had its Joint Action 1 (2010-2012) began around six years ago, with used one or more of 12 joint HTA reports but that in many cases the nearly €21.6m of this funding provided by the commission and the joint work was used only indirectly to cross-check evidence. reminder by the other organizations involved with EUnetHTA. If cooperation on HTA is to continue after JA3 ends, EUnetHTA will need to improve national uptake of its joint reports, according Extensive Commission Consultation Nears to the commission. The commission confirmed that while there would not be a fourth Poor uptake is mainly due to “legal and organizational barriers, EUnetHTA joint action, it was committed to proposing an initiative including the timing when these joint reports were [made] avail- to continue HTA cooperation after 2020. able and the difficulties to integrate jointly agreed working meth- This commitment, it explained, is in response to calls from the ods in national processes,” it said. member states following the Council of the European Union’s con- Despite these shortcomings, the commission believes that EU- clusions relating to innovation for the benefit of patients (Decem- netHTA has made breakthroughs. The network’s activities overall ber 2014) and strengthening the balance in the pharmaceutical have been “essential to create the necessary trust and understand- systems in the EU and its member states (June 2016). ing of the member states’ different ways of working” when per- The commitment also relates to Europe’s HTA Network Strategy forming HTAs, it explained. that was adopted in October 2014. In addition, the commission “The added value of the cooperation is not only the number pointed out that it had co-founded a number of projects in the of the joint reports produced but also in enabling exchange of area of HTA from both its Health Programme and the 7th research know-how… between national/local agencies and fostering con- Framework Programme.

26 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Regulatory Update

The commission is planning to publish a document setting out the status of HTA cooperation and possible ways forward. The document, which it said would be published “soon,” will be followed by an “ex- tensive” public consultation for feedback and ideas on “any possible sustainable mechanism” that could enable cooperation to continue. Pricing and reimbursement will remain a national competence and will not be affected by any future initiative on EU coopera- tion on HTA. Under the Treaty on the Functioning of the European Union, the EU has no competence in the area of pricing and reim- bursement, the commission noted. EUnetHTA, for its part, said it was expecting JA3 to build on “the lessons, success and products” of its earlier joint actions. JA1 and JA2 have “proven the ability of national HTA organizations to work together and produce valuable products,” it commented, adding that JA3 would “proceed with the final step of establishing a per- manent network on HTA in Europe.” The commission clarified that the problem of poor national up- Quick Facts take would be dealt with during the final phase of JA3 by work About EUnetHTA package (WP) 7. “Working closely with the other EUnetHTA work packages and with the individual member states, [WP7] aims to facilitate uptake EUnetHTA is a network of government appointed organi- and implementation in national, regional and local settings of EU- zations (from EU member states, EU-accession countries, netHTA tools and jointly produced HTA information in EUnetHTA plus EEA and EFTA countries) and a large number of rel- (from previous and on-going EUnetHTA joint actions),” it explained. evant regional agencies and not-for-profit organizations WP7 will also try to facilitate reuse of HTA reports produced by that produce or contribute to HTA in Europe. member states. “One important objective of WP7 is to provide sup- port to WP4 [which focuses on the production of joint HTAs], for It was established around 10 years ago to create an ef- developing a mechanism of HTA cooperation that successfully fective and sustainable network for HTA across Europe to takes implementation issues at national, regional and local (hospi- help develop “reliable, timely, transparent and transferable tal) levels into account.” information to contribute to HTAs in European countries.”

EUnetHTA’s joint assessments The EU contribution to: EUnetHTA’s joint assessment reports comprise structured informa- • JA3 is €12m (for €20m total cost of the action); tion for rapid or full HTAs. Rapid effectiveness assessments (REAs) focus on clinical/therapeutic added value, the commission ex- • JA2 was €6.6m (for €9.43m total cost of the action); and plained, adding that full HTAs include assessment of economic and organizational aspects. • JA1 was €2.98m (for €6m total cost of the action).

