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. 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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.