Regulatory Update Reimbursement New Products Cuba: A Pharmaceutical Regulatory Tagrisso Funding Journey Shows Lilly’s Lartruvo Scores Broad FDA Snapshot, p. 10 UK’s Revamped Cancer Drugs Fund Approval In Orphan Sarcomas, p. 9 Is No Soft Touch, p. 17

Pharma intelligence Pinkpink.pharmamedtechbi.comSheetVol. 78 / No. 43 October 24, 2016 informa

The second patent, No. 7,598,083, cov- How Risky Is Pfizer’s Launch Of ers particular compositions of cell culture media that are used to grow the living cells that produce biologics such as inf- Its Remicade Biosimilar? liximab. That patent, issued in October Brenda Sandburg [email protected] 2009, expires on Feb. 7, 2027. A jury trial is scheduled to begin on Feb. 13, 2017 to determine if the patent is valid and, if so, whether Inflectra infringes it. Janssen said it would seek damages and royalties on future sales if the court finds that the ‘083 patent is valid and infringed. The trial will also determine if Janssen is entitled to a permanent injunction and whether Celltrion and Pfizer followed the litigation provisions of the Biologics Price Competition and Innovation Act.

Treble Damages Seem Unlikely Janssen filed two suits against Celltrion, which have been consolidated. The first complaint, filed in March 2015, claims Celltrion infringed several patents and Shutterstock: PHOTOCREO Michal Bednarek PHOTOCREO Shutterstock: failed to provide manufacturing process information for the Inflectra biosimilar in elltrion Inc. and partner Pfizer Inc. factor inhibitor, in late November, nearly violation of the BPCIA. The second com- knocked out one of Janssen Biotech eight months after FDA’s April 5 approval. plaint, filed on June 14, alleges actual acts CInc.’s Remicade (infliximab) patents Janssen issued a release in response saying of infringement of the ‘083 patent based in district court and are betting they will it considered this to be an “at-risk” launch. on new information about the cell culture win a ruling of non-infringement of a cell The risk centers around two of Janssen’s media that was custom made for Celltrion culture media patent. But even if they don’t patents. Massachusetts District Court Judge by HyClone Laboratories Inc. prevail, they may rake in far more in rev- Mark Wolf ruled in August that patent No. Janssen seeks a preliminary and/or per- enues from an Inflectra biosimilar launch 6,284,471, which covers the infliximab anti- manent injunction prohibiting Celltrion than would pay out in potential damages. TNF antibody, is invalid for obviousness- and its partners from making, using or sell- Pfizer announced on Oct. 17 that it would type double patenting. Janssen said it is ing the cell culture media and/or a biosimi- begin shipping Inflectra (infliximab-dyyb), in the process of filing an appeal to the US lar product made with the media, as well its biosimilar to Janssen’s tumor necrosis Court of Appeals for the Federal Circuit. Continued on page 4

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exclusive online content inside: COVER How Risky Is Pfizer’s Launch Of Its Remicade Biosimilar? CHMP’s October Recommendations Include Venclyxto, Opdivo, Lucentis REIMBURSEMENT http://bit.ly/2dqCFab 20 What Is An Acceptable Drug Discount? The European Medicines Agency’s Committee for Medicinal DOJ and Industry Disagree Products for Human Use (CHMP) meets monthly to review 17 Tagrisso Funding Journey Shows UK’s Revamped applications for centralized EU marketing authorization. Here is Cancer Drugs Fund Is No Soft Touch a summary of their October recommendations. NEW PRODUCTS 9 Lilly’s Lartruvo Scores Broad FDA Approval China Approval Watch: September Dominated In Orphan Sarcomas By Generics And Vaccines 8 FDA’s NDA And BLA Approvals: Tecentriq, Lartruvo, Evzio http://bit.ly/2ebKmmv Twenty-three chemical drugs, three biologics and one traditional ADVISORY COMMITTEES Chinese medicine are among the latest approvals granted by the 6 Allergan’s Nasal Spray For Frequent Nighttime Urination China FDA, which is continuing on a hiring spree to increase its Gets Cautious Panel Nod number of reviewers. 26 Recent And Upcoming FDA Advisory Committees

Roadmap On Improvements To EMA’s Literature GENERIC DRUGS Monitoring Service Due By Year End 14 Generic Drug User Fees Will Jump More Than 50% http://bit.ly/2dsV2q4 In FY 2018 The European Medicines Agency will be looking for quick wins as 16 FDA Pushing Forward With Withdrawal well as long-term improvements when it revises its medical literature Of Two Concerta Generics monitoring service. It will soon publish a roadmap for improving the 25 FDA’s ANDA Approvals service with details of when the changes might occur. INTELLECTUAL PROPERTY FDA’s Opioid Crisis Response: More Pressure 24 Does India’s Perpetual Licensing Plan Risk Backfiring? For Treatment Drugs REGULATORY UPDATE http://bit.ly/2dDj70L 10 Cuba: A Pharmaceutical Regulatory Snapshot Sharp increases in deaths from illicit drugs (heroin and synthetic opioids) could change FDA’s priorities; rather than working with 23 EFPIA Urges Japan To Consider New Funding Models drug sponsors on more tamper-deterrent formulations of pain therapies, the agency may need to devote more attention to BIOSIMILARS overdose treatments like naloxone. 5 Biosimilar Clinical Trials Face Enrollment Challenges

MANUFACTURING QUALITY ‘Standardized’ Comment From Brexit Minister Raises 11 Despite Progress, More Work Needed To Harmonize Hopes For Parallel EU/UK Drug Approval System FDA and EMA Criteria For Biowaivers http://bit.ly/2enZd8B 13 FDA Outlines Criteria For Approving Manufacturing The way in which pharmaceuticals might be regulated in the UK Supplements Under GDUFA after the country leaves the EU is a big unknown. As MPs get to have their say on the matter, the Pink Sheet tries to gauge CONSUMER PRODUCTS government thinking. 21 Benefit From OTC Switches Supported In Study Of PPIs’ Outpatient Impact pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 3 Biosimilars

Continued from cover similar version of Amgen’s Neulasta (peg- as trebled damages. filgrastim). Amgen is asserting infringe- In a Sept. 27 joint pretrial memorandum, ment of the ‘878 patent and patent No. Janssen said it would show that Celltrion 5,824,784. Sandoz asserted counterclaims and Pfizer infringed the patent claims Pfizer has already won seeking a declaratory judgment of invalid- either literally or under the doctrine of ity and noninfringement of both patents. equivalents, whereby elements of the in- half the battle since A trial is scheduled for the week of Dec. 11, fringing product are not identical to the 2017 or at the court’s convenience. patented invention but equivalent to it. the district court Janssen said it would also show that the found the ‘471 patent Biosimilar Pricing Is Next formula for the defendants’ cell culture Frontier media contains every ingredient required invalid. If the Federal As the court battles continue, there is in- by the patent claims. The patent calls for creased focus on biosimilar pricing. Pfizer 52 required ingredients and nine optional Circuit were to reverse, said Inflectra would be introduced at a ingredients. Janssen could not 15% discount to the current wholesale For their part, Celltrion and Pfizer said acquisition cost of Remicade, before any they will show their product does not in- discounts, which equates to $946.28 per argue Pfizer had 100mg vial. fringe literally or under the doctrine of At an Oct. 18 meeting on the future of equivalents. They stated that Janssen has no good faith basis the US biosimilars market held in Washing- not alleged literal infringement and has ton, DC, Lawrence LaMotte, of the Immune been proceeding under the doctrine of to launch. Deficiency Foundation, expressed concern equivalents. that patients will be switched en masse Shashank Upadhye, of Amin Talati Upad- to biosimilars for cost reasons rather than hye, said Pfizer has already won half the clinical reasons. battle since the court found the ‘471 pat- Zarxio Infringement Suit He alluded to CVS Health Corp.’s decision ent invalid. If the Federal Circuit were to Moves Forward to remove Amgen’s Neupogen and Sano- reverse and the case went back to district Pfizer’s decision to pursue an at-risk launch fi’s glargine insulin Lantis from coverage in court to determine liability, he said Janssen mirrors that of Sandoz Inc., which opted to its national formulary in 2017. could not argue Pfizer had no good faith launch Zarxio (filgrastim-sndz), its biosimi- “This is all about costs,” LaMotte said. “I basis to launch and was liable for treble lar to Amgen Inc.’s Neupogen (filgrastim), find it interesting that with generics, the damages given Wolf’s ruling on the patent. before the resolution of a patent infringe- small molecules, we’ve been talking about With regard to the ‘083 patent, Upadhye, ment suit. Sandoz obtained FDA licensure these huge differences in costs” and yet a former attorney at Apotex Inc., said Pfizer on March 6, 2015 and launched Zarxio on Pfizer announced it is only giving a 15% dis- may have good legal opinions to support Sept. 3, 2015. The marketing was delayed count off the reference product. He said pa- its launch and thus would not be liable for as the parties fought over provisions of tient organizations are very concerned that willful infringement and treble damages. As the biosimilars statute. The dispute was their physicians will have no control over for the size of an award, he said that would resolved when the Federal Circuit ruled prescribing because they will be overruled. depend on what the patent covers and the that biosimilar sponsors have to wait until Jeff Eichholz, senior director of drug relative contribution of the ‘083 patent. FDA licensure to provide 180-day notice of trend solutions at Express Scripts, also Judge Wolf noted in an order finalizing commercial launch of their product. addressed Inflectra pricing at the event, his decision on the ‘471 patent that the In the ongoing patent litigation, Am- which was co-sponsored by Friends of court had offered Janssen several oppor- gen claims infringement of patent Nos. Cancer Research and the Duke-Robert J. tunities to seek a preliminary injunction 6,162,427 and 8,940,878. It is seeking a Margolis Center for Health Policy. to prohibit the sale of Inflectra in the US permanent injunction, damages, a decla- He said the pharmacy benefit manager pending the outcome of litigation but the ration that Sandoz’s infringement is will- was looking for a 20% to 40% discount. company declined to do so. Janssen said it ful and deliberate and justifies an increase “These are not going to be generic type could not comment on why it did not seek a up to three times the amount of damages. discounts,” he said. “We’re really looking preliminary injunction. Sandoz has counterclaimed for a declara- at these as competing brands, but overall Pfizer had agreed not to launch Inflec- tory judgement of non-infringement and when you get competition you do see the tra until at least Oct. 3, the end of the invalidity of the patents. prices drop.” required 180-day notice of launch after Amgen filed a related infringement ac- licensure, but has taken extra time to pre- tion against Sandoz in May in response to Published online October 18, 2016 pare the launch. its submission of an application for a bio- Sue Sutter contributed to this report.