A local HTA report can be produced by using full core HTAs or allstars Shutterstock: rapid HTAs produced in JA1 or JA2, where either the whole core HTA/rapid HTA or parts of the core HTA/rapid HTA are used. The treatment for adult patients with advanced gastric or gastro- minimum requirement for a national adaptation is inclusion of an oesophageal junction adenocarcinoma explicit reference to the EUnetHTA joint assessment on which the •• Sorafenib for the treatment of advanced or metastatic progres- local report was based. sive differentiated thyroid cancer As well as the 15 joint assessments that were finalized during •• Zostavax for the prevention of herpes zoster JA2, the network produced three joint assessments during JA1 and •• Use of intravenous immunoglobulins for Alzheimer’s disease two during the EUnetHTA Project (2006-2008). including mild cognitive impairment EUnetHTA’s database shows that its joint reports have been used •• Rapid relative effectiveness assessment of new pharmaceuti- in one way or another by Austria, Belgium, Croatia, Estonia, Finland, cals for the treatment of chronic hepatitis C Italy, Luxembourg, Malta, the Netherlands, Norway, Portugal, Ro- •• Vorapaxar for the reduction of thrombotic cardiovascular mania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the UK. events in patients with a history of myocardial infarction (MI) Examples of the joint assessment reports EUnetHTA has pro- duced for pharma are: •• Canagliflozin for the treatment of type 2 diabetes mellitus From the editors of Scrip Regulatory Affairs. Published online •• Ramucirumab in combination with paclitaxel as second-line September 21, 2016 pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 27 Patents New EU Patent System: Only Two More Ratifications Needed, But Will The UK Sign Up? Ian Schofield [email protected]

he Netherlands has become the latest country to ratify the Unified Patent Court Agreement, making it the 11th EU mem- T ber state to do so. Now only Germany and the UK need to ratify the agreement for it to enter into force. The problem is, the UK has voted to leave the EU, and has not decided whether it will ratify the agreement, thereby throwing the whole process into uncertainty. Announcing the Dutch ratification, the Ministry for Economic Affairs noted that the UPCA has already been signed by 10 other countries – Austria, Belgium, Bulgaria, Denmark, Finland, France, Luxembourg, Malta, Portugal and Sweden – bringing the total to 11. At least 13 signatures are required, with those of France, Ger-

many and the UK being mandatory. Zerbor Shutterstock: “Germany is likely to follow shortly,” the ministry said. “In addi- Brexit has brought confusion to the future EU patent system tion, it also requires approval by the United Kingdom. What the ex- act consequences of the announced ‘Brexit’ will be for the date of ceptable amount of uncertainty to industry across the UK and EU.” the [UPCA] coming into effect is still unclear,” it remarked. According to Fish & Richardson, this issue arose after the Court of But the UK Chartered Institute of Patent Attorneys (CIPA) said Justice of the EU rejected an early proposal for a European patent that according to a recent legal opinion from two English barris- court because it would have included non-EU member states that ters, there are no legal barriers to the UK’s joining and remaining would not be bound by EU law and the decisions of the CJEU. “It part of the UPC following Brexit, only “political” ones. was for that reason that the UPC Agreement is currently limited to Under the UPCA, the new court would have jurisdiction over cer- participation by EU member states.” tain patent disputes, including those concerning the future “unitary patents,” which would be valid in all EU member states. Given the Legal Opinion uncertainty over the UK’s future relationship with the EU, though, it’s To try to pin down the legal situation, in July this year CIPA, the not clear whether the UK will be part of this new system or not. IP Federation and the Intellectual Property Lawyers Association Law firm Fish & Richardson said there was nothing to stop the asked barrister Richard Gordon to provide an opinion on a number UK from ratifying the UPCA if it chooses to do so while it remains a of questions relating to the effect of Brexit on the UPC and the UP. member of the EU. “If the UK ratifies, Germany appears likely to also These included whether the UK could continue to be part of the ratify. That would permit the UPC to open for business and the EPO unitary patent system and the UPCA, whether it could still host the to begin granting Unitary Patents (UPs),” it remarked. pharmaceutical/chemistry section of the central division, and what If the UK either does not ratify, or withdraws from, the UPCA, “the changes might have to be made to the UPCA. UPC and UP arrangements are likely to remain in limbo until the UK In a Sept. 12 opinion, Gordon and another barrister, Tom Pascoe, either leaves the EU or withdraws from the UPC Agreement.” said that in their view the UK could only continue to participate in In July, the IP Federation said it supported both the UPC and the the unitary patent by entering into a new international agreement unitary patent, “with the UK participating on the current terms, in- with the participating EU member states. “The permissibility of cluding the location of the branch of the central division in Lon- such an agreement under EU law would turn upon essentially the don” that would deal with pharmaceutical and chemistry patents. same matters as the legality of the UK’s continuing participation in But without a guarantee of continued UK participation post- the UPCA,” they declared. Brexit, it continued, the UK should not ratify the UPC at present. As for the UPCA, they said it was “legally possible” for the UK to “We consider that ratifying the UPC to bring it into effect and sub- continue to take part in the agreement after a Brexit, although sequently being forced to leave the system would bring an unac- there was the possibility that the CJEU “would find otherwise” be- cause of its earlier opinion. If it was legally possible for the UK to “It is legally possible for the remain in the UPCA, “there is no reason why it cannot continue to host a section of the central division.” UK to continue to take part in the If this happened, a number of amendments would have to be made to the UPCA, and moreover the UK would have to “submit to EU law in agreement after a Brexit” its entirety as regards proceedings before the UPC. It would also need