4 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Biosimilars Biosimilar Clinical Trials Face Enrollment Challenges Sue Sutter [email protected]

linical trials comparing proposed biosimilars and their refer- ence products present enrollment challenges that reflect a Clack of understanding by clinicians and patients about the abbreviated development paradigm for biosimilars, stakeholders said at an Oct. 18 meeting. “The biggest stumbling block we have is accruing patients to the clinical trials,” said Robert Rifkin, medical director for biosimi- lars and associate chair of the hematology research committee of McKesson Specialty Health’s The US Oncology Network. During a panel discussion about biosimilar development, regu- lation and education at a meeting co-sponsored by Friends of Cancer Research and the Duke-Robert J Margolis Center for Health Policy, Rifkin talked about how patients and their families often have doubts and uncertainties about enrolling in a trial involving a biosimilar. He questioned how to get patients enrolled in trials for such products, which are not brand new molecules with all the “glitter and glitz and exciting promise.” “I’d be interested to hear how FDA can help us do those trials, be- cause it’s very difficult to explain to patients and physicians,” he said. FDA, industry and patient advocate representatives suggested the answer lies in education, including what’s already known Yeamake Shutterstock: about a proposed biosimilar’s properties by the time the product reaches the comparative clinical trial stage. The determination that a biosimilar

Importance Of ‘Priors’ clinical trial is safe to proceed In the traditional development paradigm for new molecular enti- ties and novel biologics, the emphasis is on demonstrating efficacy takes into account the underlying and safety in clinical trials. In contrast, the foundation for biosimilar analytical data on similarity, development is the analytical characterizations of structural and functional similarity to the reference product, with clinical trials FDA’s Christl said. conducted to address any residual uncertainties. The difference in development approaches has been a challeng- tion that underlies that.” ing concept for clinicians and patients to understand, as evidenced For example, the decision to move forward with a biosimilar clin- by FDA’s experience with its own advisory committees. ical trial is informed by what’s known about the safety and efficacy In a biosimilar development program, products reaching the of the reference product. clinical comparative trial stage have “priors” in the form of exten- “With a new molecular entity a lot of times …you’re not really sive analytical characterization, evidence of pharmacokinetic sure how it’s going to work,” she said. “You have some information similarity and, if relevant, pharmacodynamic similarity, said Leah about safety, but you have no information about efficacy. … You’re Christl, associate director for therapeutic biologics at FDA’s Center proving safety and effectiveness in that trial.” for Drug Evaluation and Research. “Here, you’re looking at whether there’s a clinically meaningful Because of these priors, decisions to move forward with a clinical difference, but it’s underpinned by all of this information connect- trial are often better informed, and based on more evidence, for ing the products from the similarity assessment that’s been gener- biosimilars than with novel products, Christl suggested. ated to date.” “There are some people who say – and I’m not going to attribute FDA uses that information in determining whether a biosimilar this to the agency – but there is some conversation that the con- trial is safe to proceed, she said. The agency would not allow a trial cept of that ‘safe to proceed’ decision for a clinical trial is actually to move forward “if they don’t think it’s going to be safe, if they somewhat better informed for a biosimilar because of the priors,” don’t think the product is highly similar, if they don’t think that she said. “You’re making this connect between the biosimilar prod- there’s going to be a similar safety and efficacy benefit to patients uct … and the reference product through this extensive informa- in that trial,” she said. pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 5 Biosimilars

Education Starts With Investigators “Engaging with the principal Tailored educational efforts targeting clinical investigators can go a long way toward encouraging enrollment in biosimilar trials, said investigator and the study staff Carlos Sattler, vice president and head of clinical development and medical affairs at Sandoz Inc. and educating them very, very well Sandoz’s Zarxio (filgrastim-sndz), which references Amgen Inc.’s Neupogen (filgrastim), was the first product approved under the and ensuring the understanding of 351(k) licensing pathway and is still the only biosimilar on the US biosimilarity … is incredibly useful,” market, although it will soon have some company. Pfizer Inc. has announced plans for a late-November launch of Celltrion Inc.’s In- Sandoz’s Sattler said. flectra (infliximab-dyyb), a biosimilar to Janssen Biotech Inc.’s Remi- cade (infliximab). proval studies,” Alexander said. “I think there’s much more eager- “What we’ve learned actually based on experience overseeing ness on that. So educating physicians about a lot of the assessment trials globally as well as in the US is that engaging with the princi- of the analytics and some of the other preclinical data that has ac- pal investigator and the study staff and educating them very, very tually already been done before the somewhat confirmatory clini- well and ensuring the understanding of biosimilarity and the bio- cal trials … I think that’s helpful for them to understand how far similar concept, all the steps that go into developing this product that product has already come in development.” prior to entering the clinic, is incredibly useful,” Sattler said. “Perhaps they can shift some of this eagerness from postmarket If “you have a dedicated group of field scientists that engage data collection into premarket data collection,” Alexander said. with study sites, and one of their many goals is to educate about Education, however, is not just for the investigators. biosimilars, that makes it much easier for the study coordinator or Kim Wright, a breast cancer survivor and Susan G Komen Advo- the principal investigator to be able to explain the study to a po- cate Scholar, suggested her willingness to participate in a biosimi- tential patient and explain what the benefits and risks are … much lar clinical trial would depend upon how well it was explained. more convincingly and with more confidence,” Sattler said. “Making the process as simple as possible and as attractive as Emily Alexander, senior director for biologics strategic develop- possible, meaning there’s no downside to it,” Wright said. Patients ment at AbbVie Inc., said educating investigators about the under- should understand they would be “getting standard of care and lying analytical and preclinical data should aid enrollment. equal to standard of care.” “One of the interesting things is that in Europe we see physicians who have enormous interest in enrolling their patients in post-ap- Published online October 18, 2016

Advisory Committees Allergan’s Nasal Spray For Frequent Nighttime Urination Gets Cautious Panel Nod Brenda Sandburg [email protected]

n FDA advisory panel concluded Drugs Advisory Committee voted 14 to 4 ment of nocturia in adults who awaken that the limited benefits of Serenity for approval (one member left early and two or more times per night to void with- APharmaceuticals LLC/Allergan PLC’s did not vote) concluding that the pivotal out respect to underlying etiology. The desmopressin nasal spray for nocturia – es- studies had shown a benefit over placebo proposed starting dose is 0.75 mcg (one sentially cutting down nighttime trips to the in the patient population that was stud- nasal spray) 30 minutes before bedtime, bathroom by a few times per week – out- ied. But many expressed caveats with their which can be increased to 1.5 mcg (two weigh its risks and recommended approval. votes. In addition to narrowing the indica- nasal sprays) if needed. However, many members advised FDA tion, they called for restrictions on use that In briefing documents issued ahead of to limit the indication to treatment of reflect the exclusion criteria in the study the meeting, FDA expressed several con- nocturnal polyuria, which is present in and for communication about appropriate cerns about the data, including that the about 80% of those with nocturia (fre- use of the drug. sponsor did not study this proposed dose quent nighttime urination). Serenity’s proposed indication for its titration but instead tested 0.75 mcg and FDA’s Bone, Reproductive and Urologic desmopressin nasal spray, SER120, is treat- 1.5 mcg in separate treatment arms. Only

6 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Advisory Committees the 1.5 mcg dose met all the prespecified She also said the sponsor’s proposed Risk criteria for efficacy. Evaluation and Mitigation strategy was in- The panel was also asked if there is suffi- sufficient. It includes a Medication Guide cient evidence to conclude that at least one and Dear Healthcare Provider letters with of the desmopressin doses is effective and information about the risk of hyponatre- they voted 17 to 1 that there is, with one ab- mia. She also noted that there had been stention and one member not voting. no mention of a black box warning. During Many of those who voted for approval FDA’s presentation, a panel member asked limited the recommendation to the 1.5 FDA if there would be a box warning and an mcg dose. But others said that as clinicians agency representative said FDA had not yet they would start a patient on the 0.75 mcg taken up the specifics of labeling. dose and would like to have that option. Hyponatremia is a known risk of desmo- pressin drugs. Serenity consultant Annette Overbroad Population, Stemhagen, senior VP Safety, Epidemiology, Drug Misuse Are Concerns Registries and Risk Management at UBC, Panel member Matthew Drake, Mayo noted in a presentation to the committee Clinic College of Medicine, said that in that the incidence of hyponatremia was casting his “yes” vote he took the question 1.1% at the 1.5 mcg dose and zero percent of whether SER120’s benefits outweigh its at the 0.75 mcg dose among 1,600 patients risks literally. But he said the drug needs in both randomized and long-term studies. to have a very narrow indication fitting the trial’s exclusion criteria. The exclusion Drug May Benefit 13% More criteria included diabetes insipidus, un- Subjects Than Placebo controlled diabetes mellitus, congestive The sponsor’s two pivotal Phase III studies

heart failure, uncontrolled hypertension, Reitmeyer Ricardo Shutterstock: (DB3 and DB4) had two co-primary efficacy among many other conditions. endpoints: change in baseline in the mean Stuart Howards, University of Virginia, number of nocturic episodes per night, and was among those who voted against ap- percentage of patients with ≥ 50% reduc- proval. He said he was concerned that tion in mean number of nocturic voids per once approved desmopressin will be night over 12 weeks of treatment. The DB3 misused by non-specialists and that most Mayo’s Matthew Drake study evaluated 0.75 mcg, 1.0 mcg and 1.5 doctors will not screen patients and con- mcg SER120 doses while DB4 evaluated the firm their clinical diagnosis. He also ex- said that in casting his 0.75 mcg and 1.5 mcg doses. pressed concern that patients will take The SER120 1.5 mcg dose met both end- extra doses of the medicine if they do “yes” vote he took the points. It demonstrated a mean reduction not have a satisfactory response, which of 0.3 to 0.4 nocturia episodes per night will lead to more cases of hyponatremia, question of whether versus placebo. And 18-19% more subjects a decrease in serum sodium that causes desmopressin’s benefits experienced ≥ 50% reduction in nocturia nausea and headache and in severe cases episode frequency vs. placebo. can lead to coma and death. outweigh its risks The DB4 study also included a secondary “I think the clinical effect is pretty trivial. endpoint, the results of a patient-reported It makes the benefit to risk ratio unsatis- literally. But he said the outcomes measurement, a questionnaire factory,” Howards said. “Getting up four on the impact of nighttime urination on times versus 3.8 times is not worth any drug needs to have a daily living. SER120 1.5 mcg reduced the risks let alone the potential risks here.” impact score (0-100-point scale) from a Barbara Berney, the patient representa- very narrow indication baseline of approximately 30 by 2.6 points tive on the panel, said that getting up just fitting the trial’s more than placebo. Panel members com- one fewer times per night would make a mented that this did not show efficacy. difference for her. exclusion criteria. In the DB3 study, 179 subjects received Committee member Sarah Sorscher, Pub- the SER120 1.5 mcg dose, 186 received the lic Citizen’s Health Research Group, who 0.75 mcg dose and 186 received placebo. voted against approval, questioned how In the DB4 study, 260 subjects received the drug could be approved for nocturnal SER120 1.5mcg, 262 received the 0.75 mcg polyuria without an additional clinical trial. dose and 260 received placebo. pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 7 Advisory Committees

In summing up the efficacy data, FDA The agency also asked for their views on Medical Officer Olivia Easley said that an the clinical significance of the observed exploratory analysis suggests SER120 treatment effects of desmopressin on noc- 1.5 mcg may benefit approximately 13% turia compared to placebo. Committee more subjects than placebo in reducing On safety, panel Chair Vivian Lewis, University of Rochester, nocturia episodes. summed up the discussion, saying most members expressed members came down on the side of a Meaningful But Modest meaningful difference though it was mod- Clinical Difference concern about est at the 1.5 mcg dose rather than the 0.75 FDA asked the committee to discuss several desmopressin’s use in mcg dose given the fact nocturia is a qual- other questions without taking a vote on ity of life issue. them. The agency asked if the sponsor had nursing homes and As for whether the safety of desmopres- studied desmopressin in the appropriate sin has been adequately characterized and patient population given that the trials lim- that the monitoring whether additional safety data are needed, ited enrollment to adults at least 50 years of used in the trials is panel members expressed concern about age, had numerous exclusion criteria, and the drug’s use in nursing homes and the fact had no restrictions on fluid intake. Although not likely to take place that the monitoring that occurred in the trials panel members were concerned about the is not likely to take place in the real world. exclusion criteria, most did not have an is- in the real world. sue with the age limit or fluid intake. Published online October 19, 2016

New Products FDA’s NDA And BLA Approvals: Tecentriq, Lartruvo, Evzio 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 Kaleo Evzio (naloxone HCl) 2 mg strength of the drugs, used with an auto-injector, for P, 3 10/19/2016 emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, and for immediate administration as emergency therapy in settings where opioids may be present New Biologics Roche Tecentriq (atezolizumab) New indication of the PD-L1 inhibitor to treat metastatic non- 10/18/2016 (Genentech) small cell lung cancer in patients whose disease has progressed during or following platinum-containing chemotherapy. Eli Lilly Lartruvo (olaratumab) Use of the PDGFR-a block antibody in combination with doxo- 10/19/2016 rubicin in adults with soft tissue sarcoma, with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery 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

8 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 New Products

Lilly’s Lartruvo Scores Broad FDA Approval In Orphan Sarcomas

Emily Hayes [email protected]

he development program for Eli Lilly & Co.’s Lartruvo (olara- tumab) is yet another demonstration of the flexibility FDA Types Of Sarcoma T will afford rare diseases; the drug was cleared for a relatively Tested In JGDG broad indication for soft tissue sarcoma based on a trial that in- cluded 25 subtypes of the disease. • 38% leiomyosarcoma FDA announced Oct. 19 that it granted accelerated approval for the • 1.5% synovial sarcoma platelet-derived growth factor receptor-alpha blocking antibody for use with doxorubicin chemotherapy in patients with STS who cannot • 17% liposarcoma (8% dedifferentiated, 4% myxoid, be cured with radiation or surgery and who have a type of STS for 3% well-differentiated, 1.5% pleomorphic, which an anthracycline (chemotherapy) is an appropriate treatment. 1% liposarcoma not otherwise specified (NOS) Lartruvo is the first new therapy approved by the FDA for the initial • 11% undifferentiated pleomorphic sarcoma treatment of soft tissue sarcoma since doxorubicin’s approval more than 40 years ago, the agency confirmed. The drug recently was also • 5% angiosarcoma recommended for conditional marketing authorization in Europe. • 5% undifferentiated sarcoma NOS According to the National Cancer Institute, there will be about • 3% extraskeletal myxoid chondrosarcoma 12,310 new STS cases diagnosed in the US in 2016. There are some 100 types of soft tissue sarcoma, which creates • 2% malignant peripheral nerve sheath tumor challenges in running clinical trials. New drugs have been targeted at • 2% myxofibrosarcoma particular types. For example, Eisai Co. Ltd.’s Halaven and Johnson & • 2% malignant solitary fibrous tumor Johnson’s Yondelis are approved for liposarcoma. Yondelis is also ap- proved for leiomyosarcoma. • 2% endometrial stromal sarcoma Lilly is running a confirmatory study in 50 subtypes called AN- • 1.5% chondrosarcoma NOUNCE that is already fully enrolled. Lartruvo holds orphan drug status and was developed under FDA’s • 1.5% epithelioid sarcoma breakthrough therapy program. Only one other sarcoma therapy has • 1.5% fibrosarcoma received a breakthrough designation. Adaptimmune Therapeutics • 1.5% low-grade fibromyxoid sarcoma PLC’s NY-ESO affinity-enhanced T-cell targeting therapy has break- through status for a genetically selected synovial sarcoma popula- • 5% other histologies, with one patient each tion; Phase III research is expected to begin by year-end 2016. Source: FDA labeling Lartruvo’s accelerated approval was supported by the Phase II JGDG study of 133 patients with metastatic cancer randomized to olaratumab with doxorubicin or doxorubicin alone. Patients involved treatment factors in the trial all confirmed the robustness of the OS in the trial had 25 different subtypes (see box) of soft tissue sarcoma, treatment effect, a Lilly spokesperson explained. the most common of which were leiomyosarcoma (38%) liposarco- Safety information was drawn from randomized and single-arm ma (17%) and undifferentiated pleomorphic sarcoma (11%). trials including a total of 485 patients with various tumor types. Participants taking doxorubicin who progressed were permitted to Prescribing information includes warnings for infusion reactions get Lartruvo as a single agent and almost half did so. and embryo-fetal toxicity. Lartruvo with doxorubicin was associated with significantly better “The most common (≥20%) adverse reactions of Lartruvo plus median overall survival (26.5 months vs. 14.7 months) compared to doxorubicin are nausea, fatigue, musculoskeletal pain, mucositis, doxorubicin alone. Median progression-free survival and response alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, rates were numerically but not significantly better for the combina- neuropathy, and headache,” labeling states. tion arm – 8.2 months vs. 4.4 months and 18.2% vs. 7.5%, respectively. Lilly is finalizing the price and patient access program and plans to The absolute improvement observed in median overall survival make the drug available “in the coming weeks.” with Lartruvo and doxorubicin (11.8 months) was greater than that With the co-pay program, qualified patients will pay no more than observed in progression-free survival (3.8 months). This is not un- $25 per infusion, the company said in a statement. common with non-cytotoxic agents, such as Lartruvo, and multiple sensitivity analyses of pre-treatment, during treatment and post- Published online October 19, 2016 pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 9 Regulatory Update Cuba: A Pharmaceutical Regulatory Snapshot Michael Cipriano [email protected]

Scientific Research. According to CENCEC’s website, only 5% of clinical studies tak- ing place at the center between 1992 and 2013 had international sponsors. CECMED, which was founded in 1989 and employs a workforce of 325, is one of eight national regulatory agencies for drug reviews recognized by the Pan American Health Organization as a National Regula- tory Authority of Regional Reference. The other Regional Reference agencies are in Argentina, Brazil, Canada, Chile, Colombia,

Shutterstock: pavalena Shutterstock: Mexico and the US. Approval times vary depending on the espite a communist regime that pro- Cuba, but Ferrer said the process for doing drug. A generic for a drug already on the hibits the promotion of pharmaceu- business in Cuba is “not impossible.” Cuban market, for example, would take Dtical products in Cuba, the island na- “One of the positive effects of terminat- three months to be approved, while prod- tion nevertheless has an “open economy” for ing the embargo will be that US and Cuban ucts with approval in a market outside of drug makers to do business, an expert says. companies will be doing business as both Cuba could take six months. A total of 318 – or 37.5% – of the drugs countries are doing nowadays with the rest New molecular entities have a review available in the national formulary in Cuba of the world,” Ferrer told the Pink Sheet. time of roughly nine months, although are imported from countries around the “Things are moving forward,” he added. innovative biological products could take world, according to Fernando Ferrer, head “With the embargo lifted, I believe better more than nine months, Ferrer said. of life sciences consulting firm Multina- things will come.” tional Partnerships. The other 531 drug products in the nation- Areas of Opportunity “The road is open. The way is open,” Fer- al formulary are produced by nationalized Ferrer said there is significant opportunity rer said of the nation with a population of R&D firms, which are separate entities from in the areas of orphan drugs and oncology roughly 11.1m. “Cuba is not a closed econ- the commercial firms. A total of 31 national drugs and hematology drugs. Together omy. Cuba is an open economy.” drug companies in Cuba conduct R&D. with cancer, other non-communicable The importing of drugs and negotiating Ferrer said his perception is that Cuba’s chronic diseases such as cerebrovascular of prices is conducted by eight national- health research culture is very patient-cen- disease, diabetes and chronic respiratory ized commercial companies. Once pur- tered. There is no over-the-counter drug in- diseases account for about 70% of total chased, the drugs are passed onto citizens dustry in Cuba. All medicines are distributed deaths in Cuba annually, he said. with prescriptions for free, as health care is at pharmacies via prescriptions from doctors. From a regulatory standpoint, Ferrer a constitutional right in Cuba. noted Cuba has a “full-standing and com- A wide range of companies from around Clinical Trials And Approvals prehensive database of patient registries” the world have exported drugs to Cuba Cuba has two separate regulatory agen- created from the beginning of a mother’s through this pathway, including Astra- cies overseeing clinical trials and product pregnancy and continued for the entire Zeneca PLC, Novo Nordisk AS, Serum In- approvals: clinical trials are overseen and lifespan of every Cuban. stitute of India Ltd., Novartis Pharma AG, coordinated by the National Coordinat- “Therefore, international life science Merz Pharmaceuticals GMBH and Roche. ing Center of Clinical Trials (CENCEC) and companies will find a unique opportu- (See chart on p. 11 for examples of imported reviews and approvals by the State Center nity to work with all the stakeholders in a products on Cuba’s formulary.) for Control of Drugs and Medical Devices streamline fashion,” Ferrer said. “Better said, Ferrer added that he expects US com- (CECMED). Cuba has a straightforward process for panies to make a push toward exporting Most trials taking place at CENCEC are market access and product supply which drugs to Cuba as relations between Cuba sponsored by Cuban national entities, is aligned with the regulatory review and and the US continue to normalize. Com- such as the Molecular Immunology Cen- approval process.” merce restrictions currently are in place ter, the Center of Genetic Engineering and for US companies under the embargo on Biotechnology, and the National Center of Published online October 17, 2016

10 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Regulatory Update

Examples Of Drugs On Cuba’s National Formulary

Drug Name Manufacturer Condition Follicular CD20-positive non-Hodgkin’s Rituxan (rituximab) Genentech lymphoma Herceptin (trastuzumab) Genentech Metastatic breast cancer Simulect (basiliximab) Novartis Prevents rejection in organ transplantation CIMAher (nimotuzumab) Cuba Center of Molecular Immunology (National) Glioma CimaVax-EGF Cuba Center of Molecular Immunology (National) Non-small-cell lung carcinoma vaccine Synthroid (levothyroxine sodium) AbbVie Hypothyroidism Zocor (simvastatin) Merck High cholesterol Captopril Laboratorios Novatec (National) Heart failure Atorvastatin Laboratorios Novatec (National) High cholesterol Human rabies immunoglobulin Adalberto Pesant (National) Rabies antibody preparation Berotec (fenoterol hydrobromide) Boehringer Ingelheim Asthma Cetrotide (cetrorelix) EMD Serono Prevents premature ovulation Acetadote (acetylcysteine) Cumberland Pharmaceuticals Prevents alcoholic liver damage Roberto Escudero Pharmaceutical Laboratory Glicerina Constipation Company (National) Glimepiride Laboratorios NOVATEC Type 2 diabetes

Manufacturing Quality Despite Progress, More Work Needed To Harmonize FDA and EMA Criteria For Biowaivers Joanne Eglovitch [email protected]