28 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 Patents

CIPA President Tony Rollins said: securing our continued participation in the Unified Patent Court and Unitary Patentfollowing Brexit, although this will take some “There is now a legal path to securing time. We are pleased that Counsel’s Opinion supports our position, but more work needs to be done before the UK can ratify the UPC our continued participation in the Agreement.”

Unified Patent Court and Unitary Italy To Seek London Branch? Patent following Brexit, although this On Sept 15, Italy’s chamber of deputies (the lower house of parlia- ment) approved a bill allowing Italy to ratify the UPCA. Among oth- will take some time. er things, the bill notes that in light of the UK Brexit vote, “it would be opportune to reflect on the central seats of the Unified Patent to sign up to an appropriate jurisdiction and enforcement regime.” Court, which are currently foreseen for Paris, London and Munich,” Finally, they said, if the UK ratified the UPCA without amend- and states that “Italy is a candidate for a regional seat.” ment, and then subsequently left the EU, “any divisions of the UPC According to law firm Bristows, the MPs who presented the bill sug- in the UK would have to cease operating. The transitional conse- gested that the London branch could instead be located in the north- quences of this are matters of detail to be negotiated as part of the ern city of Milan. The bill still has to gain approval by the Senate and UK’s exit negotiations.” then be promulgated into law by the country’s President. CIPA said the opinion supported its view that the UK could join the UPC and remain part of the UPC system after it left the From the editors of Scrip Regulatory Affairs. Published online EU. CIPA president Tony Rollins said: “There is now a legal path to September 12, 2016

Clinical Trials EU Clinical Trials Delayed By Poor Reference Safety Information Vibha Sharma [email protected]

number of clinical trials sponsored to occur for the investigational medicinal ment of clinical trial RSI and ensure that their by the innovative pharmaceutical product being administered to trial sub- approach complies with current guidance. Aindustry have experienced delay in jects and, as such, do not require expedit- EFPIA first highlighted the problems that the EU because of companies failing to sat- ed reporting to the competent authority. companies face due to the increased regu- isfy the expectations regulators have with Investigator brochures also contain RSI. latory focus on RSI in July at the European regard to the reference safety information The lack of up-to-date EU-level guidance Medicines Agency’s eighth industry meet- (RSI) submitted in clinical trial applications on RSI means that there is not enough con- ing on the operation of the EU pharma- and as updates to investigator brochures. sistency in how regulators across Europe deal covigilance legislation. It clarified that the Regulators are increasingly focusing on with RSI, the trade group explained, adding focus on RSI relates to the assessment of the RSI in submissions and are raising a num- that companies have adapted “as best they applications for clinical trials and updates ber of questions and objections on this front, can but not in a coordinated manner.” to investigator brochures and not to good according to the European Federation of EFPIA is calling for the Heads of Medicines pharmacovigilance practice inspections. Pharmaceutical Industries and Associations. Agencies’ Clinical Trials Facilitation Group to The industry group believes that the Some 87.5% of the 16 EFPIA members draft a single EU-aligned guidance on RSI. increased focus on RSI in clinical trials re- that responded to a recent survey by the The association believes that additional flects a desire by the competent authori- trade group said they were aware of prob- clarification of the regulatory expectations ties to achieve consistency in how RSI is lems in this area and that almost all their IB on this front will avoid the risk of divergent managed ahead of implementing the updates and clinical trial applications had interpretations from the member states. safety reporting provisions in the EU Clini- been impacted, EFPIA told the Pink Sheet. EFPIA is consolidating a position paper cal Trials Regulation, which is estimated to EU-level guidance is needed on regula- on the matter that it will submit to the come into effect in late 2018. tory expectations for RIS, according to EF- CTFG for discussion. PIA. RSI refers to the list of medical events In the meantime, it said that member From the editors of Scrip Regulatory Affairs. that defines which reactions are expected states should be pragmatic in their assess- Published online September 19, 2016 pink.pharmamedtechbi.com September 26, 2016 | Pink Sheet | 29 Advisory Committees

Recent And Upcoming FDA Advisory Committee Meetings

Topic Advisory Committee Date Naloxone products intended for use in the community, specifically: the most appropriate dose or Anesthetic and Oct. 5 doses to reverse effects of life-threatening opioid overdose in all ages; the role of having multiple doses Analgesic Drug Products; available in this setting; criteria prescribers will use to select the most appropriate dose in advance of Drug Safety and Risk an opioid overdose event and labeling to inform this decision if multiple doses are available Management Selection of strains to be included in an influenza virus vaccine for the 2017 southern hemi- Vaccines and Related Oct. 13 sphere influenza season Biological Products (teleconference) Serenity Pharmaceuticals’ desmopressin 0.75 mcg/0.1 ml and 1.5 mcg/0.1 ml nasal spray for Bone, Reproductive and Oct. 19 treatment of adult-onset nocturia Urologic Drugs Updates on research programs in the Laboratory of Immunobiochemistry of the Division of Allergenic Products Oct. 27 Bacterial, Parasitic and Allergenic Products in CBER’s Office of Vaccines Research and Review (teleconference) (open session); intramural research program reports and recommendations on personnel staff- ing decisions (closed session) Cempra Pharmaceuticals’ solithromycin capsules and injection for treatment of Antimicrobial Drugs Nov. 4 community-acquired bacterial pneumonia Recommendations on FDA’s draft Strategic Plan for Risk Communication and Health Literacy; pre- Risk Communication Nov. 7 sentations on some of FDA’s external communications and how these relate to the draft strategic plan Appropriate clinical trial design features, including acceptable endpoints for demonstrating Bone, Reproductive and Dec. 6 clinical benefit, for drugs intended to treat secondary hypogonadism while preserving or Urologic Drugs improving testicular function, including spermatogenesis

leadership advertising Phil Jarvis, Mike Ward Christopher Keeling Pink Sheet corporate sales design John Lucas, Elissa Langer Jean Marie Smith