DA’s guidance last year waiving bioequivalence testing require- solving drugs in new and generic drug applications to avoid human ments for highly soluble and low permeable drugs did much testing and reduce the cost of drug development. Fto harmonize these exemptions with the European Medicines The European Federation For Pharmaceutical Science’s (EUFEPS) Agency but more work is needed to resolve differing requirements Network on Bioavailability and Biopharmaceutics started GBHI in for solubility, dissolution and permeability. Until then, pharmaceuti- 2014 to harmonize bioequivalence assessment, including biowaiv- cal manufacturers may still need to submit separate biowaiver re- ers, among regulators worldwide. The first conference was held quests and conduct separate studies in the US and the EU. in Amsterdam in March 2015. The topics of the conference are se- Speakers at the 2nd annual meeting of the Global Bioequivalence lected by the Scientific Planning Committee with the intention of Harmonization Initiative (GBHI) in Rockville, Md., on Sept. 14 noted identifying differences with “realistic chances for harmonization.” that much progress has been made to reconcile differing require- Harmonizing biowaiver requirements is also high on the radar ments for biowaiver studies but that there are still areas of dishar- screen for the International Council of Harmonization. ICH has agreed mony. They noted that regulators are increasingly using biowaivers to develop a new guidance on Biopharmaceutical Classification Sys- to waive the regulatory requirement for in vivo bioavailability (BA) tem (BCS) based biowaivers under the multidisciplinary M9 process. and/or bioequivalence (BE) studies for highly soluble and rapidly dis- The aim is to support worldwide harmonization of the applicability of

pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 11 Manufacturing Quality

Despite general alignment, there highly soluble when the highest strength is soluble in 250 mL or less of acqueous are some differences. For example, media over the pH range of 1-6.8.” Yet EMA wants the highest therapeu- FDA wants solubility tested on tic dose tested. The EMA guidance said that “the drug substance is considered the highest strength, while EMA highly soluble if the highest single dose administered as immediate release Shutterstock: emin kuliyev kuliyev emin Shutterstock: wants the highest dose. formulation(s) is completely dissolved biowaivers and the data needed to support such applications. ICH an- in 250 mL of buffers within the range of pH 1-6.8 at 37 degrees nounced that the guideline is expected to help reduce the unneces- Celsius.” sary clinical trials and facilitate the production and availability of good In another area, Polli said that there is “quite a bit of difference” in quality medicines, especially in low and middle-income countries. assessing intestinal permeability. FDA allows non-human studies Jim Polli of the University of Maryland School of Pharmacy, said but this is not the case in Europe which requires human studies. that “with the 2015 FDA draft guidance on BCS there is a remarkable The FDA guidance states that “the permeability class of a drug amount of convergence between the EMA document and the FDA substance can be determined in human subjects using mass bal- document.” ance, or absolute BA [bioavailability studies], which are the pre- FDA issued a guidance in May 2015 that permits biowaivers of in ferred methods, or intestinal perfusion approaches. Recommend- vivo bioequivalence testing for Class 3 drugs under the Biopharma- ed methods not involving human subjects include in vivo or in situ ceuticals Classification System. These drugs are highly soluble and intestinal perfusion in a suitable animal model (e.g., rats), or in vitro have low permeability. FDA’s former guidance in 2010 only allowed permeability methods using excised intestinal tissues, or monolay- waivers for Class 1 drugs that are highly soluble and highly perme- ers of suitable epithelial cells.” able. FDA’s 2015 guidance more closely aligns with the EU’s guid- The EMA guidance said that “complete drug absorption should ance on biowaivers that was issued in 2010. EMA’s guidance allows be based on reliable investigations in humans. Data from ab- biowaivers for Class 1 drugs. solute bioavailability or mass-balance studies could be used to The classification system is as follows: BCS Class 1 is for those drugs support this claim. Well-performed in vitro permeability inves- with high solubility and high permeability, BCS Class 2 is for low solu- tigations including reference standards may also be considered bility and high permeability, Class 3 is for high solubility and low per- supportive to in vivo data.” meability and BCS Class 4 is for low solubility and low permeability. Polli further noted that the dissolution testing methodologies are also different. While there are similarities in both with respect to the Industry Clamoring For Harmonization rate of dissolution and the extent dissolved, there are slight differenc- The pharmaceutical industry has been clamoring for such har- es with the volume media of the drug to be tested. monization. Yu Chung Tsang, chief scientific officer for biophar- Both require at least 85 % or more of Class 1 drugs be dissolved maceuticals at Apotex, noted at the 2nd FDA/QRI Conference on in 30 minutes and for Class 3 drugs, at least 85% or more of the Advancing Product Quality held last October in Bethesda that BCS drug be dissolved in 15 minutes. Yet the volume that these drugs biowaivers offer significant savings on cost and time. For a typical should be tested in is different. FDA requires that dissolution be bioequivalence study enrolling between 24 to 36 subjects, the cost tested in a solution of 500 ml of less while EMA requires dissolution is $250,000 for a total of three months. to be measured in a solution of 900 ml or less. The waiver of bioequivalence studies in ANDAs for BCS Class 1 drugs provides significant costs and time savings and also reduces More Alignment on Excipients unnecessary human exposure to drugs. He also said that Apotex, Polli noted that there is more alignment on the permitted levels of like many generic companies, develops products for global mar- excipients in BCS Class 1 and Class 3 products. ketplaces/ He said that further savings can be achieved if only need Both allow the use of well-established excipients that do not affect to meet one set of rules. drug absorption and warn against using excipients that are known to affect absorption. Some Differences Noted FDA’s guidance said that “large quantities of certain excipients, While there is general alignment on biowaivers, Polli said that there such as surfactants (e.g. polysorbate 80) and sweeteners (e.g. man- are some differences in the criteria used by regulators to assess nitol or sorbitol) may be problematic, and sponsors are encouraged permeability, solubility and dissolution. to contact the review division when this is a factor.” For example, FDA wants solubility tested on the highest strength, The EMA guidance said that “as a general rule for both BCS while EMA wants this measured on the highest dose. Class 1 and Class 3 drug substances well-established excipients The FDA guidance said that “the solubility class boundary is based in usual amounts should be employed and possible interactions on the highest strength of an IR [Immediate Release] product that is affecting drug bioavailability and/or solubility characteristics the subject of a biowaiver request. A drug substance is considered should be considered and discussed…Excipients that might af-

12 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Manufacturing Quality fect bioavailability like sorbitol, mannitol, sodium lauryl sulfate or studied were cimetidine and acyclovir. other surfactants, should be identified as well as their potential These excipients included SLS, corn starch, sodium starch gly- impact on gastrointestinal motility, susceptibility of interactions colate, colloidal silicon dioxide, dibasic calcium phosphate, cro- with the drug substance, drug permeability and interaction with spovidone, lactose, povidone, and stearic acid. The study found membrane transporters.” that these excipients, some in very large quantities, did not affect Polli said, however, that some of the excipients that the FDA and drug absorption. The conclusions were that excipient allowances the EMA deem high risk may actually not affect absorption. should be broadened to include some common excipients that He cited research conducted by the University of Maryland are deemed higher risk. published in 2016 and funded by FDA which assessed the im- pact of nine excipients on BCS Class 3 drug absorption. The drugs From the editors of the Gold Sheet. Published online October 17, 2016

FDA Outlines Criteria For Approving Manufacturing Supplements Under GDUFA Joanne Eglovitch [email protected]

eneric drug manufacturers are told time-since-last-inspection criterion for de- by FDA when and how it will ac- termining when FDA will conduct inspec- Gcept prior approval supplements tions of facilities that are subject to prior under GDUFA. approval supplements. For example, the FDA on Oct. 17 issued final guidance draft said that FDA will use a finished prod- to generic drug applicants explaining its uct facility’s previous inspection if it is two criteria for reviewing and approving prior years old or less, a previous active pharma-

approval supplements under the Generic ceutical ingredient facility or control test- monticello Shutterstock: Drug User Fee Act. The guidance makes ing lab inspection if it is three years old or several technical changes from a draft ver- less, and a packaging only facility inspec- to be submitted on the day it arrives at FDA’s sion issued two years ago. tion if it is four years old or less. FDA no appropriate designated document room.” The guidance applies to applicants of ab- longer uses this criterion for determining Under GDUFA FDA can refuse to re- breviated new drug applications (ANDAs) inspection frequency. ceive a PAS in the following circumstances: that electronically submit a prior approval The new guidance also adds in a new sec- •• An applicant fails to pay the application supplement on or after Oct. 1, 2014. The tion for manufacturers that want to appeal fee within 20 calendar days of submit- guidance does not apply to new drug appli- a reporting category. It states that “an appli- ting the supplement; cations, biologics license applications, sup- cant may request reconsideration of FDA’s •• A supplement references a Type 2 API plements filed for NDAs or BLAs or changes supplement reporting category determi- DMF that is not on the public available being effected (CBE) supplements and an- nation. These requests will be reviewed for reference list because of non-pay- nual report filings to NDAs, BLAs, or ANDAs. and managed on a case-by-case basis. If ment of the GDUFA DMF fee; Prior approval supplements are submit- an applicant is requesting reconsideration •• A PAS references a facility on the facility ted for major changes that have a signifi- of a supplement reporting category, the arrears list for failure to pay the GDUFA cant potential to have an adverse effect on applicant must submit a written request facility fee; the identity, strength, quality or potency for reconsideration within 10 days of FDA’s •• The PAS applicant is the owner of a fa- of a drug product, and must be approved notice to the applicant that the applicant’s cility on the facility arrears list; by FDA before being implemented. FDA submissions was not accepted as a CBE •• The PAS applicant is affiliated with the started charging fees for reviewing prior supplement. If an applicant disagrees with owner of a facility on the facility arrears list; approval supplements beginning in fiscal the outcome of the reconsideration, the ap- •• The PAS applicant is listed on the back- year 2015, which began on Oct. 1, 2014. The plicant may initiate a formal appeal.” log arrears list; and user fee for preapproval supplements was The guidance also clarifies at what point •• The PAS applicant is affiliated with an $38,020 in FY 2016 and $35,240 in FY 2017. a prior approval supplement is deemed to entity on the backlog arrears list. The final guidance is slightly revised have been submitted to FDA. The guidance from a draft version issued in July 2014. states that “If a submission arrives in physical From the editors of the Gold Sheet. The guidance removes a reference to the media form in the eCTD format, it is deemed Published online October 17, 2016 pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 13 Generic Drugs

Generic Drug User Fees Will Jump More Than 50% In FY 2018

Derrick Gingery [email protected]

he generic industry should prepare Executive Programs, said in an interview A public meeting to solicit stakeholder to pay more in support of FDA’s ge- with the Pink Sheet that both sides recog- comment on the commitment letter and T neric drugs program when its user nized that FDA needed more funding to fee structure is scheduled for Oct. 21 at fee program is reauthorized. handle the generics program. FDA’s White Oak headquarters. GDUFA II will begin Oct. 1, 2017 with a “On the size of the program, I think it’s revenue target of $493.6m, which is nearly very, very important for the program, for ANDA Fee Target Doubles In 53% higher than the target for the final the public, that the program is now sized GDUFA II year of GDUFA I. In FY 2017, the agency ex- appropriately for the volume of applica- The GDUFA II agreement likely means pects to collect about $323m. tions that industry is putting forward to that some ANDA sponsors will be paying The GDUFA II starting total also likely the agency,” she said. “That is the only way much more. will adjust higher in the years after FY to meet the performance demand that I ANDA volume was underestimated 2018 to account for inflation and other think all stakeholders really are asking out when GDUFA launched in 2012. Both sides adjustments, according to the draft com- of the program.” expected FDA to receive 750 ANDAs per mitment letter and fee structure summary FDA issued a Federal Register notice year, but the actual average was about released Oct. 14. Both documents outline in September announcing the GDUFA II 1,000 ANDAs per year through the first four the agreement between FDA and industry agreement was completed, but had not years of the program. The increased work- to reauthorize the program. released the draft commitment letter. The load resulted in longer approval times and Mary Beth Clarke, director of Center for deal still requires congressional approval communication problems. Drug Evaluation and Research’s Office of to be implemented. Industry and the agency concluded that even after FDA hired many new staff GDUFA Fee Revenue Targets members to handle the increased ANDA $500m volume, more funding was necessary to “maintain FDA’s current productivity and $450m implement negotiated improvements.” $400m Clarke said the GDUFA II agreement $350m does not include a hiring goal. The agency has added more than 1,200 new staff as $300m part of its GDUFA, exceeding stated goals. $250m The new fee structure requires ANDA $200m submission charges to generate 33% of the annual revenue in GDUFA II, up from $150m 24% in GDUFA I. $100m Active pharmaceutical ingredient and $50m finished dosage form facilities will see their fee burdens decrease significantly. Active 0 pharmaceutical ingredient (API) facilities FY2013 FY2014 FY2015 FY2016 FY2017 FY2018 will generate 7% of annual revenue in GDUFA II, down from 14% in GDUFA I, and I Finished Dosage Form Manufacturer finished dosage form (FDF) facilities will I Active Pharmaceutical Ingredient Manufacturer generate 20% of annual GDUFA II revenue, I ANDA Prior Approval Supplement I Drug Master File as opposed to 56% in GDUFA I. I Backlog I ANDA Holder That may signal that ANDA submission fees will increase. The ANDA fee target When GDUFA II begins in FY 2018, the fee structure will change so facilities no will increase from $77.5m in FY 2017 longer shoulder most of the burden for revenue generation. ANDAs will have the (the last year of GDUFA I) to $162.9m most responsibility. in FY 2018 (the first year of GDUFA II), a Note: Prior approval supplement fees will be eliminated in GDUFA II. 110% increase. API facilities will see their

14 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Generic Drugs burden decrease 24% from $45.2m in Existing Fee Burden Planned Fee Burden FY 2017 to $34.6m in FY 2018. Finished dosage facilities also will see a drop, (GDUFA I) (GDUFA II) from $180.9m in FY 2017 to $98.7m in FY 2018, a 45% decrease. The drug master file fee target will in- 24% crease even though its portion of the an- 35% 33% nual burden is dropping from 6% to 5%. DMF fees will generate $19.4m in FY 2017 and $24.7m in FY 2018, a 27% increase (see 6% graphic). 56% Facility fees were a significant issue for 5% industry throughout GDUFA I. Small busi- 14% nesses in particular argued that the fees 20% 7% were a hardship. GDUFA II also includes changes to help I ANDA I Drug Master File I API Facility I FDF Facility I ANDA Holder small businesses, including that no an- nual fees be charged until a manufacturer Facilities will shoulder much less of the generic drug user fee burden when the is listed in an approved ANDA. Contract program begins its second cycle in fiscal year 2018. manufacturers also will pay one-third of the finished dosage form facility fee. But Note: GDUFA I totals do not include the one-time backlog fee charged during the there will be no small business waiver, as program’s first year. Under GDUFA II contract manufacturers will pay one-third of had been proposed. the finished dosage form facility fee. The ANDA Holder fee also will be determined based on the number of ANDAs a company and its affiliates own.

Welcome ‘ANDA Holder Fee’ Source: FDA user fee documents GDUFA II’s new fee is the ANDA Holder fee, which will generate 35% of the annual revenue. It is intended as a graduated fee there is no gaming of the system. But to designate that they would be the fee- based on the number of ANDAs a sponsor Clarke said industry preferred to have one paying entity for all of their affiliates.” and its affiliates own. large entity paying for all affiliates, rather FDA and industry decided to focus rev- Sponsors that own 20 or more ANDAs than breaking into smaller firms to pay a enue generation on applications even will pay the full fee. Those owning six to 19 reduced fee. though they are less predictable year to ANDAs will pay 40% of the fee and those “In many cases it actually works to indus- year than facility counts. The ANDA holder owning one to five ANDAs will pay 10% of try’s advantage to corporately be able to fee is intended to ensure a more stable rev- the fee. pay as one parent company for all of their enue stream each year. FDA will be policing the companies as affiliates,” she said. “Industry had a prefer- they are placed in the fee tiers to ensure ence that the top corporate entity be able Published online October 16, 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.

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pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 15 Generic Drugs

FDA Pushing Forward With Withdrawal Of Two Concerta Generics

Michael Cipriano [email protected]

allinckrodt PLC and Kremers Urban Pharmaceuticals Inc. could be gearing up for a fight with FDA, after the agency Mproposed withdrawing approval for the firms’ generic forms of Janssen Pharmaceuticals Inc.’s ADHD medication Concerta (methylphenidate). FDA concluded that Mallinckrodt’s generic fails to provide “the same extent of methylphenidate exposure as CONCERTA during the 7- to 12-hour time period after administration,” while Kremer’s generic did not provide the same extent of exposure during the 8- to 12-hour time period following administration, according to notices posted in the Federal Register on Oct. 17. Therefore, they may not be therapeutically equivalent to the brand. The agency determined at the time of approval for both generics that the Abbreviated New Drug Application contained data suffi- cient to demonstrate the bioequivalence to Concerta, the notices state, also noting that the submitted data conformed to recom- mendations in 2012 draft guidance on methylphenidate hydro- chloride. Mallinckrodt began marketing its generic in March 2013, with Kremers beginning in August 2013. uate bioequivalence of Mallinckrodt 27-mg product compared to the brand name product. CDER ultimately proposed to withdraw Under Investigation Immediately After Launch approval of both drugs. In only two months and one month, respectively, for FDA’s Adverse “In the absence of information showing bioequivalence be- Event Reporting System (FAERS) to receive reports describing in- tween the generic drug at issue and the reference listed drug, there sufficient therapeutic effect of the Kremers product. Specifically, is no basis for concluding that the Agency’s finding of safety and the drugs were reported to have an insufficient effect later in the efficacy (or substantial evidence of effectiveness) supporting ap- day, which led to the Center for Drug Evaluation and Research proval of the reference listed drug likewise supports approval of launching an investigation. the generic drug,” the agency states. A tracked safety committee met beginning in December 2013 to The first downgrade of a generic equivalency based on patient investigate specific components of the generics, including adverse complaints took place in 2012, when FDA changed the 300 mg ge- events reports, product composition and bioequivalence data. The neric bupropion extended release marketed by Teva Pharmaceuti- meetings concluded in June 2014, and resulted in FDA downgrad- cal Industries Ltd.’s and manufactured by Impax Laboratories Inc. ing the products from AB- to BX-rated. from AB to BX. In November 2014, CDER issued a revised draft guidance on bio- The agency has asked the four remaining ANDA sponsors of ge- equivalence recommendations for Concerta, and representatives nerics to GlaxoSmithKline PLC’s Wellbutrin XL to conduct bioequiv- of the Office of Generic Drugs contacted the drugmakers, giving alence studies for their products and submit them by March. After them the option to voluntarily withdraw the products from the some delay, Watson’s product was also found inequivalent. In that market or confirm bioequivalence within six months. case, neither sponsor fought FDA’s decision to boot their generics. Both companies declined to voluntarily withdraw their prod- ucts. Kremers, however, submitted data from new bioequivalence Will The Drugmakers Fight Back? studies that were conducted based on the design recommended With the proposal to withdraw approval of the generics, the in the revised guidance. FDA, however, determined the data failed sponsors are given the opportunity to make their voice heard, to demonstrate bioequivalence. The agency also conducted clini- and can request to have a hearing within 30 days of the notices cal trial simulations, or reanalyses, of both products clinical trial being posted on the Federal Register. simulation based on the initial bioequivalence data submitted in Mallinckrodt spokeswoman Rhonda Sciarra tells the Pink Sheet the ANDAs. in a statement that the company “will evaluate next steps in the Mallinckrodt never submitted any data in response to the re- coming days.” quest. CDER, however, sponsored its own 28-patient study to eval- “While we assess the Agency’s notice and rationale, it is impor-

16 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Generic Drugs tant to recognize that the Agency has stated no safety concerns led some FDA officials to call for an easier process of withdrawing with our product,” Sciarra says. drugs that fail their confirmatory trials. Barclays Investment Bank analysts Douglas Tsao and Morgan Williams said in a note that they expect Mallinckrodt to submit a Good News For Teva? request for hearing, although “it seems unlikely that the company If approval for the Concerta generics is ultimately withdrawn, it has any data to rebut the Agency’s claims. We ultimately expect the may be good news for Teva, which obtained the rights to the au- FDA’s action to be successful and [Mallinckrodt] will be forced to thorized generic of Concerta when it acquired Allergan PLC’s ge- pull the product from the market,” the analysts wrote. nerics business earlier this year. Kremers did not return a request for comment by press time. Mallinckrodt and Kremers combined for roughly 15% of the mar- Genentech Inc. previously engaged in such a fight when FDA ket share, Evercore ISI analyst Umer Raffat said in a note. He added sought to withdraw the breast cancer claim for Avastin (bevaci- that the Teva and Allergan share in this market stands at around zumab) after trials failed to confirm the extent of the benefit shown 75% currently, and will likely increase as a result of approval being in prior studies that led to accelerated approval. Then-FDA Com- withdrawn. missioner Margaret Hamburg ultimately ordered the approval be withdrawn in November 2011, but the experience nevertheless Published online October 17, 2016

Reimbursement Tagrisso Funding Journey Shows UK’s Revamped Cancer Drugs Fund Is No Soft Touch Maureen Kenny [email protected] Lucie Ellis [email protected]