US Malcolm Spicer Ian Schofield Denise Peterson Sue Sutter Alex Shimmings Nielsen Hobbs Jo Shorthouse Europe Mary Jo Laffler Sten Stovall Neena Brizmohun Sukaina Virji Europe Ian Schofield Eleanor Malone Vibha Sharma Asia Maureen Kenny Anju Ghangurde commercial Jung Won Shin Asia Brian Yang Ian Haydock US Ying Huang Joseph Haas Policy and Regulatory Emily Hayes Mandy Jackson US editorial office Jessica Merrill Michael Cipriano 52 Vanderbilt Avenue, 11th Floor Bowman Cox Europe New York, NY 10017 Joanne Eglovitch Lubna Ahmed phone 240-221-4500, fax 240-221-2561 Eileen Francis Francesca Bruce Derrick Gingery Peter Charlish customer care Cathy Kelly John Davis 1-888-670-8900 or 1-908-547-2200 Brenda Sandburg Lucie Ellis fax 646-666-9878 Bridget Silverman John Hodgson [email protected]

© 2016 Informa Business Intelligence, Inc., an Informa company. All rights reserved. No part of this publication may be reproduced in any form or incorporated into any information retrieval system without the written permission of the copyright owner.

30 | Pink Sheet | September 26, 2016 © Informa UK Ltd 2016 October 5–7, 2016 Boston, MA

PUSH NOVEL DRUGS TO MARKET BY INNOVATING CLINICAL TRAIL DESIGN, BUILDING NEW ALLIANCES, CULTIVATING EXISTING RELATIONSHIPS, LEVERAGING YOUR DATA AND DISCOVERING NEW TECHNOLOGIES

Pharmaceutical Executive Readers enjoy a 15% discount off our rates when you quote P2100PE

PCT 2016 is back Join us for New Case Studies, Provocative Industry Discussions, Strategic Neworking PCT 2016 STATS: this fall in Boston and Actionable Takeaways: with the cutting-edge and comprehensive NEW FOR 2016! • NEW! OUTSIDE-INDUSTRY KEYNOTES 50+ content you trust, a Sessions focused on innovation, on outsourcing, data analytics, customer technology, small and mid-size pharma, new intimate format, service and innovation for fresh insights and biotechs, and more. and reenergized best practices to apply to your trials networking. But you • NEW! Spotlight Presentation – R&D Challenges in Finding a Cure: have to be there to Lessons Learned from Running a Clinical Trial for ZIKA 1,100 experience it all for Clinical Trials Stakeholders from yourself. • NEW! INNOVATION PRESENTATIONS pharma, biotechs, CROs, sites, and – Rapid Fire pitches on cutting-edge more. HOT TOPICS TO BE COVERED innovation and tech to make your trials more cost effective and efficient, 10 minutes at a IN 2016 INCLUDE: time • Innovations in Clinical R&D • NEW! PARTNERING DISCUSSIONS – Find • Innovative Outsourcing Strategies and 100+ like-minded peers and technologists during Influential Thought Leaders and expert Models- Small Biotech’s/Small-Mid focused, niche round table discussions to speakers. Sized Pharma/ Medical Devices help you overcome specific challenges in your trials • Risk-Based Approaches in Clinical Development • BACK BY POPULAR DEMAND: WALL • Successful Interactions with STREET KEYNOTE – Looking for Sustainable Business Models in Pharma: Regulatory Agencies & Expedited The impact of M&A and other Risk-Sharing Register online with code INVIVO Drug Review/Approval Trends on Clinical Development and Receive a $1000 Discount • Implementing Disruptive www.partnershipsinclinicaltrialsus.com Technologies for Clinical Development *new registrations only As clinical trials expand globally, the need for a worldwide infrastructure to ensure secure delivery of pharmaceuticals is more urgent than ever. Global specialty logistics teams navigate customs regulations and address temperature- control needs to prevent delays or product loss. While a robust, worldwide infrastructure brings shipments to clinical trial sites on time. Supplying pharmaceuticals to emerging markets takes local insights and expert instincts. It takes a committed partner. It takes AmerisourceBergen. ItTakesAmerisourceBergen.com

CLINICAL TRIAL LOGISTICS \ COMMERCIALIZATION \ GLOBAL SOURCING AND DISTRIBUTION \ PATIENT SUPPORT SERVICES

33684-15-403335_ABC_ISCE_Instincts_8.5x11_TPS_4C_r0.indd 1 9/19/16 10:12 AM