ompanies hoping to get their new oncology products accepted by the CNational Health Service in England under new arrangements for assessing the cost-effectiveness of such products will be looking closely at the decision by health technology assessment body NICE to in- clude AstraZeneca PLC’s promising new lung cancer treatment, Tagrisso (osimer- tinib), in the recently relaunched Cancer Drugs Fund. Tagrisso is the first product to secure funding through the CDF under new ar- rangements intended to allow drugs with clinical uncertainty to be accessed by pa- Deliverance Shutterstock: tients in the NHS. But it took two assess- ments and happened only after AstraZen- (pembrolizumab) – is not cost-effective in is the system working as it should.” eca submitted to NICE additional updated the treatment of advanced lung cancer. AstraZeneca PLC welcomed the deci- evidence from ongoing studies and fur- With regard to Tagrisso, NICE says the sion but referred the Pink Sheet to what ther analyses of existing data. Tagrisso had new CDF process can work well “where it said when Tagrisso was initially rejected previously been available to patients in the companies work with NICE to price their by NICE, in June, that It was “disappointing UK under the Early Access to Medicines drug affordably and present a clear case for that NICE was not able to exercise more flex- Scheme since December 2015. additional evidence to be gathered while ibility with regard to the degree of accept- Merck Sharp & Dohme (Merck & Co. Inc.) on the CDF.” It says for the first time “we are able uncertainty around overall survival”. is in the spotlight, too, with NICE having able to give patients access to a promising Also in June, AstraZeneca said there were announced that its initial assessment of new cancer treatment whilst more evi- major issues with the NICE assessment pro- the company’s rival to Tagrisso – Keytruda dence is gathered on its effectiveness. This cess with respect to appraising medicines pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 17 Reimbursement that have been awarded early authoriza- converted into normal approvals. In Tagris- AURA3 trial that it hopes will lead to full ap- tion. Tagrisso has conditional EU market- so’s case, notes NICE, the marketing authori- proval in both the US and the EU. ing approval and the company argues that zation is conditional upon the company sub- NICE should either be more open to the use mitting the clinical study report of the phase Lack of Overall Survival of accepted alternative cancer endpoints al- III AURA3 study comparing osimertinib with Data Was Key Concern ready adopted by the European Medicines platinum-based doublet chemotherapy. This NICE’s principal concern during the first as- Agency and national authorities in other is expected in June 2017, the HTA body says. sessment of Tagrisso was the lack of overall countries, or be more flexible in the degree Tagrisso was granted accelerated review survival data for the drug. It said it could of uncertainty that committees can accept in the EU, under which the review usually not recommend the drug for routine use for entry into the CDF. takes 150 evaluation days rather than the on the NHS or through the CDF system because it did not meet cost-effectiveness “[The EMA and the European Commission] look at thresholds. This led to the criticism from AstraZen- whether a drug is clinically effective and safe enough eca about the new assessment system still not making allowances for products such to be prescribed to patients. We make an assessment as Tagrisso that had achieved accelerated of whether a treatment will benefit patients and if it approval in Europe on the back of positive, earlier stage data. Pressed on this matter, is worth the price that is being asked.” NICE was very clear. It told the Pink Sheet: “[The EMA and the European Commission] NICE is recommending Tagrisso for use standard 210. look at whether a drug is clinically effective on an interim basis under the CDF – which Osimertinib has regulatory approval in and safe enough to be prescribed to pa- has an annual budget of £340m – but not some 40 markets and the regulatory and tients. We make an assessment of whether for routine use on the NHS. Around 300 pa- reimbursement process in several other a treatment will benefit patients and if it is tients in England and Wales every year will countries is ongoing, an AstraZeneca worth the price that is being asked.” be eligible for treatment with osimertinib, spokeswoman said. “In markets where it is New arrangements that went live on which AstraZeneca says had “one of the possible, we have operating agreements in April 1 allow NICE to make one of three fastest development programmes ever, place to ensure patients have access in the funding recommendations for cancer from start of clinical trials to approval in interim period before commercial launch,” drugs based on whether they look likely just over two and a half years.” she added. to be cost-effective: recommend for rou- Under the new CDF arrangements, can- In the US, Tagrisso was approved by in tine commissioning; not recommend for cer drugs that receive a draft positive NICE November 2015 under accelerated review. routine commissioning; or recommend for recommendation are immediately funded As with conditional approval in the EU, this use within the revamped CDF. by NHS England. NICE issued its draft final provides earlier patient access to promising This last option is new and is only for appraisal determination on Tagrisso on new drugs while the company conducts drugs for which there is insufficient evi- Oct. 4. The appeal window closed on Oct. confirmatory trials. AstraZeneca recently re- dence to decide with certainty whether 14 and the final publication date is ex- ported that its Phase III AURA3 trial had met the drug is or is not cost-effective. Drugs pected at the end of the month, assuming its primary endpoint, demonstrating better falling into this category are reimbursed there have been no appeals. progression-free survival (PFS) compared to through the CDF for up to two years while standard platinum-based doublet chemo- the company gathers new evidence to Regulatory approval details therapy. The Pink Sheet understands the show that the drug is a cost-effective treat- Tagrisso was granted a conditional EU mar- company has now provided the FDA and ment. NICE then takes a second look and keting authorization for the treatment of the EMA with initial data from the Phase III decides whether to recommend it for rou- adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small NICE’s Review Options cell lung cancer in February this year. Condi- tional approvals allow medicines that satisfy • After assessing a cancer therapy’s likely cost-effectiveness, NICE now can: an unmet medical need to be approved be- fore confirmatory clinical trial data are avail- • recommend it for routine commissioning; able. They are renewed on a yearly basis until • not recommend it for routine commissioning; or the sponsor company has fulfilled all its obli- gations relating to the approval such as the • recommend for use within the revamped CDF. performance of further studies; they are then

18 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Reimbursement tine funding. NICE usually considers drugs like AstraZeneca and MSD, face initial rejec- with only Phase II data. If they are not will- with a cost per quality adjusted life year or tion. In the case of Merck and Keytruda in ing to do so they will need to be prepared QALY of less than £30,000 to be cost-ef- advanced lung cancer, NICE says there is a for access delays until they have additional fective although the institute’s end-of-life lack of “robust data on long-term benefits” data available,” Ignjatovic said. criteria allow NICE to consider drugs with and that the product cannot be considered a cost per QALY of up to £50,000. cost-effective. Not Just A NICE Problem NICE explained its reasoning for not cur- Keytruda got the regulatory green light in It is not only NICE that has struggled to de- rently recommending Tagrisso for routine the EU in August for the treatment of specific fine and assess new drugs that have been use. Even after AstraZeneca put forward types of advanced non-small-cell lung can- approved on data substitutes for overall newer evidence from ongoing studies as cer in adults if they have already been treated survival; other European HTA organiza- well as further analyses of the available with at least one other chemotherapy drug, tions are up against the same problem. In data, it said, the “NICE committee still felt It was already approved for the treatment of Germany, under the AMNOG assessment, that the new data was not strong enough unresectable or metastatic melanoma. Ignjatovic notes that progression free sur- to say for certain if osimertinib was value for NICE said that Merck, in its submission, as- vival (PFS) is not considered a valid end- money.” However, “as the studies were gath- sumed patients stopped using Keytruda at point for added benefit and assessments ering more information on the long term ef- two years if their disease had not worsened. of drugs with single arm trials also do not fectiveness of osimertinib, [the committee] “NICE’s appraisal committee felt that in real- result in an added benefit. decided it could be included on the CDF.” life clinical practice it was very unlikely that “Survival extrapolation, especially if AstraZeneca put forward a “conservative- patients who were benefiting from treat- from single arm studies involving an indi- ly estimated” incremental cost-effectiveness ment with the drug would stop taking it and rect comparison, is bound to yield results ratio or ICER of just under £43,000 per QALY therefore pembrolizumab could not be con- with a great uncertainty,” Ignjatovic said. for Tagrisso. NICE could have considered sidered cost-effective,” the institute said. “Payers say ‘Why should I pay for this drug this to be cost-effective if Tagrisso had met As the committee concluded Merck’s drug before I know it actually works?’ – whereas the institute’s end-of-life criteria; to qualify, was not within the range of what is consid- the companies think they should.” the firm needed to show that the drug ex- ered cost-effective for routine NHS use, it did Ignjatovic suggests this sort of situation tended life by three months compared to not meet the criteria to be included in the is ideally suited for outcomes-based deals. current standard treatment. AstraZeneca CDF. The draft guidance for Keytruda is out “While outcome-based deals had fallen did this by extrapolating its early data, but for public consultation until Oct. 24. out of favor at NICE, there is a greater will- NICE concluded the data used were too im- The average cost of a course of treatment ingness to engage in risk shares in Spain mature and that Tagrisso therefore did not with pembrolizumab is £29,114 at its full and France. For example, Celgene’s Imnov- qualify as an end-of-life drug. list price. MSD, which has offered the NHS a id/Pomalyst (pomalidomide) in multiple confidential discounted price, said it was in myeloma is subject to an outcome-based Pricing touch with NICE in an effort to secure a good reimbursement arrangement in France, NICE told the Pink Sheet that AstraZeneca outcome for patients. signaling that this is increasingly a viable did not submit a further price proposal market access route in the country.” Other between the first and second assessment. Discounts For ‘Missing’ Data experts have similarly suggested that my- Asked to comment, AstraZeneca said de- Tijana Ignjatovic, an analyst for Datamoni- eloma holds potential as a testing ground tails of the agreement between the com- tor Healthcare, suggests that companies for different kinds of reimbursement ap- pany and NHS England were confidential. should consider staggered discounts proaches. AstraZeneca had initially agreed a pa- based on the level of data they are able As well as conducting assessments on tient access scheme with the Department to provide. “What was more at play in the new cancer drugs, NICE is in the position of of Health that offered a simple discount to Tagrisso case was NICE’s end of life crite- having to examine all drugs that were al- the list price of osimertinib, taken as a once- ria – they specify at least three months’ life ready available on the CDF before the new daily tablet, with the discount applied at the extension and for drugs that do not have arrangements came into place. The insti- point of purchase or invoice. The list price is overall survival data that will not be prov- tute says that for new drugs gaining regu- £4,722.30 per pack of 30 80mg tablets and en. If the price had been low enough not latory approval in Europe, in the absence of £4,722.30 per pack of 40-mg tablet. A man- to need quality for end of life criteria to be NICE guidance, NHS bodies should make aged access scheme agreed in September considered, it would not have been such decisions locally on the funding of specific has replaced the patient access scheme. an issue,” Ignjatovic said. treatments. It also notes that it regularly Ignjatovic added that companies should reviews its processes and methodology for Merck Falls Victim To ‘Lack consider offering greater discounts if the assessing new cancer drugs. Of Data’ Assessment Hurdle cost-effectiveness is not low enough or is As more drugs come up for HTA assessment uncertain because of immature data. “You From the editors of Scrip Regulatory Affairs. by NICE, it is likely that more companies will, may have to discount even more for drugs Published online October 17, 2016 pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 19 Reimbursement

What Is An Acceptable Drug Discount? DOJ and Industry Disagree

Brenda Sandburg [email protected]

he Department of Justice’s position in throw a lot of things into question.” a False Claims Act case alleging a med- Schlanger and Hyman, Phelps director Alan T ical supply manufacturer engaged in Kirschenbaum said in an FDA Law Blog post kickbacks could potentially threaten formu- that under the DOJ’s restrictive view, manu- lary-based discounts, rebates and other dis- facturer formulary rebates, which “are condi- count arrangements. tioned not simply on purchases but also on Massachusetts US District Court Judge the payor providing certain services – i.e., Rya Zobel initially dismissed the whistle- maintaining a specified formulary status for blower complaint against Coloplast AS, the drug and enforcing the plan formulary,” maker of ostomy and continence care presumably would not be eligible for protec- products, alleging the company provided tion under the discount safe harbor. They said kickbacks to supplier CCS Medical Inc. in ex- DOJ’s interpretation may also exclude many change for “soft campaigning” to move pa- value-based purchasing arrangements, such tients to Coloplast products. But the judge as performance-based rebates triggered by reversed her ruling after the government specified clinical outcomes. submitted a statement of interest in the case asserting that remuneration to health Remuneration To Switch care providers for switching patients from “A discount is a Patients Is Not one product to another does not qualify as A Discount, DOJ Says a discount protected from claims under the reduction in price The Department of Justice declined to in- Anti-Kickback Statute. and nothing more,” tervene in either the Omnicare or Coloplast The judge came to a similar conclusion in False Claims Act case. Under the False Claims a second case, declining in an Aug. 23 order Department Act, private individuals, known as relators, to dismiss a suit by relators alleging long- file suit on behalf of the federal govern- term care pharmacy Omnicare Inc. solicited of Justice asserts. ment alleging fraudulent claims have been and/or received kickbacks from Organon submitted for government payments. If the USA Inc. in the form of discounts on Organon’s antidepressant government intervenes the relator receives up to 30 percent of Remeron (mirtazapine). the recovery. The relators claim Omnicare purchased Remeron through its After Judge Zobel initially granted Coloplast’s motion for sum- membership in several group purchasing organizations and that mary judgement, DOJ submitted the first of two statements of each GPO earned discounts on Remeron based on the drug’s mar- interest in the case. In its Aug. 8 statement of interest, the DOJ ket share within a specified group of pharmacies. They say that in laid out its position on the scope of the “discount” exception to direct purchasing agreements with Organon, Omnicare accepted a the Anti-Kickback Statute. volume-based discount for Remeron in exchange for a promise to “The United States submits that remuneration from a manufac- promote the agreement’s potential financial benefits to its clients. turer to a distributor in return for specific conversion and referral In both cases, the relators allege that the kickbacks tainted activities – even when the remuneration takes the form of a price claims to Medicaid. concession – is not a ‘discount.’ Rather, it is illegal remuneration Hyman, Phelps & McNamara attorney Serra Schlanger said in for conduct or services intended to convert patients to the manu- an interview that the two cases call into question what those in facturer’s product,” the DOJ said. the healthcare industry have regarded as fairly established pa- “Relators’ allegations carry a reasonable inference that Colo- rameters of the Anti-Kickback Statute’s discount safe harbor. It is plast was paying CCS to use its special influence with its custom- now uncertain whether certain kinds of arrangements are really ers to switch them to the Coloplast products. As alleged, CCS’s discounts. agreement to undertake conversion campaigns in exchange for The DOJ said in an Oct. 6 statement of interest in the Coloplast the price concessions thus transformed the price concessions into case that “a discount is a reduction in price and nothing more.” illegal kickbacks,” the government states. “Such an arrangement “At the moment it’s up in the air” as to how far the government is different in kind from merely offering escalating discounts in

will go in this position, Schlanger said. “If they take it literally it can return for increased sales volumes in an arms-length transaction.” Studio Africa Shutterstock:

20 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Reimbursement

Industry Faces Criminal the exception to the AKS, and other “reduc- Liability For Discount tions in price,” which do not, does not follow Arrangements – PhRMA from the plain language of the statute. In an Aug. 24 order, the court concluded In addition, PhRMA noted that through that the relators’ third amended complaint PhRMA asserts that a regulatory safe harbor last modified in had provided emails between Coloplast 1999, the OIG affirmed that discounts, in- and CCS executives negotiating discounts the government’s cluding rebates, fall outside the AKS as long that “ground the reasonable inference of an as they are “fixed and disclosed in writing to agreement between the two companies” main argument – that the buyer at the time of the initial sale” and that runs afoul of the Anti-Kickback Statute there is a distinction the buyer furnished documentation “upon (AKS). In addition, the court said the relators request” by the HHS Secretary or a state had identified claims submitted to Medicare between “discounts” agency of the discount and the buyer’s obli- while the agreement was in effect. gation to report it. The Pharmaceutical Research and Manu- which qualify for the It says that in this case, no governmen- facturers of America filed an amicus brief in exception to the AKS, tal agency requested information and CCS support of CCS Medical’s motion for the court had no obligation, or even an appropriate to reconsider its order denying dismissal of and other “reductions mechanism, to provide it. The association the complaint. The association asserted that says the court’s decision mandating that the court’s decision and the government’s in price,” which do not, buyers under a discount arrangement must statement of interest “threaten criminal and does not follow from notify the government in the absence of a quasi-criminal liability under the AKS and request is “both inconsistent with the safe FCA respectively for beneficial discount ar- the plain language of harbor’s text and in fact renders it impossi- rangements regularly used by pharmaceuti- ble for any discount arrangement to comply cal manufacturers.” the statute. with the safe harbor.” PhRMA said the government presented in- Omnicare and CCS Medical have both terpretations of the statutory discount exception to the AKS and asked the court to reconsider its rulings allowing the complaints the regulatory safe harbor adopted by HHS’s Office of Inspector to proceed, or alternatively, to certify the rulings for interlocutory General that do not appear in the AKS or any OIG regulation and appeal, whereby an appellate court would consider them before amount to “regulation by litigation.” all the claims are resolved. The association asserted that the government’s main argument – that there is a distinction between “discounts” which qualify for Published online October 16, 2016

Consumer Products Benefit From OTC Switches Supported In Study Of PPIs’ Outpatient Impact Eileen Francis [email protected]

“profound and sustained impact” emergency rooms and hospital or office- the Log Angeles Biomed Research Institute on outpatient health care visits based clinics were “significantly” reduced at Harbor-UCLA Medical Center. Asince the first proton pump inhibi- across the board after the launch of the first Chang and his colleagues noted the po- tor Rx-to-OTC switch reflects the potential OTC PPI, Prilosec OTC (20mg omeprazole) tential broader impact of OTC switches. “A benefit to US health care from making ad- marketed by Procter & Gamble Co. similar effect may be seen in other com- ditional drugs available nonprescription, The reduction marked a change in a mon conditions for which effective OTC suggest researchers and the OTC industry trend preceding the switch of increasing medications are available, such as allergic trade group. incidence of visits to health care providers rhinitis,” they said. “Thus, successful transi- A Journal of Clinical Pharmacology study due to GERD, said the researchers led by tions of medications from Rx-to-OTC status published Oct. 6 found that rates of patient Dong Chang, Division of Respiratory and may provide unique opportunities to im- visits for gastroesophageal reflux disease to Critical Care Physiology and Medicine, of prove the efficiency of outpatient health pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 21 Consumer Products care delivery in the United States. The Consumer Healthcare Products Association helped fund the study. “This is an excellent example of the value of Rx-to-OTC switch, not just for consumers, but for the overall health care system as well,” said Barbara Kochanowski, CHPA’s vice president for Scientific & Regulatory Affairs, in an Oct. 12 statement. The study looked at patient visits to pri- mary care physicians for GERD from 1993 to 2012, to allow “the inclusion of suffi- cient time intervals to examine trends in physician visits before and after” the 2003 OTC switch of Prilosec OTC, which P&G markets under license from innovator As- traZeneca PLC. Prilosec OTC (20mg omeprazole) was the first proton pump inhibitor available OTC and The study found 14.1 visits for GERD per Nexium 24HR (20mg esomeprazole) is the latest PPI brand available OTC. 1,000 primary care physician visits in 1993 and 40 in 2003, a 2.8-fold increase. The re- license from AstraZeneca. Private label switch market will grow at a 5% com- searchers said increases in known risk fac- products also have launched, most re- pounded annual growth rate through tors – obesity and alcohol abuse – could cently Perrigo Co. PLC shipping the first 2018 and forecasts that switches will be have factored, but only somewhat. generic of Zegerid OTC. made in skin care, topical analgesics, di- “We speculate that other secular trends, gestive and allergy products. such as direct-to-consumer advertising Science Informs Policy The researchers also looked into wheth- and increasing public awareness of heart- The researchers say although they expect burn and its treatment options, contribut- er making some PPIs OTC could be linked ed to a change in health care utilization for the findings speak to benefits other OTC to under-treatment of refractory GERD, the symptoms of heartburn,” they wrote. switches could have on health care, they leading to adverse clinical outcomes such However, coinciding with the introduc- recognize decisions to make drugs avail- as esophageal cancer and delayed diag- tion of Prilosec OTC, visits for GERD pla- able nonprescription are “complex and noses of more serious gastrointestinal teaued after 2003 and remained stable need to consider multiple variables includ- disorders such as gastric cancer or peptic through 2012. ing the effectiveness/safety of self-treat- ulcer disease. Those concerns were raised The study found 29.1 visits for GERD per ment as well as the consequences of mis- as potential risks when the products were 1,000 visits in 2004 and 34.8 in 2012. diagnosis, overuse and under-treatment.” introduced. “This change in the time trend of PCP Still, “our findings suggest that the The study found the incidence of esoph- visits occurred at the time predicted by impact of Rx-to-OTC switches on the ef- ageal cancer remained stable from 1993 our study hypothesis, namely, with the ficiency of health care utilization should to 2012, 4.6 cases per 100,000 people in introduction of the first PPI into the OTC also be factored into policy decisions, 1993 and 4.3 in 2012. “The mortality from market in 2003. Although this temporal especially given the shortages of primary gastric cancer declined steadily during this association does not prove a causal ef- care physicians in our current health care period, from 5.6 deaths per 100,000 people fect of the dramatic change in the rate of environment.” in 1993 to 3.2 deaths per 100,000 people in physician visits directly coinciding with FDA encourages drug firms to propose 2012,” the study stated. the Rx-to-OTC switch and the absence of additional drug ingredients for OTC sales The researchers obtained data to assess other secular trends that fully account for and has launched the Nonprescription primary endpoints from the National Am- this effect make the association compel- Drug Safe Use Regulatory Expansion ini- bulatory Medical Care Survey maintained ling,” Chang and his colleagues said. tiative to consider potential additional by the Centers for Disease and Prevention Other PPI products that have become facilitate switches. Control’s National Center for Health Statis- available OTC include GlaxoSmithKline Research firm Kline & Co. note in 2015 tics. Data included patients’ demograph- Consumer Healthcare LP’s Prevacid 24HR that despite the “favorable regulatory ics, reasons for visits, physician diagnoses (15mg lansoprazole), Bayer AG’s Zegerid environment” for switches prompted by codes and medications taken. OTC (20mg omeprazole/sodium bicar- NSURE, the switch market was relatively bonate) and Nexium 24HR (20mg esome- quiet. From the editors of the Tan Sheet. Published prazole) marketed by Pfizer Inc. under Nonetheless, Kline projects the US OTC online October 17, 2016

22 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Regulatory Update EFPIA Urges Japan To Consider New Funding Models Ian Haydock [email protected]

hile conceding that Japan needs to manage its rising “Expensive drugs can still be cost- health care costs to maintain the sustainability of its Wuniversal care system, the European pharmaceutical in- effective overall, for example if dustry federation EFPIA is proposing that now is the right time to consider wider approaches that do not focus solely on drug prices. used in combinations in immune- Pharmaceuticals currently account for around 20% of the coun- try’s total health care costs, and there is a “need to look for efficiencies oncology. But the price may have to across the whole system,” EFPIA Japan chairman Dr. Carsten Brunn told vary between indications” a media briefing in Tokyo. While a series of pro-innovation changes over the past few years, – EFPIA’s Richard Bergström including higher prices for novel products, have reduced the “drug lag” and benefited patients in Japan, “the past 12 months have not been so er the likely mid-term budget impact of new drugs in the pipeline, to positive, observed Brunn, the president of Bayer Yakuhin Ltd. in Japan. better prepare for these. The start of a pilot health technology assessment system, pricing “Innovative and non-innovative products, and simplification of threats, optimal use guidelines, and one-off price cuts for big-selling the pricing scheme would be areas for discussions, and we would products are some of the moves that have contributed to “a less need to consider what to give up in return for predictability and sta- stable and predictable” environment and may affect access to new bility,” Brunn told the meeting. drugs, he warned. Outgoing global EFPIA director general Richard Bergström The European group has been cautioning for some time that the outlined the managed entry agreement and adaptive pathway piecemeal adoption of cost control therapies and ad hoc policy initiatives underway in Europe and how these can help address changes risk negative effects, and that a fuller partnership with the budgetary uncertainties for new drugs and the shortcomings of industry –rather than just dialogue – to jointly develop ideas is the traditional HTA approaches. best way forward. Agreements may be financial or outcomes based, for instance in- Brunn pointed out that the dialog process itself is improving with volving payments for a limited number of initial doses or for compa- the start this April of the new “Kanmin Taiwa” public-private process nies to make limited free supplies. A major aim is to gather real world of talks between industry groups and the government, which held evidence about the actual performance and costs/benefits of new its first working level group meeting in September. There will be therapies, to help direct these to those patients most likely to benefit. another full meeting by year-end, and at this stage the forum is still “Expensive drugs can still be cost-effective overall, for example if largely determining focus areas. used in combinations in immune-oncology. But the price may have EFPIA would like to see the establishment of a joint working group to vary between indications depending on value and engaged at under this process to draft policy proposals, so that all relevant stake- a country level. The new tool is not HTA but adjusted value,” Berg- holders can jointly develop a medium-term plan and, over the lon- ström said. ger term, move towards a value-based healthcare system. “There have been no specific [EFPIA] proposals at the Kanmin Taiwa Data Revolution so far, but we are giving some general ideas on schemes, Brunn told Such programs link in to what EFPIA vice president and Merck KGAA the Pink Sheet. “There has been a lot of openness and willingness chairman and CEO Stefan Oschmann describers as a “data-driven rev- to engage, and as a stakeholder the industry is looking to provide olution in health care” through the increasing use of big data across thought offerings and learnings from Europe, for instance on HTA.” more areas of the care chain and new devices and technology. Such The research-based industry in Japan has greeted local HTA data can be tapped to better track outcomes, achieve sustainable care plans with some concern, highlighting the shortcomings in the ap- systems based on innovation, improve care and eliminate waste. proach in other countries. It could also feed into outcomes-based reimbursement schemes for drugs, essentially meaning that systems “don’t pay for those Time For Change? that don’t work”. Payers are steadily demanding more data on out- He added that the “environment is ripe for dialogue, and other in- comes and may link reimbursement to this, Oschmann said. dustry groups and the JMA [Japan Medical Association] are also Asked whether EFPIA is taking active steps to discuss and pro- willing to discuss these issues. But we need to move beyond the mote such approaches with the Japanese authorities, Brunn told talk to a true partnership approach.” the Pink Sheet that no formal proposals had been made but that The European industry would like to introduce a “horizon scan- the ideas form part of ongoing informal discussions through the ning” process where the government and industry consider togeth- Kanmin Taiwa and other routes. pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 23 regulatory update

One concern of the industry in the EU has been restrictive provisions away from being concerned solely about pricing towards consider- over data protection and for sharing of data, a lack of harmonization of ing funding in a broader way, and to look at alternative appropriate data protection rules, and a lack of clear definitions of public interest. models that might ensure this. Technology can be employed as part The absolute cost of drugs to Japan’s national health insurance of this change to significantly improve and personalize patient care system has become a focus of government attention in recent by optimized therapy and tracking actual outcomes, in the process months given the rapid uptake of effective but pricey new drugs lowering costs and improving efficiencies for payers. for cancer and hepatitis C, which were behind a large rise in the country’s healthcare bill last year. From the editors of PharmAsia News. EFPIA’s overall message on Japan is that there is a need to move Published online October 19, 2016

Intellectual Property Does India’s Perpetual Licensing Plan Risk Backfiring? Anju Ghangurde [email protected]

pliance” with the conditions of licenses/ eliminate graft. approvals at least once in 10 years. A gap On the issue of scaling up GMP norms in analysis of good manufacturing practice India, the source referred to a definite “po- (GMP) set out in Schedule M of India’s litical will” to ensure public safety, despite Drugs & Cosmetics Rules and plans to anticipation of protest from pockets of the make it at par with World Health Organiza- SME (small and medium enterprise) sector tion GMP guidelines is also under consid- on sharp upgrades in GMP norms. eration. Stakeholder feedback has been “The minimum safety standards must be sought on these proposals. implemented – it’s consumer interest ver- sus entrepreneurial interests,” the source Simplification And Enforcement said. “Sweeteners” for SMEs by way of soft The regulator’s efforts, industry sources in loans/attractive financing options to up- ndia is working on a series of measures to the know say, are aimed at ensuring simpli- grade their plants are available, he added. streamline and simplify the drugs regula- fication on the one hand while emphasizing Itory process. The latest tranche of propos- stricter inspections and rigorous enforce- Going A Bit Too Far? als include plans to consider a perpetual ment on the other. But not everyone appears convinced that licensing system for the manufacture and these well-meaning reforms could cut red “Inspections and license renewal could sale of drugs in line with facilitating “ease tape without undermining the overall pro- potentially become independent, with such in doing business” under one of Prime Min- cess of regulatory oversight. division of responsibility leaving little room ister Narendra Modi’s pet initiatives “Make Dr Ajit Dangi, president and CEO of for inspectors to ‘play around’ with firms. in India”. The initiative, launched in 2014, Danssen Consulting, said that the primary There probably could be timelines for sub- aims to make India a global manufacturing mandate of the regulator is to protect pub- mission of the reports of inspection, which hub, thereby upping the contribution of lic health by ensuring that the drugs pro- are increasingly risk-based,” an industry the manufacturing sector to the country’s duced in the country are safe, efficacious gross domestic product (GDP). source told the Pink Sheet. and meet the required quality standards “Validity of various licenses/approv- The source maintained that the intent ap- and that this mandate should not be “com- als granted under the Drugs & Cosmetics pears to be to develop a US Food and Drug promised” for ease of doing business. Rules 1945 for manufacture for sale, sale Administration-esque model where the in- “While the Central Drugs Standard Con- and distribution of drugs and manufacture vestigator sticks to rigorous inspection and trol Organization’s (CDSCO) ‘Sugam’ portal of cosmetics and approval of laboratories timely submission of his report, while the has made online application for various for test analysis of drugs is proposed to be Office of Compliance/ Manufacturing Qual- approvals much smoother, giving per- perpetual unless otherwise suspended or ity then typically issues the warning letter or petual validity of license would be going a cancelled by the Licensing Authority,” a no- other follow up action required. bit too far, particularly when we have over tice from the Drugs Controller General of The source, though, acknowledged 10,000 manufacturing facilities with vary- India Dr GN Singh said. that much will depend on how effective ing degree of capabilities and manage- The Oct. 6 notice, though, specified that enforcement is in India and that systems ment competence,” Dangi, a former presi- there should be an “assessment of com- will need to be modified and tightened to dent and executive director of Johnson

24 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Intellectual Property

&Johnson India, told the Pink Sheet. have a “strong, professionally managed ness of division of responsibility - delink- He believes that the CDSCO can specify and efficient” regulatory mechanism un- ing inspection and licensing - in the Indian the period required to grant a license, say der India’s Ministry of Health and Fam- context, at least for now. two weeks or a month, beyond which ily Welfare, which could be structured as a He believes that if the responsibility to timeline if a license is not granted, it should Central Drug Administration and headed ensure that companies once issued the li- be considered as “deemed” approval. by the DCGI. censes, comply with requirements, is given “License validity can be for five years or to other departments, then it could lead more provided no adverse findings are re- License Terrorism to multiple inspections, request for pa- ported during the period,” Dangi said. Other experts point out that if the sole perwork from multiple departments, etc, He also referred to the recommendation purpose of licenses are to check whether which then puts “additional administrative of the Dr Mashelkar Committee for the for- business sites in India are compliant to ba- load” on the companies. mation of a Central Drug Administration sic things such as quality, then providing However, if inspections are conducted (CDA) on the lines of the US FDA to en- “perpetual lives” to those licenses makes at frequent intervals that are practical – sure that uniform standards are followed little sense. On the other hand, staffing though definitely not 10 years – and are throughout the country. issues at the Indian regulator mean that transparent (e-paperwork) and construc- “The dispersed role and responsibili- resources are tight. tive, then it does make sense, the expert ties of the state and the central regulatory “The perpetual validity of licenses may said. “Care should be taken to see that this agency cause bureaucratic hurdles and therefore seem as a practical way to cir- does not induce ‘license terrorism’ (like tax confusion. If we have to achieve ease of cumvent that problem but will do little to terrorism) since there are many instances doing business, formation of a CDA would ensure compliance. It also provides teeth of good laws turning draconian based on be an important step forward”. to the ‘inspector raj’ style of keeping check interpretations and execution,” he said. The Government of India had, in 2003, which is reminiscent of India’s socialist era The expert reads the regulator’s latest re- set up an expert committee under the (pre-1991). It would ill behoove PM Modi’s form effort as a signal to reduce “coercion” chairmanship of Dr R.A. Mashelkar, then “Make in India’ plan in the medium to long by government agencies, which is expect- Director General of the Council of Scien- term as companies realize the downfalls ed to encourage investment in the sector. tific and Industrial Research, to undertake of a perpetual license which at the outset “The proof of the pudding will lie in how a comprehensive examination of drug seems like making it easier to start a busi- efficiently the separation of license issual/ regulatory issues, including the problem ness here,” an industry expert with a lead- renewal and periodic compliance audits of spurious drugs in the country. The com- ing foreign firm told the Pink Sheet. are conducted.” mittee had at the time, among other rec- The expert also didn’t seem to com- ommendations, suggested the need to pletely buy into the theory of the effective- Published online October 18, 2016

Generic Drugs FDA’s ANDA Approvals Sponsor Active Ingredient Dosage; Formulation Approval Date Sciegen Raloxifene HCl 60 mg; tablet 10/11/2016 Jubilant Darifenacin hydrobromide EQ 7.5 mg base and EQ 15 mg base; extended-release tablet 10/12/2016 Amneal Memantine HCl 7 mg, 14 mg, 21 mg and 28 mg; extended-release capsule 10/13/2016 Hisun Pharm Hangzhou Irbesartan/ hydrochlorothiazide 12.5 mg/150 mg and 12.5 mg/300 mg; tablet 10/14/2016 Ajanta Lansoprazole 15 mg and 30 mg; capsule, delayed-release pellets 10/17/2016 Watson (now Teva) Perphenazine 2 mg, 4 mg, 8 mg and 16 mg; tablet 10/17/2016 Actavis Dexmedetomidine HCL EQ 200 mcg base/2 mL (EQ 100 mcg base/mL); injection 10/18/2016 Tentative Approvals Accord Lurasidone HCl 20 mg, 40 mg, 60 mg, 80 mg and 120 mg; tablet, 10/12/2016 chewable tablet, capsule Gland Zoledronic acid 4 mg/ 100 mL (0.04 mg/mL); injectable 10/14/2016

pink.pharmamedtechbi.com October 24, 2016 | Pink Sheet | 25 Advisory Committees

Recent And Upcoming FDA Advisory Committees

Topic Advisory Committee Date

Serenity Pharmaceuticals’ desmopressin 0.75 mcg/0.1 ml and 1.5 mcg/0.1 ml nasal spray Bone, Reproductive and Oct. 19 for treatment of adult-onset nocturia Urologic Drugs

Updates on research programs in the Laboratory of Immunobiochemistry of the Division of Bacterial, Parasitic and Allergenic Products in CBER’s Office of Vaccines Research and Oct. 27 Allergenic Products Review (open session); intramural research program reports and recommendations on (teleconference) personnel staffing decisions (closed session)

Five bulk drug substances nominated for inclusion under Section 503A of the FD&C Act; drug products that employ transdermal and topical delivery systems that were nomi- Pharmacy Compounding Nov. 3 nated for the “difficult to compound” list

Cempra Pharmaceuticals’ solithromycin capsules and injection for treatment of communi- Antimicrobial Drugs Nov. 4 ty-acquired bacterial pneumonia

Recommendations on FDA’s draft Strategic Plan for Risk Communication and Health Literacy; presentations on some of FDA’s external communications and how these relate Risk Communication Nov. 7 to the draft strategic plan

Appropriate clinical trial design features, including acceptable endpoints for demonstrat- Bone, Reproductive and ing clinical benefit, for drugs intended to treat secondary hypogonadism while preserving Dec. 6 Urologic Drugs or improving testicular function, including spermatogenesis

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26 | Pink Sheet | October 24, 2016 © Informa UK Ltd 2016 Sitetrove-Epidemiology-Print ad_v2_11x8.5in_pink_HR.pdf 1 2016/06/13 9:10 AM

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